Ahovuosaloranta 2014

Antibiotics for acute maxillary sinusitis in adults (Review)
Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 2
http://www.thecochranelibrary.com

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Clinical failure defined as a lack of full recovery or
improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Clinical failure defined as a lack of full recovery or
improvement at 16 to 60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis 1.3. Comparison 1 Antibiotics versus placebo, Outcome 3 Clinical failure defined as a lack of full recovery at 7 to
15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Analysis 1.4. Comparison 1 Antibiotics versus placebo, Outcome 4 Clinical failure defined as a lack of full recovery at 16 to
60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days. . . . . . . . . 149
Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 Drop-outs due to adverse effects. . . . . . . 150
Analysis 2.1. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 1 Ceph versus amox-clav;
clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . 151
Analysis 2.2. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 2 Ceph versus amox-clav;
clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . 152
Analysis 2.3. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 3 Drop-outs due to adverse
effects (cephalosporins). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Analysis 2.4. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 4 Macrolides versus amox-
clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . 154
Analysis 2.5. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 5 Macrolides versus amox-
clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . 155
Analysis 2.6. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 6 Drop-outs due to adverse
effects (macrolides). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Analysis 3.1. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 1 Clinical
failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . 157
Analysis 3.2. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 2 Clinical
failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . . . 158
Analysis 3.3. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 3 Drop-outs
due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Analysis 4.1. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 1 Clinical failure defined as a lack of
full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . 160
Analysis 4.2. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 2 Drop-outs due to adverse
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Antibiotics for acute maxillary sinusitis in adults (Review) i
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Antibiotics for acute maxillary sinusitis in adults (Review) ii

[Intervention Review]
Antibiotics for acute maxillary sinusitis in adults
Anneli Ahovuo-Saloranta1 , Ulla-Maija Rautakorpi1 , Oleg V Borisenko2 , Helena Liira3 , John W Williams Jr4 , Marjukka Mäkelä5
1 FinnishOffice for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Tampere office,
Tampere, Finland. 2 Synergus AB, Danderyd, Sweden. 3 Department of General Practice, University of Helsinki, Kirkkonummi, Finland.
4 Departments of Medicine and Psychiatry, Durham VAMC and Duke University Medical Center, Durham, NC, USA. 5 Finnish Office
for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Helsinki, Finland
Contact address: Anneli Ahovuo-Saloranta, Finnish Office for Health Technology Assessment (FinOHTA), National Institute for
Health and Welfare (THL), Tampere office, Finn-Medi 3, Biokatu 10, Tampere, FI-33520, Finland. anneli.ahovuo-saloranta@thl.fi.
Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 2, 2014.
Review content assessed as up-to-date: 20 March 2013.
Citation: Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M. Antibiotics for
acute maxillary sinusitis in adults. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD000243. DOI:
10.1002/14651858.CD000243.pub3.
ABSTRACT
Background
Sinusitis is one of the most common diagnoses among adults in ambulatory care, accounting for 15% to 21% of all adult outpatient
antibiotic prescriptions. However, the role of antibiotics for sinusitis is controversial.
Objectives
To assess the effects of antibiotics in adults with acute maxillary sinusitis by comparing antibiotics with placebo, antibiotics from
different classes and the side effects of different treatments.
Search methods
We searched CENTRAL 2013, Issue 2, MEDLINE (1946 to March week 3, 2013), EMBASE (1974 to March 2013), SIGLE
(OpenSIGLE, later OpenGrey (accessed 15 January 2013)), reference lists of the identified trials and systematic reviews of placebo-
controlled studies. We also searched for ongoing trials via ClinicalTrials.gov and the WHO International Clinical Trials Registry
Platform (ICTRP). We imposed no language or publication restrictions.
Selection criteria
Randomised controlled trials (RCTs) comparing antibiotics with placebo or antibiotics from different classes for acute maxillary sinusitis
in adults. We included trials with clinically diagnosed acute sinusitis, confirmed or not by imaging or bacterial culture.
Data collection and analysis
Two review authors independently screened search results, extracted data and assessed trial quality. We calculated risk ratios (RRs)
for differences between intervention and control groups in whether the treatment failed or not. All measures are presented with 95%
confidence intervals (CIs). We conducted the meta-analyses using either the fixed-effect or random-effects model. In meta-analyses of
the placebo-controlled studies, we combined data across antibiotic classes. Primary outcomes were clinical failure rates at 7 to 15 days
and 16 to 60 days follow-up. We used GRADEpro to assess the quality of the evidence.
Antibiotics for acute maxillary sinusitis in adults (Review) 1
Main results
We included 63 studies in this updated review; nine placebo-controlled studies involving 1915 participants (seven of the studies clearly
conducted in primary care settings) and 54 studies comparing different classes of antibiotics (10 different comparisons). Five studies
at low risk of bias comparing penicillin or amoxicillin to placebo provided information on the main outcome: clinical failure rate at 7
to 15 days follow-up, defined as a lack of full recovery or improvement, for participants with symptoms lasting at least seven days. In
these studies antibiotics decreased the risk of clinical failure (pooled RR of 0.66, 95% CI 0.47 to 0.94, 1084 participants randomised,
1058 evaluated, moderate quality evidence). However, the clinical benefit was small. Cure or improvement rates were high in both the
placebo group (86%) and the antibiotic group (91%) in these five studies. When clinical failure was defined as a lack of full recovery
(n = five studies), results were similar: antibiotics decreased the risk of failure (pooled RR of 0.73, 95% CI 0.63 to 0.85, high quality
evidence) at 7 to 15 days follow-up.
Adverse effects in seven of the nine placebo-controlled studies (comparing penicillin, amoxicillin, azithromycin or moxicillin to placebo)
were more common in antibiotic than in placebo groups (median of difference between groups 10.5%, range 2% to 23%). However,
drop-outs due to adverse effects were rare in both groups: 1.5% in antibiotic groups and 1% in control groups.
In the 10 head-to-head comparisons, none of the antibiotic preparations were superior to another. However, amoxicillin-clavulanate
had significantly more drop-outs due to adverse effects than cephalosporins and macrolides.
Authors’ conclusions
There is moderate evidence that antibiotics provide a small benefit for clinical outcomes in immunocompetent primary care patients
with uncomplicated acute sinusitis. However, about 80% of participants treated without antibiotics improved within two weeks.
Clinicians need to weigh the small benefits of antibiotic treatment against the potential for adverse effects at both the individual and
general population levels.
PLAIN LANGUAGE SUMMARY
Antibiotics for acute maxillary sinusitis
Sinusitis is one of the most common reasons for visiting a doctor and an estimated 20 million cases of acute sinusitis occur every year
in the USA alone. There are four pairs of sinuses linked to the bony structures around the nose: maxillary, frontal, ethmoidal and
sphenoidal sinuses. In sinusitis, these membrane-lined air spaces become infected, which causes pain and discharge from the nose.
Treatment options include decongestants, steroid drops or sprays, mucus-clearing drugs (mucolytics), antihistamines and antibiotics
and sometimes sinus puncture and irrigation for removal of purulent secretions.
In most cases sinusitis occurs during viral infections where antibiotics are ineffective, but the few cases that also have a bacterial infection
(one or two out of every 100 patients with sinus symptoms) could benefit. Unfortunately it is difficult to distinguish between those
who have a bacterial infection and those who do not. It is important to avoid unnecessary use of antibiotics and limit the potential for
antibiotic resistance.
This updated review compiled data from 63 separate studies that used a variety of antibiotics for simple maxillary sinus infection, i.e.
non-complicated acute sinusitis in a person with a healthy immune system. Nine of the studies compared antibiotics to placebo (1915
participants; seven of the studies conducted in primary care), and 54 studies compared different classes of antibiotics. Five of the nine
placebo-controlled studies involving 1058 participants found that most participants got better within two weeks, regardless of whether
they received the antibiotic or not (roughly 9 out of 10 participants in antibiotic groups and 8 out of 10 in placebo groups). Although all
the five studies in this main outcome were assessed as having low risk of bias, the overall evidence was assessed only as being of moderate
quality (it is possible that a new large study can change the estimate). In the remaining 54 studies comparing different antibiotics (10
different comparisons), no antibiotic was found to be superior to another. The evidence is current to March 2013.
The small benefit gained by antibiotics may be overridden by the negative effects of the drugs. In addition to patient-related adverse
effects (like skin rash and gastrointestinal problems such as diarrhea, abdominal pain and vomiting), side effects include the risk of
increased resistance to antibiotics amongst community-acquired pathogens (bacteria).
This review found that antibiotics will help some people a bit, but do not make a major difference to most people with acute maxillary
sinusitis being treated in primary care.
Antibiotics for acute maxillary sinusitis in adults (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Antibiotics compared to placebo for uncomplicated acute maxillary sinusitis
Patient or population: patients with uncomplicated acute maxillary sinusitis

Settings: primary care
Intervention: antibiotics: penicillin V, amoxicillin and azithromycin
Comparison: placebo
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Placebo Antibiotics
Clinical failure rate Failure defined as a lack Failure defined as a lack RR 0.66 1084 ⊕⊕⊕ Adverse effects8 :
Follow-up: of full recovery or im- of full recovery or im- (0.47 to 0.94) patients randomised and moderate2 antibiotics 8% to 59%;
7 to 15 days provement provement 1058 evaluated placebo 6% to 38%
(5 studies1 )
136 per 1000 90 per 1000
(64 to 128)
Failure defined as a lack Failure defined as a lack RR 0.73 716 patients randomised ⊕⊕⊕⊕
of full recovery of full recovery (0.63 to 0.85) and 680 evaluated high4
(5 studies3 )
614 per 1000 448 per 1000
(387 to 522)
Clinical failure rate Failure defined as a lack Failure defined as a lack RR 0.85 169 patients randomised ⊕⊕
Follow-up: 16 to 60 days of full recovery or im- of full recovery or im- (0.36 to 1.98) and 169 evaluated low5,6
provement provement (1 study)
122 per 1000 104 per 1000

(44 to 241)
3
Failure defined as a lack Failure defined as a lack RR 0.63 169 patients randomised ⊕⊕
of full recovery of full recovery (0.38 to 1.05) and 169 evaluated low5
(1 study)
329 per 1000 207 per 1000
(125 to 346)
Quality of life and activ- Impact Number of participants ⊕

ity impairment (studies) very low
Follow-ups:
3, 6 to 8, 10 days Inconsistent effect. There were differences in: out- 270 patients evaluated
come measures, follow-up times and results (2 studies7 )
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Five studies at ’low’ risk of bias for the five key domains of allocation concealment, blinding, selective outcome reporting, incomplete
outcome data and baseline comparability.
2 Because the effect size seems to be small and the number of evaluated participants so far is 1058, it is not unreasonable to anticipate
that a new large study could change this estimate.

3 Five studies at ’low’ risk of bias for the five key domains of allocation concealment, blinding, selective outcome reporting, incomplete
outcome data and baseline comparability.

4 When including one study at ’unclear’ risk of bias in the analysis, the results did not change (RR of 0.73, 95% CI 0.63 to 0.85).
5 Only one small study at ’low’ risk of bias (Haye 1998).
6 Also the study of Hadley 2010 at ’unclear’ risk of bias (comparing moxifloxacin to placebo) did not find a significant difference between
antibiotic and placebo either (RR value of 0.62, 95% CI 0.37 to 1.03). These two studies represent almost the utmost ends of the clinical
variation; Haye 1998 excluded participants with radiographic findings more than mild and Hadley 2010 included only participants with
bacteriologically confirmed sinusitis.
4
7 Two studies at ’unclear’ risk of bias, published in 2010 and 2012 in the USA.
8 Variation of reported adverse effects in eight studies.
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5
BACKGROUND alone. Acute bacterial sinusitis is more likely if the symptoms have
lasted for more than one week (Gwaltney 2005).
Description of the condition

Sinusitis is a prevalent and important cause of ill health in adults. Description of the intervention
In the US alone, an estimated 20 million cases of acute sinusitis Clinical guidelines for acute sinusitis currently recommend an-
occur each year (Gwaltney 2005). Sinusitis is the third to fifth most tibiotic treatment for patients with severe or persistent moder-
common diagnosis for which an antibiotic is prescribed within ate symptoms and specific findings of bacterial sinusitis (Fokkens
primary care settings in Nordic countries (Andre 2002; Rautakorpi 2007; Slavin 2005; Snow 2001). Unnecessary antibiotic prescrip-
1999) and the US (SAHP 2004). Sinusitis accounts for 15% to tions should be avoided for several reasons: in addition to patient-
21% of all antibiotic prescriptions for adults in outpatient care. related adverse effects, side effects are associated with resistance to
Acute bacterial maxillary sinusitis is often preceded by an acute vi- antibiotics among community-acquired pathogens. The correla-
ral upper respiratory tract infection (URTI). Up to 90% of patients tion between resistance and community antibiotic use has been
with acute URTIs have symptoms of rhinosinusitis (Gwaltney seen in many countries (Albrich 2004; Arason 1996; Bronzwaer
1994). Following a common cold lasting for one week, up to 39% 2002; Goossens 2005; Seppälä 1995; Steinke 2001). Not only the
of adults (Puhakka 1998) have reversible abnormalities in the sinus volume of antibiotic use but also the selection of broad-spectrum
cavity which show up in magnetic resonance imaging or X-ray. It drugs, low doses and long duration of antibiotic treatment in-
has been estimated that 0.5% to 2% of patients with a common crease antibiotic resistance (Guillemot 1998; Hay 2005; Odenholt
cold have complications in the form of acute bacterial infection of 2003). The European Antimicrobial Resistance Surveillance Sys-
the sinuses (Berg 1986; Gwaltney 1996). However, distinguish- tem (EARSS) has revealed significant geographical differences in
ing patients with bacterial infection from those with symptoms of resistance rates within Europe (Goossens 2005); high rates of an-
rhinosinusitis with a viral origin is challenging. tibiotic resistance were seen more often in southern and eastern
A bacterial sinus infection can be caused by one or more bacterial European countries with high antibiotic use. For example, there are
species. Commonly isolated bacteria include Streptococcus pneumo- remarkable differences between European countries in the preva-
niae (S. pneumoniae),Haemophilus influenzae (H. influenzae) and lence of resistance to penicillin and macrolide antibiotics in treat-
Moraxella catarrhalis (M. catarrhalis) (Gwaltney 1992; Low 1997). ing S. pneumoniae (EARSS 2008). In recent years, an increas-
In approximately a third of suspected bacterial sinusitis cases, bac- ing number of published studies have also suggested that antibi-
terial cultures from the sinus cavity come back negative (Axelsson otics might have other harmful effects on health through the dis-
1972; Gwaltney 1992; Jousimies-Somer 1988). turbance of human microbiota (Kilkkinen 2002; Maxwell 2002;
Formally sinusitis is classified as acute or chronic, depending on the Velicer 2004) and perhaps predispose to new infections (Arason
pathological findings and duration of symptoms (Fokkens 2007; 2005; Howard 1976; Joki-Erkkilä 2000; Margolis 2005; Smith
ICD-10). In this classification, acute sinusitis is defined as lasting 1997).
less than 12 weeks. However, clinically sinusitis can be classified
to more than two classes: acute, subacute or chronic, depending
on the duration of the symptoms (Lanza 1997; Meltzer 2004;
How the intervention might work
Slavin 2005). In this case acute maxillary sinusitis is usually de-
fined as lasting less than four weeks and subacute as four to 12 The purpose of antibiotics is, by eradicating bacteria from the
weeks (Ah-See 2007; Lanza 1997). Subacute maxillary sinusitis, sinuses, to decrease the signs and symptoms of infections, restore
although not a distinct disease entity from acute sinusitis, may the normal function of the sinuses and to prevent complications
differ histopathologically and require different therapy from acute and the development of chronic sinusitis.
or chronic maxillary sinusitis (Hickner 2001; Lanza 1997). Many
cases of chronic sinusitis again represent a separate entity with un-
derlying problems, for example, mechanical obstruction of sinus Why it is important to do this review
drainage, abnormalities in mucociliary clearance or immunology
The purpose of this systematic review was to quantify the effec-
(Gwaltney 2005). For research purposes it is recommended that
tiveness of antibiotic therapy for patients diagnosed with acute
acute sinusitis be defined as lasting less than four weeks (Meltzer
sinusitis and treated in ambulatory settings. The word ’antibiotic’
2006).
is used as a general term referring to all antibacterials.
Typical signs and symptoms of acute sinusitis include purulent
nasal discharge, postnasal drip, sinus pain at palpation, nasal ob-
struction with poor response to decongestants, unilateral facial
pain and maxillary toothache (Axelsson 1972; Williams 1993),
but none of the signs or symptoms is diagnostic when presenting OBJECTIVES

To compare the effects of antibiotics versus placebo on clinical We included trials with a mixed population of acute (symptoms
failure rates for acute maxillary sinusitis. less than 30 days) and non-acute sinusitis or acute exacerbations of
chronic sinusitis if they separately reported data on the subgroup
To compare different classes of antibiotics for treatment of acute
with acute sinusitis, or if at least 80% of participants had acute
maxillary sinusitis.
sinusitis.
To compare the effect of short-course versus long-course antibi- We excluded trials that focused on patients with complicated si-
otics for acute maxillary sinusitis. nusitis such as pansinusitis or frontal sinusitis (or solely ethmoidal
or sphenoidal sinusitis), or infections of dental origin.
To compare the side effects of different treatments.
Types of interventions
METHODS We reviewed the following drug therapies:

1. antibiotics versus control; and
2. comparisons between different antibiotic classes.
We systematically recorded co-interventions such as deconges-
Criteria for considering studies for this review tants, antihistamines, mucolytics, non-steroidal anti-inflamma-
tory drugs and corticosteroids.
Types of studies
Types of outcome measures
Randomised controlled trials (RCTs) evaluating and comparing
antibiotics to a placebo, or different classes of antibiotics for acute
sinusitis, and reported in full-text. Primary outcomes
We included trials having a sample size of at least 30 participants 1. Clinical failure rate at 7 to 15 days after the start of
with acute maxillary sinusitis. This is to guarantee that data in treatment. Failure is defined as lack of full recovery or
individual studies are as unbiased as possible. Also in very small improvement of participants with acute maxillary sinusitis at
samples many estimators are known to be sensitive to variation. follow-up.
We excluded studies reported only as abstracts because there is 2. Clinical failure rate at 16 to 60 days after the start of
evidence that there are discrepancies between data reported in the treatment. Failure is defined as lack of full recovery or
abstract and the final published full report and that information improvement of participants with acute maxillary sinusitis at
on trial quality indicators is often lacking (Chokkalingam 1998; follow-up.
Hopewell 2006). Thus we required full-text reports to ensure re- As spontaneous cure rate or cure plus improvement rate in maxil-
liable data extraction and assessment of risk of bias. To diminish lary sinusitis is expected to also be fairly high in the placebo group,
the risk of publication bias, we attempted to contact authors of we decided after careful consideration to select the negative out-
potential abstracts to obtain information as to whether a full-text come ’failure’ instead of ’success’. This will enable clinicians to
report of the study (unpublished or published) was available. consider the risks of not prescribing antibiotics as opposed to the
benefits of prescribing them, compared to possible adverse effects
Types of participants of antibiotics.
We included trials with adults or trials that separately reported

data on subgroups of adults. We accepted adolescents (at least 12 Secondary outcomes
years old) if less than 20% of participants were under 18 years of 1. Clinical failure rate at 7 to 15 days after the start of
age. treatment. Failure is defined as lack of full recovery of
Acute maxillary sinusitis was defined by: participants with acute maxillary sinusitis at follow-up.
1. a history of URTI lasting seven to 30 days, with at least two 2. Clinical failure rate at 16 to 60 days after the start of
clinical signs or symptoms (sinus pain at palpation, postnasal treatment. Failure is defined as lack of full recovery of
drip, purulent nasal discharge, nasal obstruction, unilateral facial participants with acute maxillary sinusitis at follow-up.
pain, maxillary toothache, impaired sense of smell); or 3. Bacteriological failure.
2. radiography, ultrasound or other imaging; or 4. Radiographic failure.
3. bacterial culture from a sinus secretion obtained by 5. Relapse rates: new acute episodes of sinusitis after 60 days
puncture or endoscopy and irrigation or aspiration. from the start of the treatment.
In studies where the clinical diagnosis was not clearly described, 6. Drop-outs due to adverse effects.
diagnosis of acute maxillary sinusitis should be confirmed in at 7. Quality of life.
least of 80% of participants by imaging or culture. 8. Activity impairment and ability to work.

Search methods for identification of studies Two review authors (AAS and UMR) independently selected pa-
pers on the basis of the title, keywords and abstract, and decided
on eligibility. We obtained the full text of every article considered
Electronic searches for inclusion. If the information relevant to the inclusion criteria
For this 2013 update we searched the Cochrane Central Reg- was unavailable in the abstract or if the title was relevant but the
ister of Controlled Trials (CENTRAL) 2013, Issue 2, part of abstract was unavailable, we obtained the full text of the report.
The Cochrane Library, www.thecochranelibrary.com (accessed 20 We resolved any disagreements by consensus between these two
March 2013), which contains the Cochrane Acute Respiratory In- review authors.
fections Group’s Specialised Register, MEDLINE (1946 to March We contacted trial authors of the placebo-controlled studies to ob-
week 3, 2013) and EMBASE (1974 to March 2013). tain additional information if the study seemed to fulfil the inclu-
We searched CENTRAL and MEDLINE using the search strategy sion criteria for this review but the information in the report was
described in Appendix 1. The MEDLINE search was combined insufficient to make the final assessment of inclusion or exclusion.
with the Cochrane Highly Sensitive Search Strategy for identify-
ing randomised trials in MEDLINE: sensitivity- and precision- Data extraction and management
maximising version; Ovid format (Lefebvre 2011). We adapted
Two review authors (AAS, UMR) extracted data from all included
the search strategy for EMBASE (Appendix 2).
studies. We also extracted data presented only in graphs and figures
We also searched:
whenever possible.
1. the System for Information on Grey Literature in Europe
Extracted information relating to study methodology or quality
(SIGLE) to locate grey literature. SIGLE is currently known as
included: randomisation concealment, blinding, time of follow-
OpenGrey. The search strategy was adapted to the new system’s
up, percentage of missing data during follow-up and baseline com-
search language. The search was run on the Exalead search
parability of the groups. Characteristics relating to methods that
engine at http://www.opengrey.eu/ (accessed 15 January 2013)
we extracted included: criteria for accepting participants into the
(Appendix 3);
study (diagnosis on clinical/radiography/culture basis), definition
2. ClinicalTrials.gov (to 4 February 2013) to locate ongoing
of cure/failure and treatment compliance.
trials (Appendix 4);
Characteristics relating to participants that we extracted included
3. WHO International Clinical Trials Registry Platform
the number of participants in treatment and control groups at
(ICTRP) http://www.who.int/ictrp (to 4 February 2013) to
start, the mean age of participants (plus age range), the number of
locate ongoing trials (Appendix 4).
men and women, the year the study was published, the location
where the study was conducted (country and setting where par-
Searching other resources ticipants were recruited). Characteristics of the intervention that
We used the function for finding related articles in PubMed for we extracted included: intervention comparisons, courses of an-
the already identified placebo-controlled trials to track down addi- tibiotics and information about co-interventions.
tional, relevant articles. We reviewed reference lists of the identified We extracted information on clinical, bacteriological and radio-
trials and 14 systematic reviews (13 previously identified system- graphic outcomes and adverse event rates. We mainly extracted
atic reviews Appendix 5, and the new Cochrane review Lemiengre outcome information as numbers of participants with clinical fail-
2012) considering placebo-controlled study designs for additional, ure/non-failure by study group. We classified relapse within 60
appropriate studies. days from the onset of the treatment as a clinical failure.
For a previous review version (Williams 2003), pharmaceutical In some studies the results were given at more than one follow-up
companies that manufacture antibiotics used in the treatment of point. We extracted all data for preselected times, which were 7 to
acute sinusitis were contacted and data and references from all 15 days, 16 to 60 days and over 60 days of follow-up. We carried
published and unpublished trials on acute sinusitis were requested. out meta-analyses at these preselected times based on the available
Further, three experts in the field had been contacted and asked to data.
review the bibliography of the initial review (Williams 1999) for Two review authors (AAS, UMR) agreed on final results and
completeness. reached decisions by consensus.
Details of previous searches are in Appendix 5.
Assessment of risk of bias in included studies
Two authors (AAS, UMR) independently assessed the risk of bias
Data collection and analysis of the included studies. We resolved disagreements by consen-
sus. Attempts were made to contact trial authors of the included
placebo-controlled studies if the information in the report was
Selection of studies insufficient for assessment. We presented the questions as open-

ended, for example, “how was randomisation performed in prac- Incomplete outcome data
tice?” As recommended by the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011a), we assessed the following
How complete were the outcome data for the clinical
six domains. Within each domain, we judged each study as having
outcomes? Were drop-out rates and reasons for withdrawals
a ’low’, ’high’ or ’unclear’ risk of bias, the latter indicating either
reported? Were missing data imputed appropriately?
lack of information or uncertainty over the potential for bias.
The judgements were restricted to clinical efficacy outcomes at 7
to 15 or at 16 to 60 days after the start of treatment. If the clin-
ical efficacy outcomes in a trial were reported at both follow-up
Random sequence generation
periods, the judgement of this domain was based on the 7 to 15
days after the start of treatment but the risk of bias was separately
assessed and reported in the ’Risk of bias’ table also for the second
Was the method used to generate the allocation sequence follow-up period in case it was used in the review analyses. We
appropriate to produce comparable groups? decided to grade this domain to ’low’ risk of bias if the total pro-
portion of the missing outcome data was marginal (less than 5%);
We graded this domain ’low’ risk of bias if authors described a ran- or when the proportion of the missing outcome data was less than
dom component in the sequence generation process (for example, 20% and the groups were balanced in numbers and reasons for
random number table, coin tossing, drawing of lots). If there was missing data (regardless of reason or population used in the anal-
no or insufficient information about the random sequence genera- yses); or if missing data were imputed using appropriate methods.
tion process, we graded this domain ’unclear’ risk. In this review we Also, if reasons for exclusion of the participants after randomisa-
excluded studies which were identified as quasi-randomised (for tion were justifiable and not seen to affect the randomisation, a
example, if allocation method was alternation, use of case record higher proportion of missing data could be accepted. For example,
numbers, dates of birth or day of the week). if a positive culture of sinus excretion was defined as inclusion cri-
terion, a higher number of exclusions due to absence of pathogen
in pretreatment cultures is justifiable because it is anticipated and
Allocation concealment the results of the cultures are available only several days after the
start of the treatment. If there was no information on reasons for
missing data across intervention groups or proportions of missing
data were documented as total proportion (5% to 20%), not by
Was the method used to conceal the allocation sequence groups, the judgement was ’unclear’ risk of bias. Classifying the
appropriate to prevent the allocation being known in total proportion of the missing data over 20% as ’high’ risk of bias
advance of, or during, enrolment? (besides the exception described above) was a pragmatic approach
We graded this domain ’low’ risk of bias if the authors described to this domain to make the judgement uniform and transparent.
adequate concealment (for example, by means of central randomi-
sation or sequentially numbered, opaque and sealed envelopes) Selective reporting
and ’high’ risk of bias if inadequate concealment was documented
or allocation concealment was not used. If no information about
allocation concealment was provided or the information was un- Were appropriate outcomes reported and were key
clearly reported, we graded this domain ’unclear’ risk of bias. outcomes missing?
To be included in this review, clinical outcomes had to be reported.
However, studies could also report other (secondary) outcomes, for
Blinding example radiological and bacteriological responses, relapse rates,
chronic evolution and adverse effects. In this review, we graded
freedom from selective reporting ’low’ risk of bias if the study’s
prespecified outcomes (those of interest in this review) had been
Were participants, personnel and investigators (outcome reported in the prespecified way.
assessors) blinded about the intervention a participant had
received?
Other sources of bias
We graded this domain ’low’ risk of bias if at least the participant This domain included information on the baseline comparability
and the investigator were blinded. If the study only reported a of the intervention and control groups, on possible use of the co-
double-blind design without detailed description of the methods interventions by group and on funding. We assessed each of these
of blinding, we graded this domain ’unclear’ risk of bias. features in their own entries.

1. Balance in baseline characteristics between the study groups funding was only from academic or public sources, and ’high’
is an essential feature representing the methodological quality of risk of bias if the study was funded by a pharmaceutical
the trial. We graded this entry ’high’ risk of bias if there were company, since there is evidence that industry-sponsored trials
important differences in demographic characteristics or sinusitis may overestimate the treatment effect (Bekelman 2003;
severity at baseline between the study groups. If baseline Bhandari 2004; Lexchin 2003). The judgement was ’unclear’
characteristics were not described clearly enough we graded this risk if there was pharmaceutical industry funding but the
entry as ’unclear’ risk of bias. researchers had full rights to the data and manuscript or one or
2. We graded the co-intervention entry ’low’ risk of bias if the more of the authors had affiliations to pharmaceutical company;
groups were balanced in amount and quality of co-interventions or when the funding source was unclear.
or no co-interventions were included in the protocol, and ’high’ We completed a ’Risk of bias’ table for each included study
risk of bias if the groups received a different amount or quality of (Characteristics of included studies). Results are presented graph-
co-interventions during the trial. If no information was provided ically by domain over all studies (Figure 1) and by study (Figure
on co-interventions we graded this entry ’unclear’ risk of bias. 2).
3. We graded the funding entry ’low’ risk of bias if the
Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.

Summary assessments of risk of bias
were randomly allocated to two or several groups and a single
To draw conclusions about the overall risk of bias for the main result for each outcome from each individual was collected and
clinical outcomes within a study, we decided to classify the studies analyzed.
into three categories: studies with ’low’, ’unclear’ or ’high’ risk of
bias. The five main clinical outcomes were: clinical failure rate at
7 to 15 days after the start of treatment and failure defined as 1) a Dealing with missing data
lack of full recovery or improvement of participants, or 2) a lack We performed the analyses using an available case data analysis
of full recovery of participants; clinical failure rate at 16 to 60 as presented in the Cochrane Handbook for Systematic Reviews of
days after the start of treatment and failure defined as 3) a lack of Interventions (Higgins 2011b). This approach for calculating the
full recovery or improvement of participants, or 4) a lack of full response rate uses the total number of participants who had data
recovery of participants; 5) quality of life and activity impairment. recorded for the particular outcome in question as a denominator.
Our classification was based on five domains which we considered If the missing outcome data were reported to be over 35% or if
as most fundamental in assessing the quality of studies: allocation there was a significant imbalance in missing data rates between
concealment, blinding, selective outcome reporting, incomplete the intervention and control groups, we excluded the study from
outcome data and baseline comparability. the meta-analyses. Excluding these studies in the analyses was seen
The ’Risk of bias’ categories were defined as follows. as a quality issue, especially when there are a lack of universal
1. Low risk of bias (plausible bias unlikely to seriously alter the strategies for handling missing data (Unnebrink 2001). In this
results) if all five fundamental domains defined above were review, limiting meta-analyses to studies with a missing data rate
graded as ’low’ risk of bias. of less than 35% was a pragmatic approach to make comparisons
2. Unclear risk of bias (plausible bias that raises some doubt without compromising the reliability of the overall results.
about results) if one or more of the domains were graded as In assessing the influence of missing data (less than 35%) on the
’unclear’. overall results of the meta-analyses of primary outcomes in studies
3. High risk of bias (plausible bias that seriously weakens comparing antibiotic with placebo, we used two ways of imput-
confidence in the results) if one or more domains were graded as ing data for sensitivity analyses: assuming the outcomes of par-
’high’ risk of bias. ticipants for whom no outcome was recorded as a) failures, or b)
We used the GRADEprofiler software version 3.2 (GRADEpro non-failures. The analyses comparing antibiotic versus antibiotic
2008) to provide the overall grading of the quality of evidence were undertaken by using available case data without imputations.
for the clinical outcomes in the following comparisons: antibi- When a study provided available case data for the first follow-up
otics compared to placebo (Summary of findings for the main but not for the second one, we included the study in the second
comparison) and antibiotic versus antibiotic (Summary of findings follow-up meta-analyses if the missing data rate (compared to the
2). first follow-up) was marginal (about 5% at most).
Measures of treatment effect Assessment of heterogeneity

All studies presented the outcome results in dichotomous form. We assessed the significance of any discrepancies in the estimates of
We calculated risk ratios (RR) for differences between interven- the treatment effects from the different trials by means of Cochran’s
tion and control groups for whether the treatment failed or not, test for heterogeneity and by a measure of the I2 statistic. The I
along with appropriate standard errors and 95% confidence in- 2 statistic describes the percentage of the variability in effect esti-
tervals (CI), using RevMan 2012. In calculating drop-out rates mates that is due to heterogeneity rather than sampling error. A
due to adverse effects, we used the Peto odds ratio (OR) as the value greater than 50% may be considered to represent substantial
outcome measure. In placebo-controlled studies with multiple an- heterogeneity (Higgins 2003).
tibiotic arms, the data from the antibiotic arms were combined
and compared to placebo or control group as recommended in the
Assessment of reporting biases
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011b). If there had been sufficient numbers of trials (more than 10) in any
meta-analysis, publication bias would have been assessed according
to the recommendations on testing for funnel plot asymmetry
Unit of analysis issues as described in the Cochrane Handbook for Systematic Reviews of
The unit of analysis was an individual because all RCTs included in Interventions (Sterne 2011). If asymmetry was identified we would
this review were simple parallel-group trials in which participants have examined possible causes.

Data synthesis Description of studies
The data consisted of comparisons for antibiotic versus placebo
and antibiotic versus antibiotic. The antibiotic versus antibiotic
comparisons were macrolide/cephalosporins versus amoxicillin- Results of the search
clavulanate, non-penicillin antibiotics versus beta-lactamase sen- In this 2013 update, we retrieved a total of 138 new records, after
sitive penicillins and tetracyclines versus mixed classes of antibi- duplicates were removed from searches in MEDLINE (60 records),
otics. EMBASE (137 records), CENTRAL (20 records) and OpenGrey
We conducted the meta-analyses in RevMan 2012, using either (three records). One of the 138 records was identified by checking
the fixed-effect or the random-effects model. In meta-analyses in- the reference list of a new systematic review by Lemiengre 2012.
cluding two or three studies, we used the fixed-effect model, and The electronic searches did not identify any potential ongoing
in those including four or more studies, the random-effects model. trials for this review.
We pooled the data for the studies in each comparison regardless The total number of records considered from all updates was 2347,
of whether the studies could represent somewhat different kinds of including 2209 records from the earlier searches and 138 new
populations (depending on the definition of the diagnosis of acute records from this 2013 update search. Detailed descriptions of the
maxillary sinusitis; clinical diagnosis only versus radiological/bac- earlier search results are in Appendix 6. Of these 2347 records,
teriological confirmation). In meta-analyses of the placebo-con- we rejected 2052 records as definitely not meeting the inclusion
trolled studies, we combined data across antibiotic classes. These criteria simply on the basis of title or abstract or because they were
decisions were made because the main interest was to estimate the duplicates (in the earlier searches). From all updates we obtained
average intervention effects. We pooled the Peto ORs of individual altogether 295 full-text reports. From these 295 reports, 131 were
studies, estimating the drop-out rate due to adverse effects, using clearly irrelevant for this review leaving 164 reports for final assess-
the fixed-effect model. ment. The main reasons for irrelevance were: trials without con-
To incorporate the ’Risk of bias’ assessments in analyses, we de- trol group, studies with treatments other than antibiotic, studies
cided to pool data from the studies in each comparison by restrict- comparing the same classes of antibiotics and studies regarding
ing the analyses to studies at ’low’ risk of bias. We performed sen- children.
sitivity analyses to see how conclusions were affected by including We identified 164 reports to be evaluated in detail. We considered
studies at ’unclear’ risk or ’high’ risk of bias in the analyses, as 68 reports representing 63 individual studies to be eligible for in-
recommended in the Cochrane Handbook for Systematic Reviews of clusion in the review. Compared to the previous version of this
Interventions (Higgins 2011a). However, if all studies in a com- review, we included three new antibiotic versus placebo studies
parison were graded as ’unclear’ or ’high’ risk of bias, we pooled (Garbutt 2012; Hadley 2010; Meltzer 2005) and one new antibi-
the results of these studies in a meta-analysis. The methodological otic versus antibiotic study (Lari 2010).
classifications were taken into consideration when interpreting the The reasons for exclusion of the 89 studies with 96 reports are
results. explained in the Characteristics of excluded studies table.
Subgroup analysis and investigation of heterogeneity

Included studies
We had planned to conduct further analyses to identify subgroups
Nine of the 63 included studies compared antibiotic treatment
of participants that might get more benefit from antibiotic treat-
to placebo. The remaining 54 studies compared different classes
ment (for example, regarding type of signs or symptoms, their
of antibiotics. The studies of Lindbaek 1996 and Lindbaek 1998
severity or duration). Due to insufficient information from stud-
were conducted as the same trial but used different randomised
ies, it was not possible to undertake such subgroup analyses.
study populations with different inclusion criteria, and they are
handled as separate studies in the study descriptions and analyses.
Sensitivity analysis
To test the robustness of the results, we undertook sensitivity anal-
yses to explore the effect of missing data and overall risk of bias in Description of the studies comparing antibiotics versus
the studies on the clinical outcomes. We also planned to carry out placebo
sensitivity analyses to examine the effect of different diagnostic Nine trials with 1915 randomised participants evaluated antibiotic
criteria for acute sinusitis (clinical or radiograph/bacteriological) treatments compared with non-antibiotic controls for acute max-
but the number of trials was not sufficient for such analysis. illary sinusitis (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye
1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein
2005; van Buchem 1997). Four studies compared amoxicillin ver-
sus placebo (Garbutt 2012; Meltzer 2005; Merenstein 2005; van
RESULTS Buchem 1997), two studies compared penicillin V and amoxicillin

to placebo (Lindbaek 1996; Lindbaek 1998), one study compared and a history of sinus disease in 74% of participants in each group;
azithromycin to placebo (Haye 1998), and one study compared in this study 13% were smokers in the amoxicillin group and 26%
moxifloxacin to placebo (Hadley 2010). The study by Axelsson in placebo group. The study by Meltzer 2005 reported that 42%
1970 did not have a placebo group but the comparison of peni- of participants had either seasonal or perennial allergic rhinitis in
cillin V plus oxymetazoline versus oxymetazoline alone was in- the amoxicillin and placebo groups. In the study of Axelsson 1970
cluded in this review. patients with a history of nasal allergy were excluded.
In four studies diagnosis was based on clinical signs and symptoms In addition to clinical outcomes, radiological outcomes were re-
lasting at least seven days (Garbutt 2012; Haye 1998; Meltzer ported in three studies (Axelsson 1970; Lindbaek 1996; van
2005; Merenstein 2005). In four studies, diagnosis was confirmed Buchem 1997). No studies reported bacteriological outcomes.
by a radiograph (criteria: secretion in the study of Axelsson 1970;
and mucosal thickening more than 5 mm, presence of air-fluid
Description of the studies comparing antibiotic versus
level or total opacification in the van Buchem 1997 study); or by a
antibiotic
computer tomography (criteria: presence of air-fluid level or total
opacification in the study by Lindbaek 1996; and mucosal thick- Fifty-four studies comparing different classes of antibiotics were
ening of 5 mm or more without fluid level or total opacification included in the review. Treatment comparisons were: non-peni-
in the study by Lindbaek 1998). In one study (Hadley 2010) the cillin antibiotic versus beta-lactamase sensitive penicillins (n = 8);
diagnosis was confirmed by a radiograph (criteria: presence of air- non-tetracycline versus tetracycline (n = 5) (one study of these was
fluid levels and/or opacification on a radiographic paranasal si- also included in the comparison of non-penicillin antibiotic versus
nus film) and a sinus puncture for bacterial culture of the sinuses; beta-lactamase sensitive penicillin); macrolides versus amoxicillin-
only culture-positive patients with target pathogen (Streptococcus clavulanate (n = 11); cephalosporins versus amoxicillin-clavulanate
pneumonia (S. pneumoniae), Haemophilus influenzae (H. influen- (n = 10); and miscellaneous comparisons (n = 21).
zae), Moraxella catarrhalis (M. catarrhalis), Streptococcus pyogenes Participants were recruited from otolaryngology speciality settings
(S. pyogenes) or Staphylococcus aureus (S. aureus)) were included in in 17 studies, primary care settings in 12 studies and mixed set-
the analyses. In the study by Haye 1998 radiography was used to tings in three studies. The recruitment or treatment setting was
exclude patients with empyema. not described or unclear in 22 studies. The average age of the par-
Nasal decongestants and/or analgesics were allowed but not pre- ticipants was approximately 38 years; three studies did not report
scribed in three studies (Hadley 2010; Lindbaek 1996; Lindbaek the mean age of the participants. In 37 studies, the male to female
1998). Three studies used decongestants, cough medication and/ ratio was mostly about 1:1 or 1:1.5. Fourteen studies assessed ENT
or analgesics as a prescribed supplementary therapy in all groups co-morbidity.
(Axelsson 1970; Garbutt 2012; van Buchem 1997). Over-the- The diagnosis was based only on clinical signs and symptoms in
counter medications without further specification were allowed in three studies. In 38 studies diagnosis was confirmed by a radio-
one study (Merenstein 2005) and one study did not provide any graph and in 13 studies by radiograph and/or culture. In addition
information on co-interventions (Haye 1998). One study allowed to clinical outcomes, bacteriological outcomes were reported in
nasal or broncho-inhaled corticosteroids if they had been in sta- 28 studies and radiological outcomes in 11 studies. Three studies
ble use for over four weeks prior to enrolment (Hadley 2010). In reported the effects on function or quality of life.
one study all concomitant medications were prohibited (Meltzer Topical decongestants and/or antihistamines were prescribed in
2005) (Table 1). seven studies. They were allowed but not prescribed in 21 studies,
Of the nine studies, three were conducted in Norway (Haye 1998; prohibited in one study and not described in 25 studies. One trial
Lindbaek 1996; Lindbaek 1998), three in the USA (Garbutt 2012; prescribed nasal corticosteroids as part of the intervention (Pessey
Hadley 2010; Merenstein 2005), one in Sweden (Axelsson 1970) 1996).
and one in the Netherlands (van Buchem 1997). One study was For more detailed information on the included studies see the
multinational (Meltzer 2005). Characteristics of included studies table.
Participants were clearly recruited from community-based general
practices in seven of the nine studies. The study by Axelsson 1970 Excluded studies
did not describe the treatment setting, and in the multinational
The Characteristics of excluded studies table presents the reasons
study by Meltzer 2005 the nature of participating medical centres
for exclusion of controlled clinical studies. Only those controlled
was not described. The average age of the participants was approx-
clinical studies which compared antibiotic treatment with placebo
imately 36 years and some 65% were women. Ear, nose and throat
or antibiotics of different classes for acute maxillary sinusitis are
(ENT) co-morbidity was assessed in three studies (Garbutt 2012;
included in the table. Studies without a control group were ex-
Meltzer 2005; van Buchem 1997). The study of van Buchem 1997
cluded.
reported that 12% of participants had an allergic disease. The study
Of the 89 excluded studies, 13 studies included comparison of
of Garbutt 2012 reported allergic rhinitis in 32%, asthma in 11%
antibiotic versus placebo and 76 studies compared antibiotic ver-

sus antibiotic. The reasons for exclusion were varied and in many concealment had been fulfilled (additional information not re-
studies there were several reasons for exclusion. In 19 out of the 89 ceived from the trial authors). Two studies did not report the al-
studies there was no mention of random allocation or the study de- location concealment method (Axelsson 1970; Hadley 2010) and
sign was clearly not randomised; two of these studies were placebo- the judgement was ’unclear’ risk of bias.
controlled. In the other 11 randomised, placebo-controlled stud-
ies, the diagnostic criteria for acute sinusitis did not fulfil the in-
clusion criteria for this review. Antibiotics versus antibiotics
Random sequence generation was adequate, indicating ’low’ risk
of bias in 19 of the 54 studies (35%) comparing different classes of
Risk of bias in included studies antibiotics. In most of these studies the sequence generation was
computer-based. Thirty-five studies did not report the random
We contacted the authors of the included placebo-controlled stud- sequence generation method and the judgement was ’unclear’ risk.
ies to obtain additional information to assess the methodological However, although random sequence generation was reported in
quality issues if the information in the report was insufficient to 19 studies, the allocation concealment was adequately described
make final decisions. We requested additional information from in only 13 out of 54 studies (24%) to allow this domain be graded
seven studies (Garbutt 2012; Hadley 2010; Haye 1998; Lindbaek ’low’ risk of bias. In these studies, the allocation concealment was
1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005). Authors mostly executed by a third party (for example, in pharmaceutical
of four of those seven studies could deliver additional information company or by a statistician not involved with the personnel in the
on quality issues (Garbutt 2012; Lindbaek 1996; Lindbaek 1998; studies). Forty-one studies did not report the random allocation
Merenstein 2005) and information was not available for this up- concealment method at all or the description was not clear enough
date from three studies (Hadley 2010; Haye 1998; Meltzer 2005). to make the assessment and the judgement was ’unclear’ risk of
We did not contact the authors of the Axelsson 1970 study because bias.
the report was published 40 years ago.
Quality assessments for each individual study are presented in
’Risk of bias’ tables included in the Characteristics of included Blinding
studies, and the results are presented graphically by study (Figure
2) and by domain over all studies (Figure 1).
Antibiotics versus placebo
Seven of the nine placebo-controlled studies documented adequate
Allocation blinding of participants and investigators (Garbutt 2012; Haye
1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein
2005; van Buchem 1997). The study medications were delivered
Antibiotics versus placebo by a third party and the authors did not know which medicine
Random sequence generation was adequate, indicating ’low’ risk each participant had received. The participants were not aware
of bias in seven of the nine placebo-controlled studies (Garbutt which treatment they received, and most of the studies stated that
2012; Haye 1998; Lindbaek 1996; Lindbaek 1998; Meltzer 2005; treatment and placebo products were indistinguishable from each
Merenstein 2005; van Buchem 1997). In five studies the random other. Two studies were justified as ’unclear’ risk of bias: the study
sequence generation was made by computer (Garbutt 2012; Haye of Axelsson 1970 did not report anything about the blinding,
1998; Meltzer 2005; Merenstein 2005; van Buchem 1997) and in and Hadley 2010 only stated the study to be double-blinded with
the other two studies by dice (Lindbaek 1996; Lindbaek 1998). matching placebos but did not give any other information on the
Two studies did not report the randomisation method (Axelsson procedures.
1970; Hadley 2010) and the judgement was ’unclear’ risk of bias.
Allocation concealment was graded ’low’ risk of bias in the same
seven studies as those assessed to have adequate random sequence Antibiotics versus antibiotics
generation. Allocation concealment was performed centrally in We documented and assessed blinding of participants and inves-
the study of van Buchem 1997 (hospital pharmacy-controlled tigators as adequate in 19 out of the 54 studies (35%) comparing
randomisation), by an investigational pharmacist in the study of different classes of antibiotics. In most cases study medications
Garbutt 2012 and by a statistician in the studies of Lindbaek were delivered by a third party and matched placebo tablets were
1996, Lindbaek 1998 and Merenstein 2005. Although the stud- used to ensure blinding of participants. Twenty of the 54 studies
ies of Haye 1998 and Meltzer 2005 did not give exact informa- were open-labelled (37%) and 10 studies (19%) single-blinded
tion on how the randomisation result was concealed, the method and we graded these as having ’high’ risk of bias. In five studies
of random sequence generation (computer-randomised code) and the description was not clear enough to assess this domain and the
information on double-dummy design gave the impression that judgement was ’unclear’ risk of bias.

Incomplete outcome data Selective reporting
Antibiotics versus placebo Antibiotics versus placebo
We assessed eight placebo-controlled studies to have ’low’ risk of All nine placebo-controlled studies reported all prespecified out-
bias in this domain (Axelsson 1970; Hadley 2010; Haye 1998; comes adequately and were graded as ’low’ risk of bias in this do-
Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; main (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998;
van Buchem 1997). The reported total missing data rates were Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005;
between 0.6% and 14% at 7 to 15 days follow-up. All of those eight van Buchem 1997).
studies except one (Lindbaek 1998) adequately reported missing
data rates by study group. In the study by Lindbaek 1998 the Antibiotics versus antibiotics
total missing data rate was 5/68 (7.4%). However, we obtained
Prespecified outcomes were adequately reported in 47 out of 54
additional information from the trial author that there were drop-
studies (87%) comparing different classes of antibiotics. In two
outs in each of the three groups. Thus we assessed the study of
studies the reporting was deficient and they were graded as having
Lindbaek 1998 as having a ’low’ risk of bias in this domain.
’high’ risk of bias. In five studies the description was too vague to
The ninth placebo-controlled study by Garbutt 2012 was graded
make an assessment and the judgement was ’unclear’ risk of bias.
as ’unclear’ risk of bias at day 10. The study reported different
drop-out rates: in the amoxicillin group 4/85 (4.7%) and in the
placebo group 10/81 (12.3%) on day 10. Although there prob- Other potential sources of bias
ably was not any systematic difference in reasons for drop-outs
between the groups (the authors gave additional information that
participants simply missed the interviews), the difference in pro- Antibiotics versus placebo
portions of missing outcomes (7.6%) compared to the difference
in anticipated failure risks (10% to 20%) may be big enough to
cause bias. Baseline comparability
Two studies reported results at 16 to 60 days follow-up and had Demographic characteristics and disease severity ratings were de-
total missing data rates of 0% (Haye 1998) and 6% (Hadley 2010), scribed and assessed to be balanced across the groups in eight
indicating ’low’ risk of bias. placebo-controlled studies. In the study of Hadley 2010 this do-
main was graded as ’unclear’ risk of bias because in the placebo
group there were 9% more bilateral sinus infections than in the
Antibiotics versus antibiotics
moxifloxacin group (38% versus 29%) and no by-group descrip-
In this domain we assessed 31 out of 54 studies (57%) comparing tion was provided on allowed concomitant medications (especially
antibiotics with antibiotics to have ’low’ risk of bias, 12 studies stable-use nasal corticosteroids).
(22%) to have ’high’ risk of bias, and in 11 studies (20%) the
judgement was ’unclear’ risk of bias. The way of reporting the
results made it difficult to assess this domain in many of the stud- Co-interventions
ies. Several of the 12 studies graded as having ’high’ risk of bias Seven of the nine placebo-controlled studies reported co-interven-
reported responses only for per-protocol populations and the pro- tions during the trial (Axelsson 1970; Garbutt 2012; Hadley 2010;
portion of missing data was high. Even when studies reported clin- Lindbaek 1996; Lindbaek 1998; Merenstein 2005; van Buchem
ical responses for both intention-to-treat (ITT) and per-protocol 1997). In these studies co-interventions were mainly symptom-
populations, often only the clinical cure rates were reported while relieving over-the-counter medications which we judged not to
failure rates were not. The indeterminate/missing data were then cause bias. The study of Meltzer 2005 prohibited all concomitant
usually categorised as failures in ITT analyses and it remained un- medications, and the study of Haye 1998 did not provide any
clear how many of the responses were true failures in each group. information on co-interventions.
Three studies had to be downgraded from ’unclear’ to ’high’ risk We graded seven out of the nine studies as having a ’low’ risk of bias
of bias because of this particular problem. In the 11 studies with in this domain (Axelsson 1970; Garbutt 2012; Lindbaek 1996;
the judgement ’unclear’ risk, the description was not clear enough Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem
to assess this domain (especially regarding reasons for missing data 1997. The study of Hadley 2010 did not give a detailed descrip-
across groups). tion of the use of allowed co-interventions (especially nasal corti-
We excluded three studies from the meta-analyses because the costeroids which also may have a curative effect) and was judged
proportion of missing data was too high (38% in Marple 2010, as having ’unclear’ risk of bias, as well as Haye 1998 which had no
44% in Luterman 2003 and 52% in Steurer 2000). information on co-interventions.

Funding placebo-controlled studies reported bacteriological outcomes. Ra-
Four of the nine placebo-controlled studies were funded by gov- diographic outcomes are described qualitatively due to the small
ernmental or academic sources, or independent research founda- number of trials reporting these data.
tions (Garbutt 2012; Lindbaek 1996; Lindbaek 1998; Merenstein
2005) and were judged as having a ’low’ risk of bias. Two stud- Primary outcomes
ies did not state the funding source (Axelsson 1970; van Buchem
1997) and in one study (Haye 1998) one of the trial authors was
affiliated with a pharmaceutical company. In these three studies Antibiotics versus placebo
the funding domain was graded as ’unclear’ risk. Two studies were
supported by a pharmaceutical company and were classified as
having a ’high’ risk of bias in this domain (Hadley 2010; Meltzer 1. Clinical failure defined as a lack of full recovery or
2005). improvement at 7 to 15 days follow-up
Eight studies provided data for comparison of antibiotic treatment
to placebo when clinical failure was defined as a lack of full recovery
Antibiotics versus antibiotics
or improvement at 7 to 15 days follow-up (Axelsson 1970; Garbutt
2012; Hadley 2010; Haye 1998; Lindbaek 1996; Lindbaek 1998;
Meltzer 2005; van Buchem 1997). In two studies unclearness of
Baseline comparability data (Garbutt 2012; Hadley 2010) and in one study the difference
Demographic characteristics and disease severity ratings were de- in the design (Hadley 2010) were seen to cause too much uncer-
scribed and assessed to be balanced across the groups in 34 out tainty, which prevented including them in the meta-analysis. Five
of 54 studies (63%) comparing different classes of antibiotics. In of the remaining six studies were assessed as ’low’ risk of bias and
two studies we assessed the groups to be imbalanced and they were were included in the main analysis (Haye 1998; Lindbaek 1996;
graded as having ’high’ risk of bias. In 18 studies the information Lindbaek 1998; Meltzer 2005; van Buchem 1997) and one study
was insufficient to assess this domain and the judgement was ’un- at ’unclear’ risk of bias was used in the sensitivity analysis (Axelsson
clear’ risk. 1970).
In each of the five individual studies of the main analysis the effect
estimate of risk ratio (RR) indicated a small benefit for antibiotics
Co-interventions but the confidence interval in all studies crossed the no difference
In 30 out of the 54 studies (56%) we graded this domain as having line 1.0. When pooling the estimates of effects of these studies in
’low’ risk of bias. In most cases the co-interventions were symptom- the meta-analysis, antibiotics were found to be statistically signifi-
relieving over-the-counter medications and they were seen not to cantly beneficial with a RR of 0.66 (95% confidence interval (CI)
cause bias. In 24 studies the judgement was ’unclear’ risk because 0.47 to 0.94), based on a random-effects model using available
no information was provided. case data (1058 evaluated participants; Analysis 1.1). The failure
rates were 8.7% and 13.6% in antibiotic and placebo groups, re-
spectively. This is the main result presented in the Summary of
Funding findings for the main comparison. There was no statistically sig-
Thirty out of the 54 studies (56%) were supported by a pharma- nificant heterogeneity between the studies in the analysis (I2 statis-
ceutical company and they were graded as having ’high’ risk of tic = 0%). When double-checking the result using a fixed-effect
bias. In 24 studies one or more of the authors were affiliated to model the result was similar (RR 0.65, 95% CI 0.46 to 0.92). Also,
a pharmaceutical company or the funding source was not stated, when using odds ratio (OR) as the effect measure the inference of
and this domain was graded as ’unclear’ risk. the result was similar (OR 0.62, 95% CI 0.41 to 0.92) and there
was no heterogeneity (data not shown).
When including Axelsson 1970 (at ’unclear’ risk of bias) in the
main analysis (with the five other studies) the results did not change
Effects of interventions (RR 0.66, 95% CI 0.47 to 0.91) (data not shown). The Axelsson
See: Summary of findings for the main comparison Antibiotics 1970 study was graded as ’unclear’ risk of bias because no infor-
compared to placebo for uncomplicated acute maxillary sinusitis; mation on randomisation, allocation concealment and blinding
Summary of findings 2 Antibiotics compared to other antibiotics was given. Lack of information may be related to the way studies
for uncomplicated acute maxillary sinusitis were reported 40 years ago but it was not possible to get additional
Clinical outcomes were reported in all trials and evaluated information.
quantitatively. We evaluated radiological and bacteriological out- The amount of missing data in each of the five studies was balanced
comes only for placebo-controlled studies. However, none of the between the antibiotic and placebo groups, ranging from 0% to

5% by group (actual numbers zero to five per treatment group). In Secondary outcomes
sensitivity analyses assuming missing outcomes as failures or full
recoveries/improvements did not significantly affect the result of
the meta-analysis: RR 0.68, 95% CI 0.50 to 0.93 and RR 0.67,
95% CI 0.48 to 0.95, respectively (data not shown). 1. Clinical failure defined as a lack of full recovery at 7 to 15
The meta-analyses, including sensitivity analyses, slightly favoured days follow-up
antibiotics. However, in the individual six studies the difference Five studies were included in the meta-analysis (Haye 1998;
between groups in the full recovery or improvement rates was Lindbaek 1996; Lindbaek 1998; Merenstein 2005; van Buchem
small, being on average 90% (range 83% to 98%) in antibiotic 1997) and one was used in the sensitivity analysis (Axelsson 1970).
groups and 84% (range 72% to 89%) in placebo groups. These studies found a significant benefit for antibiotics with a RR
of 0.73 (95% CI 0.63 to 0.85) (Analysis 1.3). The failure rates
were 47% and 61% in the antibiotic and placebo groups, respec-
tively. There was no statistically significant heterogeneity between
The results of the studies by Hadley 2010 and Garbutt 2012
studies. When including the study by Axelsson 1970 at ’unclear’
The results by Hadley 2010 (at ’unclear’ risk of bias) comparing risk of bias in the analysis, the results did not change: RR of 0.73
moxifloxacin 400 mg once daily to placebo for five days and (unlike (95% CI 0.63 to 0.85) (data now shown).
the other placebo-controlled trials) recruiting only patients with
isolation of pathogenic bacteria from the sinus secretion, were in
line with the results of the individual studies included in the main
2. Clinical failure defined as a lack of full recovery at 16 to
analysis. Hadley 2010 reported that on day six to eight, clinical
60 days follow-up
cure rates were numerically greater in the moxifloxacin arm (57/73,
78.1%) than the placebo arm (30/45; 66.7%) but this difference One study at ’low’ risk of bias provided data for an antibiotic versus
was not statistically significant (P = 0.189). Hadley 2010 measured placebo comparison at 16 to 60 days follow-up (Haye 1998). The
clinical response at days six to eight after the start of therapy while difference failed to reach statistical significance with a RR of 0.63
other studies included in the meta-analysis did so at days 10 to (95% CI 0.38 to 1.05) (Analysis 1.4). The failure rates were 20.7%
14. and 33% in the antibiotic and placebo groups, respectively.
The study by Garbutt 2012 (graded as having an ’unclear’ risk of
bias) comparing amoxicillin 500 mg three times daily to placebo
reported there was no statistically significant difference in symp- 3. Bacteriological failure
tom improvement at day 10 (78% in amoxicillin group versus
None of the studies reported this outcome.
80% in placebo group; P = 0.71). The study was not considered in
the main analysis because it remained unclear whether the patients
who received rescue therapy were classified as non-improved or
not. 4. Radiographic failure
Radiographic outcomes were reported in three studies (Axelsson
1970; Lindbaek 1996; van Buchem 1997) and the results were
2. Clinical failure defined as a lack of full recovery or
consistent with the clinical outcomes in the individual studies.
improvement at 16 to 60 days follow-up
In the study by Axelsson 1970, the nasal decongestant group
Two studies provided data for an antibiotic versus placebo com- was less improved than the other groups, measured by the mean
parison at 16 to 60 days follow-up (Hadley 2010; Haye 1998). number of radiological severity points per sinus. In the study by
Neither of these studies found a significant difference between Lindbaek 1996, computer tomography scores improved signifi-
antibiotic treatment and placebo at this follow-up, Hadley 2010 cantly more for individuals treated with antibiotics. In the study
with a RR value of 0.62 (95% CI 0.37 to 1.03) and Haye 1998 by van Buchem 1997, more participants treated with antibiotics
with a RR value of 0.85 (95% CI 0.36 to 1.98) (Analysis 1.2). showed radiographic resolution (74% versus 60%).
The study of Haye 1998 was assessed to be at ’low’ risk of bias
at this follow-up, and the study of Hadley 2010 at ’unclear’ risk
of bias, and thus data from these two studies were not pooled in
the meta-analysis. Further, the populations of these studies were 5. Relapse rate after 60 days
very different; Haye 1998 excluded participants with radiographic Only one study reported long-term relapse rates (van Buchem
findings of more than a mild sinusitis and Hadley 2010 included 1997). During a one-year follow-up, relapse and recurrence rates
only participants with bacteriologically confirmed sinusitis. were not significantly different between antibiotic (21%) and
At this follow-up, the drop-out rate was 6% in the study of Hadley placebo (17%) groups, with a RR of 1.25 (95% CI 0.72 to 2.19)
2010 and 0% in the study of Haye 1998. (Analysis 1.5).

6. Drop-outs due to adverse effects Antibiotics versus antibiotics
Drop-outs due to adverse effects were rare in both groups: 15 In comparisons of antibiotic versus antibiotic, we only analyzed
out of 1013 (1.5%) in antibiotic groups and 8 out of 805 (1%) data for the primary outcomes measures: clinical failure rate at
in control groups (Analysis 1.6). Three out of the nine placebo- seven to 15 days follow-up and at 16 to 60 days follow-up (clinical
controlled studies reported no drop-outs due to side effects in the failure defined as a lack of full recovery or improvement) and for
antibiotic or control groups. two secondary outcome measures: relapse rates and drop-outs due
to adverse effects.
7. Quality of life Cephalosporins and macrolides versus amoxicillin with

clavulanate
Two studies (Garbutt 2012; Hadley 2010) documented patient-re-
Twenty-one studies compared a cephalosporin or a macrolide
ported symptom improvements evaluated by the SNOT-16 ques-
(cephalosporin, n = 10; macrolide, n = 11) to amoxicillin-clavu-
tionnaire (Sinonasal Outcome Test-16, a validated disease-specific
lanate. Seventeen studies provided data for meta-analyses; nine
quality of life instrument, where lower scores indicate less severe
studies compared cephalosporin (other than first generation) to
symptoms (scale from 0 to 3)). The study of Garbutt 2012 re-
amoxicillin-clavulanate and eight studies compared macrolides
ported the results as mean scores (baseline value 1.71 in amoxi-
(azithromycin, clarithromycin, roxithromycin or telithromycin)
cillin and 1.70 in placebo group). Similar quality of life in both
to amoxicillin-clavulanate. We assessed all the studies to be at ’un-
groups was documented at day three and 10 but a difference at
clear’ or ’high’ risk of bias regardless of the follow-up time.
day seven favoured amoxicillin (P = 0.02). The mean change in
Six studies, involving 1887 participants, provided data for com-
SNOT-16 scores was at three days: amoxicillin group 0.59 (95%
parison of cephalosporins to amoxicillin-clavulanate at seven to 15
CI 0.47 to 0.71) versus placebo group 0.54 (95% CI 0.41 to 0.67);
days follow-up when clinical failure was defined as a lack of full re-
at seven days 1.06 (95% CI 0.93 to 1.20) versus 0.86 (95% CI
covery or improvement. These studies found a statistically signifi-
0.71 to 1.02); and at 10 days 1.23 (95% CI 1.08 to 1.37) versus
cant difference for amoxicillin-clavulanate with a RR of 1.37 (95%
1.20 (95% CI 1.07 to 1.32), respectively.
CI 1.04 to 1.80) (Analysis 2.1). The average failure rate was 12%
The study of Hadley 2010 reported the results as SNOT-16 total
in the cephalosporin group and 8% in the amoxicillin-clavulanate
scores (scale from 0 to 48). Moxifloxacin-treated patients were
group. The missing data rates ranged from 2% to 21%, and the
stated to have experienced a significantly greater mean reduction
missing data rates were approximately equal across the treatment
in total score compared to placebo-treated patients at day six to
groups in the studies. None of the studies were graded as having
eight (-17.54 versus -12.83 (P = 0.032) from baseline values of
’low’ risk of bias and the two studies having highest weight (70%
about 28 in both groups).
altogether) in the meta-analysis were graded as having ’high’ risk
of bias. Confidence in this finding is limited by the low method-
ological quality.
Seven studies provided data for comparison of cephalosporins to
8. Activity impairment and ability to work
amoxicillin-clavulanate at 16 to 60 days follow-up. These studies
Only one study gave information on patients’ ability to work ( did not find any significant difference between the antibiotics,
Garbutt 2012). The mean period missed from work was stated to with a RR of 1.08 (95% CI 0.85 to 1.37) (Analysis 2.2).
be the same, 0.55 days in both groups (amoxicillin and placebo). Seven studies, involving 1807 participants, provided data for com-
In addition, two studies provided information on patients’ activity parison of macrolides to amoxicillin-clavulanate at seven to 15
impairment (Garbutt 2012; Hadley 2010). Hadley 2010 stated days follow-up. These studies failed to reach significant difference
that from day three moxifloxacin-treated patients experienced a between the antibiotics with a risk ratio value of 0.83 (95% CI
greater improvement in activity impairment than placebo-treated 0.62 to 1.13) (Analysis 2.4). The missing data rates ranged from
patients evaluated by a five-item questionnaire (scale from 0 (no 3.4% to 15%.
impairment) to 20 (maximum impairment)). At day six to eight, Four studies provided data for comparison of macrolides to amox-
the mean changes in the scores for activity impairment were: -6.1 icillin-clavulanate at 16 to 60 days follow-up. These studies did
(standard deviation (SD) ± 5.9) in the moxifloxacin group and - not find any significant difference between the antibiotics, with a
3.7 (± 5.8) in the placebo group. RR of 0.85 (95% CI 0.57 to 1.27) (Analysis 2.5).
The study by Garbutt 2012 reported a non-significant difference None of the studies comparing cephalosporins or macrolides to
between the groups in the period of being unable to do usual non- amoxicillin-clavulanate reported long-term relapse rates after 60
work activities (mean 1.15 days (95% CI 0.76 to 1.54) in the days.
amoxicillin group and 1.67 days (95% CI 1.08 to 2.26) in the Drop-outs due to adverse effects occurred significantly less often
placebo group). in the macrolide group (2.1%) compared to the amoxicillin-clavu-

lanate group (4.8%), with a Peto OR of 0.47 (95% CI 0.30 to Drop-outs due to adverse effects were infrequent, occurring
0.72) (the macrolide group ranged from 0% to 3.4%; the amoxi- in 1.3% and 2.3% of the non-penicillin and penicillin-treated
cillin-clavulanate group ranged from 0% to 10.3%) (Analysis 2.6). groups, respectively (Analysis 3.3).
Participants dropped out significantly more often also in the amox-
icillin-clavulanate group (4.4%) compared to the cephalosporin
group (1.3%) with a Peto OR of 0.32 (95% CI 0.21 to 0.49) (in Tetracycline antibiotics versus mixed classes of antibiotics
the cephalosporin group range 0% to 2.1%; in the amoxicillin- Five studies, involving 807 participants, compared a tetracycline
clavulanate group 0% to 11%) (Analysis 2.3). (doxycycline, n = 3; tetracycline, n = 1; minocycline, n = 1) to a het-
erogenous mix of antibiotics (folate inhibitor, n = 2; cephalosporin,
n = 1; macrolide, n = 1; amoxicillin, n = 1). All these studies pro-
vided data for clinical failure defined as a lack of full recovery or
Non-penicillins versus beta-lactamase sensitive penicillins
improvement at 7 to 15 days follow-up, and we combined the data
Eight from these studies, despite the antibiotic used. The studies failed
studies compared a non-penicillin antibiotic (cephalosporins, n = to find a significant difference between antibiotics, with a RR of
3; macrolides, n = 3; minocycline, n = 1; folate inhibitor, n = 1) 1.09 (95% CI 0.70 to 1.71) (Analysis 4.1). The missing data rates
to a penicillin-class antibiotic (amoxicillin, n = 7; penicillin V, n of these five studies ranged from 0% to 20%, and the missing data
= 1), where n is the number of studies. Seven of the eight studies rates were approximately equal across the treatment groups in the
were classified as having ’unclear’ or ’high’ risk of bias, and one as studies. All the studies in this comparison were graded as ’unclear’
’low’ risk of bias (Haye 1996). Because there was only one study or ’high’ risk of bias.
at ’low’ risk of bias, we combined the results of all studies in the None of the studies reported long-term relapse rates after 60 days.
meta-analyses. Drop-outs due to adverse effects were infrequent, occurring in
Seven of these eight studies (involving 1083 participants) pro- 2.6% and 3.5% of the tetracycline and mixed classes of antibiotics
vided data for clinical outcome at 7 to 15 days follow-up and we groups, respectively (Analysis 4.2).
combined the data from these studies regardless of the antibiotic
used. The studies failed to find a significant difference between
antibiotics, with a RR of 0.70 (95% CI 0.47 to 1.06) (Analysis Miscellaneous comparisons
3.1). When excluding the study of Haye 1996(at ’low’ risk of bias) Twenty-one studies made the following comparisons: macrolide
from the analyses, the result of the meta-analysis did not change to fluoroquinolone (n = 5), fluoroquinolone to cephalosporin (n =
the conclusions (RR of 0.75, 95% CI 0.48 to 1.17). The missing 4), macrolide to cephalosporin (n = 3), fluoroquinolone to amox-
data rates of these seven studies ranged from 0% to 33%, and the icillin-clavulanate (n = 5), streptogramin to cephalosporin (n = 2)
missing data rates were approximately equal across the treatment and faropenem to cephalosporin (n = 2). None of these studies re-
groups in the studies. ported a statistically significant difference in the clinical outcomes.
One study (Haye 1996) provided data at 16 to 60 days follow-
up and did not find a significant difference between the treatment
Comparison of the effect of short versus long courses of
groups with a risk ratio value of 0.67 (95% CI 0.37 to 1.20)
antibiotics
(Analysis 3.2). This study was assessed to be at ’low’ risk of bias
also at this second follow-up. We did not perform this comparison because there were no
None of the studies reported long-term relapse rates after 60 days. placebo-controlled studies available to undertake it.

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Antibiotics compared to other antibiotics for uncomplicated acute maxillary sinusitis
Patient or population: patients with uncomplicated acute maxillary sinusitis

Settings: primary care
Comparisons: non-penicillin antibiotic versus beta-lactamase sensitive penicillins (n = 8), non-tetracycline versus tetracycline (n =
5, of which one study was also included in the comparison of non-penicillin antibiotic versus beta-lactamase sensitive penicillins)
, macrolides versus amoxicillin-clavulanate (n = 11), cephalosporins versus amoxicillin-clavulanate (n = 10) and miscellaneous
comparisons (n = 21)
Outcomes Impact No of participants Quality of the evidence Comments

(studies) (GRADE)
Clinical failure rate (fail- No difference in failure 54 studies representing ⊕⊕⊕ Adverse effects3
ure defined as a lack of rates 10 different comparisons moderate2
full recovery or improve- 1
ment or a lack of full re-

covery)
Follow-ups:
7 to 15 days and 16 to 60
days
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk
(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change
the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to
change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Many of the 54 studies were non-inferiority studies.
2 Four
studies were at ’low’ risk of bias and the other 50 at ’unclear’ or ’high’ risk of bias.
3
Amoxicillin-clavulanate had significantly more drop-outs due to adverse effects than cephalosporins and macrolides.
DISCUSSION In this review, the risk of treatment failure (defined as lack of full
recovery or improvement) was statistically slightly smaller in an-
tibiotic groups than in placebo groups, at 7 to 15 days in partic-
Summary of main results ipants with acute sinusitis diagnosed either clinically or by radio-
graphy (main analysis, five studies; Summary of findings for the
main comparison). However, the clinical benefit was small. The
Antibiotics versus placebo difference between groups in the full recovery or improvement
rates was 10% at most in all of the eight studies available for this in favour of the antibiotic group. The significance of the results
comparison. The average cure or improvement rate in the antibi- remains unclear because baseline scores (in the scale 0 to 20) were
otic groups was 87% (range 78% to 98%) and in the placebo not reported, and even the five items of the questionnaire were
groups 81% (range 67% to 89%) (Table 1). not specified.
On the other hand, stronger statistical significance favouring an- In both studies it remained unclear whether data for participants
tibiotics in terms of clinical failure rates, defined as lack of full who received rescue therapy were included in these results.
recovery (at 7 to 15 days; five studies; Summary of findings for the In this review the primary outcome was failure at 7 to 15 days after
main comparison), might indicate a faster cure rate with antibi- the start of the treatment because recovery from acute maxillary
otics than without. The average full recovery rate in the antibiotic sinusitis takes generally more than one week (Gwaltney 2005).
groups was about 50% (range 30% to 65%) and in the control However, from the patient’s perspective, fast symptom relief is im-
groups 35% (range 11% to 52%) (all six available studies for this portant and data are also needed on short-term improvement. Six
comparison, Table 1). studies (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998;
At day 16 to 60 follow-up there was no significant difference be- Lindbaek 1996; Merenstein 2005) also reported cure or improve-
tween the antibiotic and placebo groups in relieving signs and ment rates prior to one-week follow-up. Three of the six stud-
symptoms regardless of the definition of failure (full recovery or ies reported higher improvement rates for antibiotic than placebo
improvement (Hadley 2010; Haye 1998); full recovery (Haye (Hadley 2010: improvement rate 85% versus 73% at day three;
1998)) (Summary of findings for the main comparison). Although Lindbaek 1996: improvement rate 60% versus 36% at day three;
not statistically significant, Haye 1998 reported higher full recov- Merenstein 2005: the average number of days to entire improve-
ery rates in the antibiotic group (69 out of 87 patients (79%)) ment was consistently two to two and a half days shorter in the
than in the placebo group (55 out of 82 of patients (67%)). antibiotic group among those participants who had entirely im-
None of the nine placebo-controlled studies reported severe com- proved by day 14). Two of these studies represented patients with
plications. a more severe form of disease (Hadley 2010; Lindbaek 1996). The
Even longer follow-up times would be needed to assess the efficacy other three studies reported only minor differences between the
of antibiotic treatment in the longer term and to assess potential groups at day three to five (Axelsson 1970: full recovery or im-
adverse effects. There is some evidence from other respiratory tract provement rate was 69% in the antibiotic group versus 65% in
infections that the use of antibiotics increases relapse rates and may the placebo group; Garbutt 2012: 37% versus 34%; Haye 1998:
end up increasing antibiotic consumption (Arason 2005; Joki- 80% versus 79%, respectively). The data do not make it possible
Erkkilä 2000). Therefore, in optimal circumstances, the sinusitis to draw strong conclusions on the short-term improvement of pa-
trials should monitor signs, infection rates and drug use over one tients’ symptoms.
year. Only one study in this review reported long-term relapse rates Although we found slight statistical significance and potentially
(van Buchem 1997) during a one-year follow-up. The relapse and faster resolution of symptoms favouring antibiotics, the clinical
recurrence rates were not significantly different between groups. significance of the result is questionable because of the consider-
able improvement rate in the placebo group. Also, the possible
benefit needs to be weighed against the potential for adverse ef-
Patient perspective on recovery fects at both the individual and population levels. The results were
based on studies of penicillin, amoxicillin, azithromycin and mox-
Quality of life and activity impairment were assessed in two studies
ifloxacin performed in middle and northern Europe in five stud-
(Garbutt 2012; Hadley 2010) (Summary of findings for the main
ies (Axelsson 1970; Haye 1998; Lindbaek 1996; Lindbaek 1998;
comparison). Both of these studies reported somewhat better qual-
van Buchem 1997), in the USA in three studies (Garbutt 2012;
ity of life in the antibiotic than in the placebo group at days six to
Hadley 2010; Merenstein 2005) and one study was multinational
eight. However, the Garbutt 2012 trial documented that quality
(Meltzer 2005).
of life was similar in the antibiotic and placebo groups at day three
Key information about placebo-controlled studies is collated in
and day 10 follow-ups. Garbutt 2012 also reported equal mean
Table 1.
periods missed from work in the antibiotic and placebo groups
(0.55 days) and a non-significant difference in the period where
participants were unable to do usual non-work activities (mean
1.15 days in amoxicillin and 1.67 days in the placebo group; P = Different classes of antibiotics
0.14). In the study designs comparing different classes of antibiotics,
Hadley 2010, on the other hand, reported that from day three the antibiotics had a similar efficacy to each other (Summary
to days six to eight, patients in the antibiotic group experienced of findings 2). However, at 7 to 15 days follow-up, the risk of
a greater improvement in activity impairment than patients in clinical failure was statistically significantly lower for amoxicillin-
the placebo group. The differences in change in mean activity clavulanate than for cephalosporins, but the significance of the
impairment scores were 1 at day three and 2.4 at days six to eight difference disappeared at longer follow-up.

Amoxicillin and penicillin have the advantage of low cost but are (medians 2% in eight studies and 1.4% in nine studies, respec-
often recommended at a three times a day dose, a dosing sched- tively).
ule associated with decreased compliance compared to once or One problem in the sinusitis trials is that standardised information
twice daily regimens. A more serious concern is the rising preva- on side effects is available in fewer than half of the cases (Ioannidis
lence of beta-lactamase-producing organisms and penicillin and 2002). It may be that the true rate of side effects equals or even
macrolide-resistant pneumococci. In eight studies comparing non- exceeds the marginal benefits of the treatments. On the other
penicillin antibiotics to a beta-lactamase sensitive penicillin, clin- hand, both severe adverse effects and severe complications (for
ical outcomes were virtually identical. These studies were con- example, anaphylaxis and meningitis) are such rare events that
ducted mostly in the 1990s, four of them in the USA, three in they are seldom manifested in randomised controlled trials with
Nordic countries and one in Switzerland. limited numbers of patients.
Among the newer, extended-spectrum antibiotics, the long-term
efficacy (at 16 to 60 days follow-up) was similar but amox-
icillin-clavulanate had significantly more adverse effects than
cephalosporins and macrolides. At 7 to 15 days follow-up, how- Overall completeness and applicability of
ever, the risk of clinical failure was statistically significantly lower evidence
for amoxicillin-clavulanate than for cephalosporins, but the sig-
nificance of the difference disappeared at longer follow-up. The
studies were conducted in the 1990s and 2000s. Setting and diagnostic methods
None of the antibiotic preparations were superior to each other.
This review is restricted to adults. This is because sinusitis in chil-
Given the similar efficacy, the differences in the adverse effects,
dren differs from that in adults, for example regarding anatomy, di-
costs and risk of promoting bacterial resistance should be consid-
agnosis, epidemiology and microbiology (Hsin 2010). Newborns
ered when choosing antibiotic treatment for acute sinusitis.
have maxillary sinuses the size of a bean. The sinuses start to widen
at the age of three or four, the development takes a long time
and only by the age of 15 to 18 is the anatomy of the sinuses
Adverse effects fully developed (Lawson 2008). It is difficult to find figures, but a
In general, adverse effects were more common in the antibiotic common expert opinion is that although purulent nasal discharge
than in the placebo groups (median of difference between groups is a common symptom in children, sinusitis appears to be more
10.5% in seven of the nine studies, range 2% to 23%) (Table rare than among adults and often chronic, concentrating in spe-
1). The adverse effects rates of penicillin and amoxicillin differed cial groups like asthmatic and immunocompromised children and
among the placebo-controlled studies. In the study by Axelsson those with cystic fibrosis (Wu 2009). On the other hand, com-
1970, the rate for penicillin was 8% (in the control group 6%) and plications of acute sinusitis appear to be about three times more
in the study by Lindbaek 1996 59% (in the placebo group 36%). common among children than adults (Hansen 2012) and these
The mean adverse effect rate based on five studies for amoxicillin develop during the first days of acute respiratory infection (Kristo
was 31% (range 16% to 56%), while the corresponding rate for 2009). Because sinusitis in children seems to be quite different in
placebo was 22% (9% to 38%) (Garbutt 2012; Lindbaek 1996; many aspects compared to that in adults, we chose to limit our
Meltzer 2005; Merenstein 2005; van Buchem 1997). The study review to studies of adults.
by Haye 1998 reported 28% adverse effects for azithromycin and As the role of radiographs in diagnosing acute sinusitis is con-
18% for placebo; and the study by Hadley 2010 reported 14% for troversial, we decided also to include trials that included par-
moxifloxacin and 7% for placebo. The most commonly reported ticipants based on clinical criteria only. The diagnosis of acute
adverse effects in antibiotic groups were: gastrointestinal prob- maxillary sinusitis was based solely on clinical diagnosis in four
lems (for example, diarrhea, abdominal pain, vomiting) and skin studies (Garbutt 2012; Haye 1998; Meltzer 2005; Merenstein
rash. However, drop-outs due to adverse effects were rare (1.5%) 2005), confirmed by radiograph in three studies (Axelsson 1970;
for penicillin, amoxicillin, azithromycin and moxifloxacin in the Hadley 2010; van Buchem 1997) and confirmed by computer to-
placebo-controlled studies. mography (CT) scan in two studies (Lindbaek 1996; Lindbaek
In the antibiotic versus antibiotic comparisons, the drop-out rates 1998). Haye 1998 used X-rays to exclude patients who had evi-
due to adverse effects were significantly different only in the com- dence of empyema. The studies with radiographic confirmation
parisons of amoxicillin-clavulanate versus macrolides (Analysis of diagnosis accepted participants with air-fluid level or opacifi-
2.6) and cephalosporins (Analysis 2.3). There were 17 studies com- cation (Axelsson 1970; Hadley 2010) and van Buchem 1997 also
paring amoxicillin-clavulanate to macrolides or cephalosporins. those with more than 5 mm mucosal thickening. In the study
The drop-out rate due to adverse effects varied from 0% to 11% by Lindbaek 1996 the acute maxillary sinusitis was confirmed by
in the amoxicillin-clavulanate groups (median 3.4% in 17 stud- a CT scan showing opacity or air-fluid level. Lindbaek 1998 in-
ies), and from 0% to 3.4% in macrolide and cephalosporin groups cluded only patients with mucosal thickening in a CT scan.

Three studies reported that bacteriological samples were taken. to background factors that have an effect on recovery. Therefore,
Hadley 2010 included only culture-positive patients with specified studies with acute exacerbations of chronic sinusitis were included
target pathogens in the analyses. Lindbaek 1996 reported that in only if they reported separately data on the subgroup with acute
58% of participants bacteriological specimens obtained from the sinusitis, or if not reported separately at least 80% of participants
nasopharynx grew bacteria connected with sinusitis. Haye 1996 had acute sinusitis.
reported that only in some samples taken from the posterior part
of the nasal cavity was growth of pathogenic bacteria obtained.
On the whole, the proportion of participants with true bacterial Different classes of antibiotics
sinusitis remained unclear in seven out of the nine placebo-con- We combined data from all placebo-controlled studies, regardless
trolled studies, as is the case in real clinical practice. Participants of the type of antibiotic used. We anticipated that there would
in seven of the nine studies were clearly recruited from commu- be only some placebo-controlled studies available for the analyses,
nity-based general practices, where these kinds of patients are fre- and the main interest would be whether antibiotic treatment in
quently treated. Thus the results in this review are valid in adult general is beneficial. We presumed that researchers in different
patients in general practice settings. countries had local reasons for selecting particular antibiotics for
their trials, for example taking into account local resistance rates
to antibiotics among community-acquired pathogens.
Strengths and weaknesses of diagnostic options
The diagnosis of acute sinusitis is challenging in primary care, es-
Duration of treatment
pecially when trying to differentiate between a viral or bacterial
origin of disease. The high proportion of participants that im- One of our aims was to evaluate the effect of short and long
proved in the non-antibiotic group indicates that only some of courses of antibiotics. Our view is that, for this purpose, antibi-
the participants defined (by these criteria) as having acute sinusitis otic versus antibiotic study designs without a non-antibiotic group
benefit from antibiotic treatment. Clinical examination is sensi- are not valid enough. Unfortunately, there were no placebo-con-
tive in ruling out sinusitis (Williams 1993) but not in identifying trolled studies available to undertake this comparison. Antibiotics
bacterial disease. Specific methods would be needed to find the also have side effects; therefore more placebo-controlled trials are
subgroups of patients that might benefit from antibiotics. Some needed to find the optimal duration of treatment and those sub-
official opinions support the practice of diagnosing acute maxillary groups that might benefit from the treatment. The same applies
sinusitis by clinical examination. For example, the expert panel of to other respiratory tract infections in primary health care.
five national societies in the USA has stated that sinusitis can be
diagnosed, in the majority of patients, by using only the history
and physical examination (Meltzer 2004). In the referral guide- Quality of the evidence
line for imaging of the European Commission, radiograph is not
indicated as a routine diagnostic method (ECRP 2000). Further,
it states that thickened mucosa is a non-specific finding and may Antibiotics versus placebo
occur in asymptomatic patients. CT scan has a role in cases of The body of evidence comparing antibiotics with placebo at one
treatment failure with suspicion of complications or malignancy to two weeks comprised five randomised studies. When a failure
or when surgery is considered (ECRP 2000; Meltzer 2004). In was defined as a lack of full recovery or improvement (the main
Nordic countries, the diagnosis of sinusitis is often confirmed by analysis), we assessed the body of evidence as being of moderate
means of an ultrasound device that is suitable for primary care but quality according to the GRADE assessment criteria (Summary
its use requires training and experience. Sinusitis can be ruled out of findings for the main comparison). This implies that further
in patients with no fluid retention in sinuses with this method, research is likely to have an important impact on our confidence
so it may reduce the use of antibiotics (Puhakka 2000; Varonen in the estimate of effect and may change the estimate. The pooled
2003b). estimate of the five studies slightly favoured antibiotics with a RR
of 0.66 (95% CI 0.47 to 0.94). Because the effect size seems to be
small and the number of evaluated participants so far is 1058, it
Duration of signs and symptoms is not unreasonable, however, to anticipate that a new large study
Bacterial sinusitis is more likely if the signs and symptoms have could change this estimate.
lasted at least seven days (Meltzer 2004) and therefore studies with When a failure was defined as a lack of full recovery, we assessed
shorter illness duration, without confirmed diagnosis by radio- the body of evidence as being of high quality according to the
graph or culture, were excluded. Acute exacerbations of chronic GRADE assessment criteria (the RR for failure was 0.73 (95% CI
sinusitis were considered as part of the chronic form of the dis- 0.63 to 0.85). This implies that further research is very unlikely
ease, which is a separate and more complicated entity, often related to change our confidence in the estimate of effect.

The body of evidence comparing antibiotics with a placebo at two 2010 compared to the other studies. The study of Lindbaek 1996
to nine weeks comprised only one randomised study which was differed in only accepting participants with opacity or fluid-level
assessed as being of low quality according to the GRADE assess- in the sinuses, not with mucosal thickening alone, by using CT
ment criteria (Summary of findings for the main comparison). scan. The study also reported pathogenic bacteria connected with
This implies that further research is very likely to have an im- acute sinusitis in 58% of participants. The study of Hadley 2010,
portant impact on our confidence in the estimate of effect and is which was not included in the meta-analyses, differed by including
likely to change the estimate. The RR for failure was 0.85 (95% only patients with isolation of pathogenic bacteria from the sinus
CI 0.36 to 1.98) when a failure was defined as a lack full recovery secretion. It is obvious that the participants selected for these two
or improvement, and 0.63 (95% CI 0.38 to 1.05) when a failure studies represented people with a more severe form of the disease.
was defined as a lack of full recovery.
Definition of cure
Antibiotics versus antibiotics The definitions of full recovery, improvement and failure in in-
We assessed the quality of the body of evidence for comparing one dividual studies can influence the data extraction and the results,
class of antibiotic against another as being of moderate quality ac- both at study and meta-analysis level, especially in cases where only
cording to the GRADE assessment criteria (Summary of findings a few studies are available for analysis. In studies with a dichoto-
2). Although the number of the studies was large (54 studies) most mous classification of the outcomes, the criteria can vary between
of them were non-inferiority studies and often supported by phar- studies, as well as compared to studies with multi-level classifica-
maceutical companies. Because most patients with sinusitis will tions. In this review, four of the nine placebo-controlled studies
improve without antibiotics and the margin of getting added clin- reported success dichotomously. The highest number of categories
ical benefit from antibiotics on the whole, compared to placebo, was used in the studies by Lindbaek 1996 and Lindbaek 1998.
is small (about 10%), it is easy to show non-inferiority between The outcomes were classified into five categories: restored, much
antibiotics. better, somewhat better, unimproved and worse. Two other studies
There were 54 studies comparing an antibiotic to another an- reported outcomes in three categories and one in four categories.
tibiotic. In general, we assessed the methodological quality of the Dichotomising different outcome classifications for the analyses
studies to be modest, mostly due to incomplete blinding and/or causes uncertainty in the results.
incomplete reporting of other methodological issues, especially of
randomisation (Figure 1; Figure 2). We graded only four of the
54 studies as having ’low’ risk of bias based on the methodolog- Agreements and disagreements with other
ical criteria used in this review, and graded the other 50 as ’un- studies or reviews
clear’ or ’high’ risk of bias. In the only comparison in this review
Three other recent systematic reviews have considered comparison
where a slight statistical difference was found between antibiotics,
of antibiotics with placebo for acute maxillary sinusitis. These re-
we graded none of the studies as having ’low’ risk of bias and the
views have used more permissive eligibility criteria than our review
two studies having highest weight (70% altogether) in the meta-
and would therefore include a more heterogeneous sample of in-
analysis also had a ’high’ risk of bias. This comparison was for
dividuals with and without acute bacterial rhinosinusitis. Overall,
cephalosporins versus amoxicillin-clavulanate at seven to 15 days
these reviews found similar antibiotic treatment effects, despite
follow-up with clinical failure defined as a lack of full recovery or
differing eligibility criteria.
improvement (Analysis 2.1). Confidence in this finding is limited
The study by Rosenfeld 2007 found that antimicrobials, com-
by the low methodological quality and the disappearance of sig-
pared to placebo control, increased clinical improvement rates at
nificance at longer follow-up.
two weeks for 800 patients by an absolute difference of 7% (95%
CI 2 to 13%). Diarrhoea (1583 patients, risk difference (RD) of
0.05 (95% CI 0.01 to 0.09)) and any adverse events (1853 pa-
Potential biases in the review process tients, RD of 0.11 (95% CI 0.05 to 0.16)) were more common in
the group treated with antimicrobials. A patient-level meta-anal-
ysis (Young 2008) of 10 placebo-controlled trials involving 2640
Diagnosis patients specifically excluded trials that enrolled patients on the
We expected that the diagnostic method in an individual placebo- basis of laboratory, imaging or bacterial culture results. This study
controlled study (clinical diagnosis alone versus radiological/bac- found a small increase in clinical cures with antibiotics within two
teriological confirmation) might have had an influence on the re- weeks (OR of 1.35, 95% CI 1.15 to 1.59) and a number needed to
sults. In the meta-analyses, however, no statistically significant het- treat to benefit (NNTB) of 15 (95% CI 7 to infinity). The authors
erogeneity between individual study results was observed. Clinical conclude that “common clinical signs and symptoms cannot iden-
diversity was plausible in the studies of Lindbaek 1996 and Hadley tify patients with rhinosinusitis for whom antibiotic treatment is

clearly justified, not even if a patient reports symptoms for longer both individual and general population level (for example, local
than 7 to 10 days”. In the third meta-analysis by Falagas 2008a, bacterial resistance).
including 16 randomised, double-blind trials with 2648 patients,
antibiotics were associated with a higher rate of cure or improve- Implications for research
ment within two weeks (OR 1.64, 95% CI 1.35 to 2.00) but with
Given the small number of trials, additional high-quality, placebo-
more adverse effects (12 trials with 1963 patients, OR 1.87 (95%
controlled trials are needed to identify the potential subgroups
CI 1.21 to 2.90)). The authors conclude that “use of antibiotics
of sinusitis patients that may benefit from antibiotics. Diagno-
for acute sinusitis confers a small therapeutic benefit over placebo
sis should be made on prespecified recommended clinical criteria
with a raise in risk of adverse effects, and that antibiotics should
which also allow subgroup analyses according to severity of the
be reserved for carefully selected patients with a higher probability
disease. The benefit of adding a nasopharyngeal swab in the di-
for bacterial disease”.
agnosis of patients with sufficient clinical criteria is also unclear.
Another review by Falagas 2008b evaluated the effects of short
The data in this review did not allow such subgroup analyses.
(up to seven days) versus longer-course (at least two days longer
than short-course) antibiotic treatment for acute rhinosinusitis. Special attention should be paid to identifying the prognostic
Twelve trials compared the same antibiotic for varying durations. factors of sinusitis and finding factors that potentially modify
Rates of clinical success did not vary significantly for short- versus the treatment effect, such as co-morbid conditions (for example,
longer-term treatment (OR 0.95, 95% CI 0.81 to 1.12). Our asthma, allergies), lifestyle and other individual factors (for ex-
review did not include studies comparing different durations of the ample, smoking). Effects on functional status, work performance
same antibiotic because there were no placebo-controlled studies and quality of life may provide important additional information.
measuring this. The trials should be double-blinded, with adequate allocation and
concealment procedures, and should report clinical outcomes and
time to clinical response. Large trials may be needed to identify
clinical predictors of the need for antibiotics. Different treatment
AUTHORS’ CONCLUSIONS durations should also be studied in placebo-controlled settings.
Implications for practice

Antibiotics have a small benefit for clinical outcomes in patients
ACKNOWLEDGEMENTS
with symptoms of uncomplicated acute sinusitis lasting for more
than seven days in a primary care setting. However, about 80% of We would like to thank the Cochrane Acute Respiratory Infec-
patients treated with a placebo also improve within two weeks. tions Group’s Trials Search Co-ordinator Sarah Thorning for help
in searching the literature and the Managing Editor, Elizabeth
The patients in the placebo-controlled studies were enrolled from
Dooley, for all her help. We warmly thank Information Specialist
unselected primary care populations (except perhaps Axelsson
Jaana Isojärvi at National Institute for Health and Welfare/THL,
1970; Meltzer 2005). The individual studies represented clinical
Finland for her help in the supplementary search of the literature.
conditions ranging from mild to more severe, depending on the
We would also like to thank Johannes Hang Guo, Ryuki Kassai,
inclusion criteria, as in a real general practice setting. All but one
Sachiyo Yoshida, Jaana Elberkennou, Tiina Lehmussaari and He-
of the placebo-controlled studies favoured antibiotics to some ex-
lena Laasonen for translating trial reports published in Chinese,
tent. We see that the overall result of the meta-analysis for the
Japanese, French, Spanish and Portuguese. We are also grateful to
main outcome corresponds fairly well to the mixture of patients in
Systems Manager Marko Ekqvist, English Language Editor Mark
primary care. However, compared to situations where no imaging
Phillips, and MSC Niina Kovanen for their inputs in the previous
is used, the benefit of antibiotics may be somewhat overestimated.
version of this review. We would also like to thank Dr An de Sut-
It seems that even when special effort is put into selecting patients
ter, Dr Jane M. Garbutt, Dr Morten Lindbaek, Dr Eli O. Meltzer,
from primary care settings who most probably have bacterial si-
Dr Dan Merenstein and Dr Ian G Williamson for providing ad-
nusitis, the actual benefit of antibiotics is modest. It is obvious
ditional information about their trials, and Schering-Plough Re-
that there are individual patients who benefit from antibiotics but
search Institute for providing information on their unpublished
we do not have proper means to identify them in primary care
study. We are grateful to Bruce Arroll, Sree Nair, Dilip Raghavan
settings.
and Meenu Singh for valuable referee comments in previous ver-
Clinicians and people responsible for producing guidelines need sions, and to Bruce Arroll, Abimbola Farinde, José Luis Ferrero
to weigh the moderate benefits of antibiotic treatment against the Albert, Terry Neeman and Devada Singh-Franco in the current
patient’s general condition and the potential for adverse effects at version.

REFERENCES
References to studies included in this review maxillary sinusitis. Archives of Family Medicine 1993;2(8):
837–40. [MEDLINE: 94154893]
Adelglass 1998a {published data only}
Camacho 1992 {published data only}
Adelglass J, Jones TM, Ruoff G, Kahn JB, Wiesinger BA,
Camacho AE, Cobo R, Otte J, Spector SL, Lerner CJ,
Rielly-Gauvin K, et al.A multicenter, investigator-blinded,
Garrison NA, et al.Clinical comparison of cefuroxime axetil
randomized comparison of oral levofloxacin and oral
and amoxicillin/clavulanate in the treatment of patients
clarithromycin in the treatment of acute bacterial sinusitis.
with acute bacterial maxillary sinusitis. American Journal of
Pharmacotherapy 1998;18(6):1255–63.
Medicine 1992;93(3):271–6. [MEDLINE: 92397909]
Adelglass 1998b {published data only}
Chatzimanolis 1998 {published data only}
Adelglass J, Bundy JM, Woods R. Efficacy and tolerability
Chatzimanolis E, Marsan N, Lefatzis D, Pavlopoulos A.
of cefprozil versus amoxicillin/clavulanate for the treatment
Comparison of roxithromycin with co-amoxiclav in patients
of adults with severe sinusitis. Clinical Therapeutics 1998;
with sinusitis. Journal of Antimicrobial Chemotherapy 1998;
20(6):1115–29. [MEDLINE: 99113644]
41(Suppl B):81–4. [MEDLINE: 98239321]
Adelglass 1999 {published data only}
Clement 1998 {published data only}
Adelglass J, DeAbate A, McElvaine P, Fowler CL, LoCocco J,
Clement PA, de Gandt JB. A comparison of the efficacy,
Campbell T. Comparison of the effectiveness of levofloxacin
tolerability and safety of azithromycin and co-amoxiclav in
and amoxicillin-clavulanate for the treatment of acute
the treatment of sinusitis in adults. Journal of International
sinusitis in adults. Otolaryngology - Head and Neck Surgery
Medical Research 1998;26(2):66–75. [MEDLINE:
1999;120:320–7.
98265694]
Arndt 1994 {published data only}
Clifford 1999 {published data only}
Arndt J, Riebenfeld D, Maier H, Weidauer H. Therapeutic
Clifford K, Huck W, Shan M, Tosiello R, Echols RM,
efficacy and tolerability of brodimoprim in comparison
Heyd A. Double-blind comparative trial of ciprofloxacin
with doxycycline in acute sinusitis in adults. Journal of
versus clarithromycin in the treatment of acute bacterial
Chemotherapy 1994;6(5):322–7. [MEDLINE: 95165185]
sinusitis. Sinusitis Infection Study Group. Annals of
Arrieta 2007 {published data only} Otology, Rhinology and Laryngology 1999;108(4):360–7.
Arrieta JR, Galgano AS, Sakano E, Fonseca X, Amabile- [MEDLINE: 99229596]
Cuevas CF, Hernandez-Oliva G, et al.Moxifloxacin vs Desrosiers 2008 {published data only}
amoxicillin/clavulanate in the treatment of acute sinusitis. Desrosiers M, Ferguson B, Klossek JM, Drugeon H, Mösges
American Journal of Otolaryngology 2007;28(2):78–82. R. Clinical efficacy and time to symptom resolution of 5-
Axelsson 1970 {published data only} day telithromycin versus 10-day amoxicillin-clavulanate in
Axelsson A, Chidekel N, Grebelius N, Jensen C. Treatment the treatment of acute bacterial sinusitis. Current Medical
of acute maxillary sinusitis. A comparison of four different Research and Opinion 2008;24(6):1691–702.
methods. Acta Otolaryngologica (Stockholm) 1970;70(1): Dubois 1993 {published data only}
71–6. [MEDLINE: 70286389] Dubois J, Saint-Pierre C, Tremblay C. Efficacy of
Boezeman 1988 {published data only} clarithromycin vs. amoxicillin/clavulanate in the treatment
Boezeman AJ, Kayser AM, Siemelink RJ. Comparison of of acute maxillary sinusitis. Ear, Nose and Throat Journal
spiramycin and doxycycline in the empirical treatment of 1993;72(12):804–10. [MEDLINE: 94147948]
acute sinusitis: preliminary results. Journal of Antimicrobial Ferguson 2004 {published data only}
Chemotherapy 1988;22(Suppl B):165–70. [MEDLINE: Ferguson BJ, Guzzetta RV, Spector SL, Hadley JA. Efficacy
89033421] and safety of oral telithromycin once daily for 5 days versus
Buchanan 2003 {published data only} moxifloxacin once daily for 10 days in the treatment of
Buchanan PP, Stephens TA, Leroy B. A comparison of the acute bacterial rhinosinusitis. Otolaryngology - Head and
efficacy of telithromycin versus cefuroxime axetil in the Neck Surgery 2004;131:207–14.
treatment of acute bacterial maxillary sinusitis. American Garbutt 2012 {published and unpublished data}
Journal of Rhinology 2003;17(6):369–77. Garbutt J, Spitznagel E, Piccirillo J. Use of the modified
Burke 1999 {published data only} SNOT-16 in primary care patients with clinically diagnosed
Burke T, Villanueva C, Mariano H, Huck W, Orchard acute rhinosinusitis. Archives of Otolaryngology - Head and
D, Haverstock D, et al.Comparison of moxifloxacin and Neck Surgery 2011;137(8):792–7.
cefuroxime axetil in the treatment of acute maxillary ∗
Garbutt JM, Banister C, Spitznagel E, Piccirillo JF.
sinusitis. Clinical Therapeutics 1999;21(10):1664–77. Amoxicillin for acute rhinosinusitis: A randomized
[MEDLINE: 20030839] controlled trial. JAMA 2012;307(7):685–92.
Calhoun 1993 {published data only} Gehanno 1996a {published data only}
Calhoun KH, Hokanson JA. Multicenter comparison of Gehanno P, Barry B, Chauvin JP, Hazebroucq J.
clarithromycin and amoxicillin in the treatment of acute Clarithromycin versus amoxicillin/clavulanic acid in acute
maxillary sinusitis in adults [Clarithromycine versus clavulanate regimen for treatment of acute bacterial sinusitis.
amoxicilline acide–clavulanique dans le traitement de la Antimicrobial Agents and Chemotherapy 2003;47(9):2770–4.
sinusite maxillaire aigue de l’adulte]. Pathologie Biologie
Henry 2004 {published data only}
(Paris) 1996;44(4):293–7. [MEDLINE: 96306077] Henry DC, Kapral D, Busman TA, Paris MM. Cefdinir
Gehanno 1996b {published data only} versus levofloxacin in patients with acute rhinosinusitis of
Gehanno P, Berche P, Sinusitis Study Group. Sparfloxacin presumed bacterial etiology: a multicenter, randomized,
versus cefuroxime axetil in the treatment of acute purulent double-blind study. Clinical Therapeutics 2004;26(12):
sinusitis. Journal of Antimicrobial Chemotherapy 1996;37 2026–33.
(Suppl A):105–14. Huck 1993 {published data only}
Gehanno 1998 {published data only} Huck W, Reed BD, Nielsen RW, Ferguson RT, Gray DW,
Gehanno P, Pessey JJ, Beauvillain De Montreuil C, Dubreuil Lund GK, et al.Cefaclor vs amoxicillin in the treatment of
C, Levy D, Berche P, et al.Cefatrizine versus amoxicillin- acute, recurrent, and chronic sinusitis. Archives of Family
clavulanate in acute maxillary sinusitis in adults [Etude Medicine 1993;2(5):497–503. [MEDLINE: 94163345]
comparative de la cefatrizine et de l’amoxicilline–acide Jareoncharsri 2004 {published data only}
clavulanique dans le traitement des sinusites maxillaires Jareoncharsri P, Bunnag C, Fooanant S, Tunsuriyawong
aigues de l’acute]. Médecine et Maladies Infectieuses 1998; P, Voraprayoon S, Srifuengfung S, et al.An open label,
28:208–15. randomized comparative study of levofloxacin and
Gehanno 2004 {published data only} amoxicillin/clavulanic acid in the treatment of purulent
Gehanno P, Berche P, Hercot O, d’ Arras L, Cabrillac- sinusitis in adult Thai patients. Rhinology 2004;42(1):23–9.
Rives S, Derobert E, et al.Efficiency of a four-day course of Karma 1991 {published data only}
pristinamycin compared to a five-day course of cefuroxime Karma P, Pukander J, Penttilä M, Ylikoski J, Savolainen
axetil for acute bacterial maxillary sinusitis in adult S, Olen L, et al.The comparative efficacy and safety
outpatients [Efficacite comparee de la pristinamycine en of clarithromycin and amoxycillin in the treatment of
quatre jours et du cefuroxime axetil en cinq jours dans outpatients with acute maxillary sinusitis. Journal of
le traitement des sinusites maxillaires aigues bacteriennes Antimicrobial Chemotherapy 1991;27(Suppl A):83–90.
de l’adulte]. Medecine et Maladies Infectieuses 2004;34: [MEDLINE: 91216883]
293–302.
Klapan 1999 {published data only}
Gwaltney 1997 {published data only} Klapan I, Culig J, Oreskovic K, Matrapazovski M,
Gwaltney JM Jr, Savolainen S, Rivas P, Schenk P, Scheld Radosevic S. Azithromycin versus amoxicillin/clavulanate
WM, Sydnor A, et al.Comparative effectiveness and safety in the treatment of acute sinusitis. American Journal of
of cefdinir and amoxicillin-clavulanate in treatment of acute Otolaryngology 1999;20(1):7–11. [MEDLINE: 99133606]
community-acquired bacterial sinusitis. Cefdinir Sinusitis
Lari 2010 {published data only}
Study Group. Antimicrobial Agents and Chemotherapy 1997;
Lari AR, Ghaffariyeh A, Etesam N, Mostafavi H,
41(7):1517–20. [MEDLINE: 97354383]
Alaghehbandan R. A randomized controlled trial of 5-
Hadley 2010 {published data only} day regimen of azithromycin and a 10-day regimen of co-
Hadley JA, Mösges R, Desrosiers M, Haverstock D, van amoxiclav for treatment of acute sinusitis. Iranian Journal of
Veenhuyzen D, Herman-Gnjidic Z. Moxifloxacin five-day Clinical Infectious Diseases 2010;5(3):137–41.
therapy versus placebo in acute bacterial rhinosinusitis.
Lasko 1998 {published data only}
Laryngoscope 2010;120(5):1057–62.
Lasko B, Lau CY, Saint-Pierre C, Reddington JL, Martel A,
Haye 1996 {published data only} Anstey RJ. Efficacy and safety of oral levofloxacin compared
Haye R, Lingaas E, Hoivik HO, Odegård T. Efficacy and with clarithromycin in the treatment of acute sinusitis in
safety of azithromycin versus phenoxymethylpenicillin in adults: a multicentre, double-blind, randomized study. The
the treatment of acute maxillary sinusitis. European Journal Canadian Sinusitis Study Group. Journal of International
of Clinical Microbiology and Infectious Diseases 1996;15(11): Medical Research 1998;26(6):281–91. [MEDLINE:
849–53. [MEDLINE: 97151573] 99327309]
Haye 1998 {published data only} Lindbaek 1996 {published and unpublished data}
Haye R, Lingaas E, Hoivik HO, Odegård T. Azithromycin Lindbaek M, Hjortdahl P, Johnsen UL. Randomised,
versus placebo in acute infectious rhinitis with clinical double blind, placebo controlled trial of penicillin V and
symptoms but without radiological signs of maxillary amoxycillin in treatment of acute sinus infections in adults.
sinusitis. European Journal of Clinical Microbiology and BMJ 1996;313(7053):325–9. [MEDLINE: 96343743]
Infectious Diseases 1998;17:309–12.
Lindbaek 1998 {published and unpublished data}
Henry 2003 {published data only} Lindbaek M, Kaastad E, Dolvik S, Johnsen U, Laerum E,
Henry DC, Riffer E, Sokol WN, Chaudry NI, Swanson Hjortdahl P. Antibiotic treatment of patients with mucosal
RN. Randomized double-blind study comparing 3- and 6- thickening in the paranasal sinuses, and validation of cut-
day regimens of azithromycin with a 10-day amoxicillin- off points in sinus CT. Rhinology 1998;36:7–11.
Luterman 2003 {published data only} [Amoxicilina–acido clavulanico y axetilo de cefuroxima en
Luterman M, Tellier G, Lasko B, Leroy B. Efficacy and el tratamiento de la sinusitis aguda. Evaluacion clinica,
tolerability of telithromycin for 5 or 10 days vs amoxicillin/ radiologica y bacteriologica]. Acta Otorrinolaringologica
clavulanic acid for 10 days in acute maxillary sinusitis. Ear, Espanola 1994;45(1):25–9. [MEDLINE: 94263593]
Nose & Throat Journal 2003;82(8):576-80, 582-4, 586
Otte 1983 {published data only}
passim.
Otte J, Viada JA, Buchi MD, Salgado O. Tratamiento de los
Marple 2010 {published data only} procesos sinusales agudos del adulto con tetraciclina y una
Marple BF, Roberts CS, Frytak JR, Schabert VF, Wegner combinacion de sulfametopirazona-trimetoprim. Revista
JC, Bhattacharyya H, et al.Azithromycin extended release Medica de Chile 1983;111(11):1157–61. [MEDLINE:
vs amoxicillin/clavulanate: symptom resolution in acute 84273842]
sinusitis. American Journal of Otolaryngology - Head and
Pessey 1996 {published data only}
Neck Medicine and Surgery 2010;31(1):1–8.
Pessey JJ, Dubreuil C, Gehanno P, Artaz MA, Scheimberg
Matthews 1997 {published data only} A. Four days cefixime, 10 days cefixime, or 10 days
Matthews BL, Suprax/Amoxicillin Clinical Sinusitis Study amoxicillin-clavulanate, for the treatment of acute sinusitis
Team. Effectiveness and safety of cefixime and amoxicillin in adults [Efficacite et tolerance du cefuxime en traitement
in adults with acute bacterial sinusitis. Managing Sinusitis: de 4 jour ou de 10 jours versus 10 jours d’amoxicilline–acide
A Postgraduate Medicine Special Report 1997:41–9. clavulanique dans les sinusites aigues de l’adulte]. Medecine
Mattucci 1986 {published data only} et Maladies Infectieuses 1996;26(10):839–45.
Mattucci KF, Levin WJ, Habib MA. Acute bacterial sinusitis. Pessey 2001 {published data only}
Minocycline vs amoxicillin. Archives of Otolaryngology - Pessey JJ. Pristinamycin in the outpatient treatment of
Head and Neck Surgery 1986;112(1):73–6. [MEDLINE: acute sinusitis in adults [Place de la pristinamycine dans le
86076561] traitement des sinusites aigues de l’adulte en ville]. Presse
Meltzer 2005 {published and unpublished data} Medicale 1999;28(Suppl 1):10–2. [MEDLINE: 99436765]
∗
Meltzer EO, Bachert C, Staudinger H. Treating acute ∗
Pessey JJ, Gehanno P, Dabernat H. Pristinamycin versus
rhinosinusitis: comparing efficacy and safety of mometasone cefuroxime axetil in the treatment of acute sinusitis in adults.
furoate nasal spray, amoxicillin, and placebo. Journal of Medicine et Maladies Infectieuses 2001;31(6):425–32.
Allergy and Clinical Immunology 2005;116:1289–95.
Meltzer EO, Gates D, Bachert C. Mometasone furoate nasal Rakkar 2001 {published data only}
spray increases the number of minimal-symptom days in Rakkar S, Roberts K, Towe BF, Flores SM, Heyd A,
patients with acute rhinosinusitis. Annals of Allergy, Asthma Warner J. Moxifloxacin versus amoxycillin clavulanate in
& Immunology 2012;108:275–9. the treatment of acute maxillary sinusitis: a primary care
experience. International Journal of Clinical Practice 2001;
Merenstein 2005 {published and unpublished data} 55(5):309–15.
Merenstein D, Whittaker C, Chadwell T, Wegner B,
D’Amico F. Are antibiotics beneficial for patients with Riffer 2005 {published data only}
sinusitis complaints? A randomized double-blind clinical Riffer E, Spiller J, Palmer R, Shortridge V, Busman TA,
trial. Journal of Family Practice 2005;54(2):144–51. Valdes J. Once daily clarithromycin extended-release vs
twice-daily amoxicillin/clavulanate in patients with acute
Murray 2005 {published data only}
bacterial sinusitis: a randomized, investigator-blinded study.
Murray JJ, Emparanza P, Lesinskas E, Tawadrous M, Breen
Current Medical Research and Opinion 2005;21(1):61–70.
JD. Efficacy and safety of a novel, single-dose azithromycin
microsphere formulation versus 10 days of levofloxacin Russell 1997 {published data only}
for the treatment of acute bacterial sinusitis in adults. Russell MD, Nolen T, Allen JM, Skuba K, De Regis
Otolaryngology - Head and Neck Surgery 2005;133:194–201. RG, Nicaise C. Cefprozil versus amoxicillin/clavulanate
in the treatment of acute, uncomplicated maxillary
Nyffenegger 1991 {published data only}
sinusitis in adults. A randomized, prospective clinical trial.
Nyffenegger R, Riebenfeld D, Macciocchi A. Brodimoprim
Infections in Medicine 1997;14(Suppl):43–50. [MEDLINE:
versus amoxicillin in the treatment of acute sinusitis.
1998004027]
Clinical Therapeutics 1991;13(5):589–95. [MEDLINE:
92191253] Sher 2002 {published data only}
O’Doherty 1996 {published data only} Sher LD, McAdoo MA, Bettis RB, Turner MA, Li NF, Pierce
O’Doherty B. An open comparative study of azithromycin PF. A multicenter, randomized, investigator-blinded study
versus cefaclor in the treatment of patients with upper of 5- and 10-day gatifloxacin versus 10-day amoxicillin/
respiratory tract infections. Journal of Antimicrobial clavulanate in patients with acute bacterial sinusitis. Clinical
Chemotherapy 1996;37(Suppl C):71–81. [MEDLINE: Therapeutics 2002;24(2):269–81.
96415941] Siegert 2000 {published data only}
Olmo 1994 {published data only} Siegert R, Gehanno P, Nikolaidis P, Bagger-Sjöbäck D,
Olmo A, Sabater F, Broto J, Traserra J. Amoxicillin/ Ibanez JM, Hampel B, et al.A comparison of the safety and
clavulanic acid versus cefuroxime axetil in acute sinusitis efficacy of moxifloxacin (BAY 12-8039) and cefuroxime
axetil in the treatment of acute bacterial sinusitis in adults. sinusitis. Lancet 1997;349(9053):683–7. [MEDLINE:
Respiratory Medicine 2000;94:337–44. [MEDLINE: 97232963]
20302041] von Sydow 1995 {published data only}
Siegert 2003 {published data only} von Sydow C, Savolainen S, Söderqvist A. Treatment of
Siegert R, Berg O, Gehanno P, Leiberman A, Martinkenas acute maxillary sinusitis-comparing cefpodoxime proxetil
JL, Nikolaidis P, et al.Comparison of the efficacy and with amoxicillin. Scandinavian Journal of Infectious Diseases
safety of faropenem daloxate and cefuroxime axetil for the 1995;27(3):229–34. [MEDLINE: 96143362]
treatment of acute bacterial maxillary sinusitis in adults.
European Archives of Oto-Rhino-Laryngology 2003;260(4): References to studies excluded from this review
186–94.
Agbim 1974 {published data only}
SSG 1993 {published data only} Agbim OG. A comparative study of doxycycline and
Scandinavian Study Group. Loracarbef versus doxycycline ampicillin in the treatment of acute sinusitis. Chemotherapy
in the treatment of acute bacterial maxillary sinusitis. 1975;21(Suppl 1):68–75.
Journal of Antimicrobial Chemotherapy 1993;31(6):949–61. ∗
Agbim OG. A comparative trial of doxycycline
[MEDLINE: 93366716] (’Vibramycin’) and ampicillin in the treatment of acute
Stefansson 1998 {published data only} sinusitis. Current Medical Research and Opinion 1974;2(5):
Stefansson P, Jacovides A, Jablonicky P, Sedani S, Staley H. 291–4.
Cefuroxime axetil versus clarithromycin in the treatment Alvart 1992 {published data only}
of acute maxillary sinusitis. Rhinology 1998;36(4):173–8. Alvart R. An open multicentre study to compare the efficacy
[MEDLINE: 99121815] and safety of sultamicillin with that of cefuroxime axetil in
Sterkers 1997 {published data only} acute ear nose and throat infections in adults. Journal of
Sterkers O. Efficacy and tolerability of ceftibuten versus International Medical Research 1992;20(Suppl 1):53A–61A.
amoxicillin/clavulanate in the treatment of acute sinusitis. Axelsson 1971 {published data only}
Chemotherapy 1997;43(5):352–7. [MEDLINE: 97454963] Axelsson A, Chidekel N, Grebelius N, Jensen C, Särne S.
Treatment of acute maxillary sinusitis. II. A comparison
Steurer 2000 {published data only}
of five further methods. Acta Otolaryngologica (Stockholm)
Steurer M, Schenk P. Efficacy and safety of cefdinir in
1971;72(1):148–54.
the treatment of maxillary sinusitis. European Archives
of Otorhinolaryngology 2000;257:140–8. [MEDLINE: Axelsson 1973 {published data only}
20296297] Axelsson A, Chidekel N, Jensen C, Grebelius N, Singer F.
Treatment of acute maxillary sinusitis. Doxycycline and
Sydnor 1992 {published data only}
spiramycin with and without irrigation. Annals of Otology,
Nielsen RW. Acute bacterial maxillary sinusitis: results of
Rhinology and Laryngology 1973;82(2):186–91.
U.S. and European comparative therapy trials [review].
American Journal of Medicine 1992;92(Suppl 6A):70–3. Axelsson 1975 {published data only}
[MEDLINE: 92321191] Axelsson A, Grebelius N, Jensen C, Melin O, Singer F.
∗
Sydnor TA Jr, Scheld WM, Gwaltney J Jr, Nielsen Treatment of acute maxillary sinusitis. IV. Ampicillin,
RW, Huck W, Therasse DG. Loracarbef (LY 163892) vs cephradine and erythromycinestolate with and without
amoxicillin/clavulanate in bacterial maxillary sinusitis. Ear, irrigation. Acta Otolaryngologica (Stockholm) 1975;79(5-6):
Nose and Throat Journal 1992;71(5):225–32. [MEDLINE: 466–72.
92371213] Axelsson 1981 {published data only}
Upchurch 2006 {published data only} Axelsson A, Jensen C, Melin O, Singer F, von Sydow C.
Upchurch J, Rosemore M, Tosiello R, Kowalsky S, Echols Treatment of acute maxillary sinusitis. V. Amoxicillin,
R. Randomized double-blind study comparing 7- and azidocillin, phenylpropanolamine and pivampicillin. Acta
10-day regimens of faropenem medoxomil with a 10-day Otolaryngologica (Stockholm) 1981;91(3-4):313–8.
cefuroxime axetil regimen for treatment of acute bacterial Bandak 1999 {published data only}
sinusitis. Otolaryngology - Head and Neck Surgery 2006;135 Bandak S, Bolzon L, Johns D, Henle S, Allen B.
(4):511–7. Cefaclor advanced formulation 750mg twice daily versus
van Buchem 1997 {published data only} clarithromycin 500mg twice daily in the treatment of acute
Van Buchem F, Knottnerus J, Schrijnemaekers V, Peeters maxillary sinusitis. Current Therapeutic Research 1999;60
M. No benefit of antibiotic treatment in acute maxillary (4):185–94.
sinusitis: a randomized double-blind placebo-controlled Beatson 1985 {published data only}
study. Nederlands Tijdschrift Voor Geneeskunde 1997;141 Beatson JM, Marsh BT, Talbot DJ. A clinical comparison
(49):2405–11. of pivmecillinam plus pivampicillin (Miraxid) and a triple
∗
van Buchem FL, Knottnerus JA, Schrijnemaekers VJ, tetracycline combination (Deteclo) in respiratory infections
Peeters MF. Primary-care-based randomised placebo- treated in general practice. Journal of International Medical
controlled trial of antibiotic treatment in acute maxillary Research 1985;13(4):197–202.
Bockmeyer 1994 {published data only} Ekedahl 1987 {published data only}
Bockmeyer M, Riebenfeld D, Clasen B. Controlled study of Ekedahl C. [Akute Sinusitis bei Erwachsenen]. Infection
brodimoprim and cephalexin in the treatment of patients 1987;15(Suppl 3):120–2.
with acute sinusitis in general practice. Clinical Therapeutics Elies 2001 {published data only}
1994;16(4):653–61. Elies W. Short course therapy with cefuroxime axetil
Brodie 1989 {published data only} for five days in comparison to ten days of therapy
Brodie DP, Knight S, Cunningham K. Comparative study with clarithromycin in acute sinusitis [Kurzzeittherapie
of cefuroxime axetil and amoxicillin in the treatment of mit cefuroximaxetil uber funf tage im vergleich zur
acute sinusitis in general practice. Journal of International zehn–tage–therapie mit clarithromycin bei akuter sinusitis].
Medical Research 1989;17(6):547–51. Chemotherapie Journal 2001;10(3):105–9.
Brook 2006 {published data only} Falser 1988 {published data only}
Brook I, Hausfeld JN. Effect of telithromycin and Falser N, Mittermayer H, Weuta H. Antibacterial treatment
azithromycin on nasopharyngeal bacterial flora in patients of otitis and sinusitis with ciprofloxacin and penicillin V. A
with acute maxillary sinusitis. Archives of Otolaryngology - comparison. Infection 1988;16(Suppl 1):51–4.
Head & Neck Surgery 2006;132(4):442–5.
Federspil 1983 {published data only}
Bucher 2003 {published data only} Federspil P, Koch J. Double-blind comparative trial
Bucher HC, Tschudi P, Young J, Periat P, Welge-Luussen A, of trimethoprim/sulfamethopyrazine once daily vs
Zust H, et al.Effect of amoxicillin-clavulanate in clinically erythromycin 4 x daily in patients with ENT infections.
diagnosed acute rhinosinusitis: a placebo-controlled, International Journal of Clinical Pharmacology, Therapy, and
double-blind, randomized trial in general practice. Archives Toxicology 1983;21(10):535–9.
of Internal Medicine 2003;163(15):1793–8.
Felstead 1991 {published data only}
Carenfelt 1975 {published data only} Felstead SJ, Daniel R. Short-course treatment of sinusitis and
Carenfelt C, Eneroth CM, Lundberg C, Wretlind B. other upper respiratory tract infections with azithromycin:
Evaluation of the antibiotic effect of treatment of maxillary a comparison with erythromycin and amoxycillin. European
sinusitis. Scandinavian Journal of Infectious Diseases 1975;7 Azithromycin Study Group. Journal of International Medical
(4):259–64. Research 1991;19(5):363–72.
Casiano 1991 {published data only}
Fiscella 1991 {published data only}
Casiano RR. Azithromycin and amoxicillin in the treatment
Fiscella RG, Chow JM. Cefixime for treatment of maxillary
of acute maxillary sinusitis. American Journal of Medicine
sinusitis. American Journal of Rhinology 1991;5(5):193–7.
1991;91(Suppl 3A):27–30.
Freche 1988 {published data only}
Correa 1986 {published data only}
Freche C, Fombeur JP, Pappo M. Evaluation du cefuroxime-
Correa A, Hernandez C. Estudio comparativo de la
axetil dans le traitement des sinusites aigues de l’adulte.
asociacion trimetoprim - sulfametopirazina y amoxocilina
Etude comparative avec le cefaclor. Therapie 1988;43(Suppl
en sinusitis maxilar aguda. Revista Medica de Chile 1986;
4):365–8.
114(3):215–20.
Gananca 1973 {published data only}
De Abate 1992 {published data only}
Gananca M, Trabulsi LR. The therapeutic effects of
De Abate CA, Perrotta RJ, Dennington ML, Ziering RM.
cyclacillin in acute sinusitis: in vitro and in vivo correlations
The efficacy and safety of once-daily ceftibuten compared
in a placebo-controlled study. Current Medical Research and
with co-amoxiclav in the treatment of acute bacterial
Opinion 1973;1(6):362–8.
sinusitis. Journal of Chemotherapy 1992;4(6):358–63.
Gananca 1977 {published data only}
De Sutter 2002 {published and unpublished data}
Gananca M, Gasel J. A double-blind study with the
De Sutter A, Lemiengre M, Van Maele G, van Driel M, De
association tetracycline, acetylsalicylic acid, phenacetin,
Meyere M, Christiaens T, et al.Predicting prognosis and
caffeine and phenyltoloxamine in the treatment of acute
effect of antibiotic treatment in rhinosinusitis. Annals of
sinusitis. Folha Medica 1977;75(5):583–5.
Family Medicine 2006;4(6):486–93.
∗
De Sutter AI, De Meyere MJ, Christiaens TC, Van Driel Garcia 1998 {published data only}
ML, Peersman W, De Maeseneer JM. Does amoxicillin Garcia C, Velert V, Orts A, Pardo M, Esparcia N.
improve outcomes in patients with purulent rhinorrhea? Comparison of azithromycin, amoxicillin/clavulanic acid
A pragmatic randomized double-blind controlled trial in and cefaclor in the treatment of acute ENT infections
family practice. Journal of Family Practice 2002;51(4): [Comparacion de azithromicina, amoxicilina/acido
317–23. clavulanico y cefaclor en el tratamiento de la infeccion
Edelstein 1993 {published data only} aguda otorrinolaringologica]. Acta Otorrinolaringologica
Edelstein DR, Avner SE, Chow JM, Duerksen RL, Johnson Espanola 1998;49(4):306–12.
J, Ronis M, et al.Once-a-day therapy for sinusitis: a Gladkov 1979 {published data only}
comparison study of cefixime and amoxicillin. Laryngoscope Gladkov AA, Andrijchuk AI, Neporada VP. Sravnitel’naia
1993;103(1 Pt 1):33–41. effektivnost’ lecheniia bol’nykh ostrym i khronicheskim
gnoinym vospaleniem verkhnecheliustnoi pazukhi Jeppesen 1970 {published data only}
rastvorami dekametoksina, formal’degida i penitsillina. Jeppesen F, Schaldemose HJ. Doxycycline (Vibramycin)
Zhurnal Ushnykh, Nosovykh i Gorlovykh Boleznei 1979;3: in the treatment of sinusitis [Doxycyclinum (Vibramycin)
21–5. i behandlingen af sinuitis]. Ugeskrift for Laeger 1970;132:
437–43.
Goumas 1997 {published data only}
Goumas P, Naxakis S, Bassaris C, Skoutelis A. Comparative Johnson 1999 {published data only}
efficacy and tolerability of clarithromycin and cefaclor in Johnson PA, Rodriquez HP, Wazen JJ, Huck W, Shan M,
the treatment of outpatients with acute maxillary sinusitis. Tosiello R, et al.Ciprofloxacin versus cefuroxime axetil in
Clinical Drug Investigation 1997;13(3):128–33. the treatment of acute bacterial sinusitis. Sinusitis Infection
Study Group. Journal of Otolaryngology 1999;28(1):3–12.
Gurdogan 2001 {published data only}
Karpov 1998 {published data only}
Gurdogan K, Senol E. Comparison of 3-day course of
Karpov OI. The clinical and economic efficacies of short
azithromycin with penicillin V and amoxicillin+clavulanate
courses of azithromycin in acute sinusitis. Antibiotiki i
in the treatment of upper respiratory tract infections [Ust
Khimioterapiia 1999;44(10):28–32.
solunum yolu enfeksiyonlarinin tedavisinde uc gun sureli ∗
Karpov OI, Riabova MA, Karpishchenko SA, Zaitseva
azitromisin ile penisilin V ve amoksisilin+klavulonatin
AA. Comparative trial of 3-day azithromycin versus 10-day
karsilastirilmasi]. Mikrobiyoloji Bulteni 2001;35(2):239–43.
coamoxilav course efficacy in acute sinusitis. Terapevticheskii
Gwaltney 1981 {published data only} Arkhiv 1998;70(5):72–6.
∗
Gwaltney JM Jr, Sydnor A Jr, Sande MA. Etiology and Klein 1998 {published data only}
antimicrobial treatment of acute sinusitis. Annals of Otology, Klein GL, Whalen E, Echols RM, Heyd A. Ciprofloxacin
Rhinology and Laryngology 1981;90(Suppl 84):68–71. versus cefuroxime axetil in the treatment of adult patients
Hamory BH, Sande MA, Sydnor A Jr, Seale DL, Gwaltney with acute bacterial sinusitis. Journal of Otolaryngology
JM Jr. Etiology and antimicrobial therapy of acute 1998;27(1):10–6.
maxillary sinusitis. Journal of Infectious Diseases 1979;139 Lacroix 2002 {published data only}
(2):197–202. Kaiser L, Morabia A, Stalder H, Ricchetti A, Auckenthaler
Hansen 2000 {published data only} R, Terrier F, et al.Role of nasopharyngeal culture in
Hansen J, Schmidt H, Grinsted P. [Penicillinbehandling af antibiotic prescription for patients with common cold or
akut kaebehulebetaendelse hos voksne]. Ugeskrift for Laeger acute sinusitis. European Journal of Clinical Microbiology &
2000;162(40):5351–3. infectious Diseases 2001;20(7):445–51.
∗
Hansen JG, Schmidt H, Grinsted P. Randomised, double
∗
Lacroix JS, Ricchetti A, Lew D, Delhumeau C, Morabia
blind, placebo controlled trial of penicillin V in the A, Stalder H, et al.Symptoms and clinical and radiological
treatment of acute maxillary sinusitis in adults in general signs predicting the presence of pathogenic bacteria in acute
practice. Scandinavian Journal of Primary Health Care 2000; rhinosinusitis. Acta Oto-Laryngologica 2002;122(2):192–6.
18:44–7. [MEDLINE: 20269180] Li 2000 {published data only}
Hebblethwaite 1987 {published data only} Li XP, Qin ZM, Zheng RH, Tan QL, Zhou YY, Zhu
Hebblethwaite EM, Brown GW, Cox DM. A comparison of L, et al.Comparison of the effectiveness of levofloxacin
the efficacy and safety of cefuroxime axetil and augmentin and cefuroxime for the treatment of sinusitis. Lin
in the treatment of upper respiratory tract infections. Drugs Chuang Erh Pi Yen Hou Ko Tsa Chih (Journal of Clinical
Under Experimental and Clinical Research 1987;13(2):91–4. Otorhinolaryngology) 2000;14(12):573–5.
Lopez 1975 {published data only}
Henry 1999a {published data only}
Lopez Rubio A, Estrada Velasco A, Ibarra J, Lazos O.
Henry DC, Moller DJ, Adelglass J, Scheld WM, Jablonski
[Antibioticoterapia de espectro intermedio en infecciones
CK, Zhang H, et al.Comparison of sparfloxacin and
O.R.L]. Prensa Medica Mexicana 1975;40(7-8):256–8.
clarithromycin in the treatment of acute bacterial maxillary
sinusitis. Sparfloxacin Multicenter AMS Study Group. Luchikhin 2005 {published data only}
Clinical Therapeutics 1999;21(2):340–52. Luchikhin LA, Troitskii SA. Etiotropic therapy with
sparfioxamine in ENT practice. Vestnik Otorinolaringologii
Henry 1999b {published data only} 2005;6:43–5.
Henry DC, Sydnor A Jr, Settipane GA, Allen J, Burroughs Mannhardt 1980 {published data only}
S, Cobb MM, et al.Comparison of cefuroxime axetil and Mannhardt J, Held J. Eine randomisierte Vergleichsstudie
amoxicillin/clavulanate in the treatment of acute bacterial der therapeutischen Wirkung von amoxicillin und
sinusitis. Clinical Therapeutics 1999;21(7):1158–70. doxycyclin bei Sinusitis. Therapiewoche 1980;30:2087–9.
Husfeldt 1993 {published data only} Manzini 1993 {published data only}
Husfeldt P, Egede F, Nielsen PB. Antibiotic treatment Manzini M, Caroggio A. Efficacy and tolerability of
of sinusitis in general practice. A double-blind study brodimoprim and roxithromycin in acute sinusitis of
comparing ofloxacin and erythromycin. European Archives bacterial origin in adults. Journal of Chemotherapy 1993;5
of Otorhinolaryngology 1993;250(Suppl 1):S23–5. (6):521–5.
Marchi 1990 {published data only} Panosetti 1992 {published data only}
Marchi E. Comparative efficacy and tolerability of Panosetti E. Phlegmonous and abscess-forming ENT
clarithromycin and amoxycillin in the treatment of out- infections: comparative efficacy of ceftriaxone versus
patients with acute maxillary sinusitis. Current Medical amoxicillin-clavulanic acid. ORL - Journal for Oto-Rhino-
Research and Opinion 1990;12(1):19–24. Laryngology and its Related Specialties 1992;54(2):95–9.
Marcolino 1999 {published data only} Peyramond 1991 {published data only}
Marcolino FMD, Ferracini NW, Gobbato LH, Hernandes Peyramond D, Abenhaim N, Chiche D. Community
MAR. Open comparative study of the efficacy and acquired respiratory infections: cefuroxime axetil
tolerability of azithromycin versus amoxycillin in the versus amoxicillin/clavulanic acid [Etude du traitement
treatment of acute rhinosinusitis [Estudo comparativo e antibiotique des infections respiratoires acquises en ville:
aberto sobre a eficacia e a tolerabilidade da azithromicina vs cefuroxime axetil vs amoxicilline/acide clavulanique].
amoxicilina em rinossinusites agudas em adultos]. Revista Medecine et Maladies Infectieuses 1991;21(Special Issue):
Brasileira de Medicina 1999;56(4):294–8. 98–102.
Mesure 1973 {published data only} Piragine 1988 {published data only}
Mesure R. [Essai en double aveugle de l’association de Piragine F, Sellari-Franceschini S, Berrettini S, Bruschini P,
sulfamethoxazole et de trimethoprime dans les infections Grossi P. Amoxicillin-clavulanic acid combination in ORL
oto–rhino–laryngologiques]. Acta Otorhinolaryngologica infection with a proven bacterial etiology. Rivista Italiana
Belgica 1973;27(1):27–33. di Otorinolaringologia, Audiologia e Foniatria 1988;8(4):
Mira 2001 {published data only} 321–5.
Mira E, Benazzo M. A multicenter study on the clinical Podvinec 1982 {published data only}
efficacy and safety of roxithromycin in the treatment of Podvinec M. [Co–tetroxazin (Tibirox) und Doxycyclin
ear-nose-throat infections: comparison with amoxycillin/ (Vibramycin) in der Behandlung von Infekten der Oberen
clavulanic acid. Journal of Chemotherapy 2001;13(6):621–7. Luftwege: eine Doppelblindstudie]. Therapeutische
Miyamoto 2005 {published data only} Umschau 1982;39(10):815–20.
Miyamoto N, Murakami S, Watanabe N, Ozeki M. Polonovski 2006 {published data only}
Bacteriological and clinical evaluation of azithromycin and Polonovski JM, El Mellah M. Treatment of acute maxillary
cefcapene-pivoxil in otorhinolaryngological infections. sinusitis in adults. Comparison of cefpodoxime-proxetil
Japanese Journal of Chemotherapy 2005;53(7):417–20. and amoxicillin-clavulanic acid. Presse Medicale 2006;35(1
Moorhouse 1985 {published data only} Pt 1):33–8.
Moorhouse EC, Hickey MP, O’Hanrahan MT, Clarke PC. Quick 1973 {published data only}
General practice studies with combined pivampicillin/ Quick CA, Wagner D. Trimethoprim-sulfamethoxazole in
pivmecillinam (Miraxid). Irish Medical Journal 1985;78 the treatment of infections of the ears, nose and throat.
(11):314–7. Journal of Infectious Diseases 1973;128(Suppl):696–700.
Norrelund 1978 {published data only} Quick 1975 {published data only}
Norrelund N. [Behandling af sinusitis i almenpraksis. En Quick CA. Comparison of penicillin and trimethoprim-
kontrolleret undersogelse over pivampicillin (Pondocillin)]. sulfamethoxazole in the treatment of ear, nose and throat
Ugeskrift for Laeger 1978;140(45):2792–5. infections. Canadian Medical Association Journal 1975;112
Olsson 1976 {published data only} (13 Spec No):83–6.
Olsson O, Henning C. Clinical study on bacampicillin Rantanen 1973 {published data only}
in otitis media acuta and sinusitis acuta. Penicillins and Rantanen T, Arvilommi H. Double-blind trial of doxicycline
cephalosporins. In: Williams JD, Geddes AM editor(s). in acute maxillary sinusitis. A clinical and bacteriological
Chemotherapy. Vol. 5, New York: Plenum Press, 1976: study. Acta Otolaryngologica (Stockholm) 1973;76(1):58–62.
145–50.
Rechtweg 2004 {published data only}
Osman 1983 {published data only}
Rechtweg J, Moinuddin R, Houser S, Mamikoglu B, Corey
Osman MF, Menday AP. Single-blind comparison of
J. Quality of life in treatment of acute rhinosinusitis with
miraxid and co-trimoxazole in patients with sinusitis and
clarithromycin and amoxicillin/clavulanate. Laryngoscope
otitis. Proceedings of the 13th International Congress of
2004;114(5):806–10.
Chemotherapy. Vienna, 1983; Vol. 1, issue 1–5:26–9.
Riedel 1987 {published data only}
Pallestrini 1995 {published data only}
Riedel H, Schmidt A, Upmeyer HJ. Is supplementary
Pallestrini E, Cimino A, Colletti V, Conticello S, De
antibiotic treatment of sinusitis advantageous?.
Campora E, De Martini E, et al.[Rufloxacina in confronto a
Therapiewoche 1987;37:4189–97.
claritromicina nel trattamento short–term delle patologie
infettive di interesse otorinolaringoiatrico]. Rivista Italiana Rimmer 1997 {published data only}
di Otorinolaringologia, Audiologia e Foniatria 1995;15(3): Rimmer D, Suprax/Amoxicillin Clinical Study Team.
236–45. Efficacy of cefixime and amoxicillin in adults with
acute sinusitis. A Special Report. Sinusitis: optimizing Stalman 1997a {published data only}
management strategies. Postgraduate Medicine 1998:50–7. ∗
Stalman W, van Essen GA, van der Graaf Y, de Melker
RA. The end of antibiotic treatment in adults with acute
Roenning 1987 {published data only}
sinusitis-like complaints in general practice? A placebo-
Roenning Arnesen A, Spada L. Double-blind comparison
controlled double-blind randomized doxycycline trial.
of spiramycin and phenoxymethylpenicillin in treatment
British Journal of General Practice 1997;47(425):794–9.
of upper respiratory tract infections (tonsillitis and
rhinosinusitis). Chemioterapia 1987;6(Suppl 2):451–2. Strachunskii 1993 {published data only}
Strachunskii LS, Tikhonov VG, Kuleshov SE, Asmolovski
Sabater 1995 {published and unpublished data} VM. [Sravnitel’naia klinicheskaia effektivenost’ i
Sabater F, Larrosa F, Guiroa M, Ciges M, Figuerola A, perenosimost’ azitromitsina (sumamded) i eritromitsina u
Fernandez F. Cefpodoxime proxetil (5 days) vs amoxicillin/ bol’nykh s sinusitami]. Antibiotiki i Khimioterapiia 1993;38
clavulanic acid (8 days) in the treatment of acute maxillar- (1):13–6.
ethmoidal sinusitis in adult outpatients. Canadian Journal Sydnor 1989 {published data only}
of Infectious Diseases 1995;6(Suppl C):Abstract 3100. Sydnor A Jr, Gwaltney JM Jr, Cocchetto DM, Scheld WM.
Salmi 1986 {published data only} Comparative evaluation of cefuroxime axetil and cefaclor
Salmi HA, Lehtomäki K, Kylmämaa T. Comparison of for treatment of acute bacterial maxillary sinusitis. Archives
brodimoprim and doxycycline in acute respiratory tract of Otolaryngology - Head and Neck Surgery 1989;115(12):
infections. A double-blind clinical trial. Drugs Under 1430–3.
Experimental and Clinical Research 1986;12(4):349–53. Taub 1967 {published data only}
Taub SJ. The use of bromelains in sinusitis: a double-blind
Salmi 1993 {published data only} clinical evaluation. Eye, Ear, Nose and Throat Monthly 1967;
Salmi HA. Brodimoprim in acute respiratory tract 46(3):361–5.
infections. Journal of Chemotherapy 1993;5(6):532–6. Varonen 2003a {published data only}
Schering-Plough 2003 {unpublished data only} Varonen H, Kunnamo I, Savolainen S, Mäkelä M, Revonta
Schering-Plough Research Institute. Efficacy and safety M, Ruotsalainen J, et al.Treatment of acute rhinosinusitis
of 200 mcg QD or 200 mcg BID mometasone fuorate diagnosed by clinical criteria or ultrasound in primary
(MFNS) vs. amoxicillin vs. placebo as primary treatment care. A placebo-controlled randomised trial. Scandinavian
of subjects with acute rhinosinusitis (Protocol P02692). Journal of Primary Health Care 2003;21:121–6.
Kenilworth: Schering-Plough Research Institute 2003. von Sydow 1984 {published data only}
von Sydow C, Axelsson A, Jensen C. Treatment of acute
Serra 2007 {published data only}
maxillary sinusitis. Erythromycin base and phenoxymethyl-
Serra A, Schito GC, Nicoletti G, Fadda G. A therapeutic
penicillin (penicillin V). Rhinology 1984;22(4):247–54.
approach in the treatment of infections of the upper airways:
thiamphenicol glycinate acetylcysteinate in sequential Wallace 1985 {published data only}
treatment (systemic-inhalatory route). International Journal Wallace RB, Marsh BT, Talbot DJ. A multi-centre
of Immunopathology and Pharmacology 2007;20(3):607–17. general practice clinical evaluation of pivmecillinam plus
pivampicillin (’Miraxid’) and co-trimoxazole (’Septrin’) in
Söderström 1991 {published data only} respiratory tract infections. Current Medical Research and
Söderström M, Blomberg J, Christensen P, Hovelius B. Opinion 1985;9(10):659–65.
Erythromycin and phenoxymethylpenicillin (penicillin V) Weis 1998 {published data only}
in the treatment of respiratory tract infections as related Weis M, Hendrick K, Tillotson G, Gravelle K, Rhinosinusitis
to microbiological findings and serum C-reactive protein. Investigation Group. Multicenter comparative trial of
Scandinavian Journal of Infectious Diseases 1991;23(3): ciprofloxacin versus cefuroxime axetil in the treatment of
347–54. acute rhinosinusitis in a primary care setting. Clinical
Spindler 1985 {published data only} Therapeutics 1998;20(5):921–32.
Spindler JJ, Marsh BT, Talbot DJ. Respiratory infections in Westerman 1975 {published data only}
general practice. A clinical comparison of pivmecillinam- Westerman T, Panzer JD, Atkinson WH. Comparative
plus-pivampicillin (Miraxid) and cephalexin (Ceporex). efficacy of clindamycin HC1 and tetracycline HCl in acute
Clinical Trials Journal 1985;22(4):293–9. sinusitis. Eye, Ear and Nose Monthly 1975;54(6):236–8.
Stahl 1989 {published data only} Williamson 2007 {published and unpublished data}
Stahl JP, Pappo M. A multicenter randomized trial of Williamson IG, Rumsby K, Benge S, Moore M, Smith
cefuroxime-axetil versus amoxicillin with clavulanic acid PW, Cross M, et al.Antibiotics and topical nasal steroid for
in community-acquired ENT and lower respiratory tract treatment of acute maxillary sinusitis. JAMA 2007;298(21):
infections [Etude comparative du cefuroxime–axetil versus 2487–96.
l’association d’amoxicilline et d’acide clavulanique dans les Young 2003 {published data only}
infections ORL et bronchiques]. Semaine des Hopitaux ∗
Young J, Bucher H, Tschudi P, Periat P, Hugenschmidt C,
1989;65(5):247–51. Welge-Lussen A. The clinical diagnosis of acute bacterial
rhinosinusitis in general practice and its therapeutic Berg 1986
consequences. Journal of Clinical Epidemiology 2003;56: Berg O, Carenfelt C, Rystedt G, Änggård A. Occurrence
377–84. of asymptomatic sinusitis in common cold and other acute
Young J, Tschudi P, Periat P, Hugenschmidt C, Welge- ENT-infections. Rhinology 1986;24:223–5.
Lussen A, Bucher HC. Patients’ expectations about the Bhandari 2004
benefit of antibiotic treatment: lessons from a randomised Bhandari M, Busse JW, Jackowski D, Montori VM,
controlled trial. Forschende Komplementärmedizin und Schunemann H, Spraque S, et al.Association between
Klassische Naturheilkunde 2005;12:347–9. industry funding and statistically significant pro-industry
Zbären 1983 {published data only} findings in medical and surgical randomized trials.
Zbären P, Pradervand M. [Etude clinique comparative en Canadian Medical Association Journal 2004;170(4):477–80.
double aveugle entre co–tetroxacine et amoxicilline dans les Bronzwaer 2002
infections ORL courantes]. Schweizerische Rundschau fur Bronzwaer SL, Cars O, Buchholz U, Mölstad S, Goettsch W,
Medizin Praxis 1983;72(47):1491–3. Veldhuijzen IK, et al.A European study on the relationship
between antimicrobial use and antimicrobial resistance.
Additional references Emerging Infectious Diseases 2002;8(3):278–82.
Chokkalingam 1998
Ah-See 2007
Chokkalingam A, Scherer R, Dickersin K. Agreement of
Ah-See KW, Evans AS. Sinusitis and its management. BMJ
data in abstracts compared to full publications. Controlled
2007;334:358–61.
Clinical Trials 1998;19(Suppl):61–2.
Albrich 2004 de Bock 1997
Albrich WC, Monnet DL, Harbarth S. Antibiotic selection de Bock GH, Dekker FW, Stolk J, Springer MP, Kievit J,
pressure and resistance in Streptococcus pneumoniae and van Houwelingen JC. Antimicrobial treatment in acute
Streptococcus pyogenes. Emerging Infectious Diseases 2004; maxillary sinusitis: a meta-analysis. Journal of Clinical
10(3):514–7. Epidemiology 1997;50(8):881–90.
Andre 2002 de Ferranti 1998
Andre M, Odenholt I, Schwan Å, The Swedish Study Group de Ferranti SD, Ioannidis JPA, Lau J, Anninger WV, Barza
on Antibiotic Use. Upper respiratory tract infections in M. Are amoxycillin and folate inhibitors as effective as other
general practice: diagnosis, antibiotic prescribing, duration antibiotics for acute sinusitis? A meta-analysis. BMJ 1998;
of symptoms and use of diagnostic tests. Scandinavian 317:632–7.
Journal of Infectious Diseases 2002;34(12):880–6.
EARSS 2008
Arason 1996 The European Antimicrobial Resistance Surveillance
Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, System. EARSS interactive database. http://www.rivm.nl/
Mölstad S, Gudmundsson S. Do antimicrobials increase the earss/database (accessed August 2010).
carriage rate of penicillin resistant pneumococci in children? ECRP 2000
Cross sectional prevalence study. BMJ 1996;313:387–91. European Commission on Radiation Protection 118.
Arason 2005 Referral guidelines for imaging. http://ec.europa.eu/energy/
Arason VA, Sigurdsson JA, Kristinsson KG, Getz L, nuclear/radioprotection/publication/doc/118˙en.pdf
Gudmundsson S. Otitis media, tympanostomy tube (accessed June 2010).
placement, and use of antibiotics. Scandinavian Journal of Falagas 2008a
Primary Health Care 2005;23(3):184–91. Falagas ME, Giannopoulou KP, Vardakas KZ, Dimopoulos
G, Karageorgopoulos DE. Comparison of antibiotics with
Axelsson 1972
placebo for treatment of acute sinusitis: a meta-analysis
Axelsson A, Chidekel N. Symptomatology and bacteriology
of randomised controlled trials. Lancet Infectious Diseases
correlated to radiological findings in acute maxillary
2008;8:543–52.
sinusitis. Acta Otolaryngologica 1972;74:118–22.
Falagas 2008b
Bekelman 2003 Falagas ME, Karageorgopoulos DE, Grammatikos AP,
Bekelman JE, Li Y, Gross CP. Scope and impact of financial Matthaiou DK. Effectiveness and safety of short vs. long
conflicts of interest in biomedical research: a systematic duration of antibiotic therapy for acute bacterial sinusitis:
review. JAMA 2003;289(4):454–65. a meta-analysis of randomized trials. British Journal of
Benninger 2000 Clinical Pharmacology 2008;67(2):161–71.
Benninger MS, Sedory Holzer SE, Lau J. Diagnosis and Fokkens 2007
treatment of uncomplicated acute bacterial rhinosinusitis: Fokkens WJ, Lund VJ, Mullol J, on behalf of the European
Summary of the Agency for Health Care Policy and Position Paper on Rhinosinusitis and Nasal Polyps group.
Research evidence-based report. Otolaryngology - Head and European Position Paper on Rhinosinusitis and Nasal
Neck Surgery 2000;122(1):1–7. Polyps. Rhinology 2007;45(Suppl 20):1–139.
Goossens 2005 Higgins 2003
Goossens H, Ferech M, Vander Stichele R, Elseviers M, Higgins JPT, Thompson SG, Deeks JJ, Altman DG.
for the ESAC Project Group. Outpatient antibiotic use in Measuring inconsistency in meta-analyses. BMJ 2003;327:
Europe and association with resistance: a cross-national 557–60.
database study. Lancet 2005;365:579–87. Higgins 2011a
GRADEpro 2008 Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8:
Brozek J, Oxman A, Schünemann H. GRADEpro Version Assessing risk of bias in included studies. In: Higgins JPT,
3.2 for Windows. 2008. Green S editor(s). Cochrane Handbook for Systematic Reviews
of Interventions. Version 5.1.0 [updated March 2011]. The
Guillemot 1998 Cochrane Collaboration. Available from www.cochrane-
Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, handbook.org. 5.1. Chichester, UK: Wiley-Blackwell, 2011.
Vauzelle-Kervroedan F, et al.Low dosage and long treatment
Higgins 2011b
duration of ß-lactam. Risk factors for carriage of penicillin-
Higgins JPT, Deeks JJ, Altman DG (editors). Chapter
resistant Streptococcus pneumoniae. JAMA 1998;279(5):
16: Special topics in statistics. In: Higgins JPT, Green
365–70.
S editor(s). Cochrane Handbook for Systematic Reviews of
Gwaltney 1992 Interventions. Version 5.1.0 [updated March 2011]. The
Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The Cochrane Collaboration. Available from www.cochrane-
microbial etiology and antimicrobial therapy of adults handbook.org. 5.1. Chichester, UK: Wiley-Blackwell, 2011.
with acute community-acquired sinusitis: a fifteen-year
Hopewell 2006
experience at the University of Virginia and review of other
Hopewell S, Clarke M, Askie L. Reporting of trials presented
selected studies. Journal of Allergy and Clinical Immunology
in conference abstracts needs to be improved. Journal of
1992;90:457–62.
Clinical Epidemiology 2006;59:681–4.
Gwaltney 1994
Howard 1976
Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK.
Howard JE, Nelson JD, Clahsen J, Jackson LH. Otitis
Computed tomographic study of the common cold. New
media of infancy and early childhood. A double-blind study
England Journal of Medicine 1994;330(1):25–30.
of four treatment regimens. American Journal of Diseases of
Gwaltney 1996 Children 1976;130(9):965–70.
Gwaltney JM Jr. Acute community-acquired sinusitis. Hsin 2010
Clinical Infectious Diseases 1996;23:1209–25. Hsin CH, Su MC, Tsao CH, Chuang CY, Liu CM.
Gwaltney 2004 Bacteriology and antimicrobial susceptibility of pediatric
Gwaltney JM Jr, Wiesinger BA, Patrie JT. Acute community- chronic rhinosinusitis: a 6-year result of maxillary sinus
acquired bacterial sinusitis: the value of antimicrobial punctures. American Journal of Otolaryngology 2010;31(3):
treatment and the natural history. Clinical Infectious Diseases 145–9.
2004;38:227–33. ICD-10
International Classification of Diseases (ICD-10). http://
Gwaltney 2005
apps.who.int/classifications/apps/icd/icd10online/ 2010
Gwaltney JM Jr. Sinusitis. In: Mandell GL, Bennett JE,
(accessed September 2010).
Dolin R editor(s). Mandell, Douglas, and Bennett’s Principles
and Practice of Infectious Diseases. Philadelphia: Elsevier, Ioannidis 2001
2005:772–83. Ioannidis JPA, Contopoulos-Ioannidis DG, Chew P, Lau
J. Meta-analysis of randomized controlled trials on the
Hansen 2012
comparative efficacy and safety of azithromycin against
Hansen FS, Hoffmans R, Georgalas C, Fokkens WJ.
other antibiotics for upper respiratory tract infections.
Complications of acute rhinosinusitis in The Netherlands.
Journal of Antimicrobial Chemotherapy 2001;48:677–89.
Family Practice 2012;29(2):147–53.
Ioannidis 2002
Hay 2005 Ioannidis JPA, Chew P, Lau J. Standardized retrieval of
Hay AD, Thomas M, Montgomery A, Wetherell M, side effects data for meta-analysis of safety outcomes.
Lovering A, McNulty C, et al.The relationship between A feasibility study in acute sinusitis. Journal of Clinical
primary care antibiotic prescribing and bacterial resistance Epidemiology 2002;55(6):619–26.
in adults in the community: a controlled observational
Ip 2005
study using individual patient data. Journal of Antimicrobial
Ip S, Fu L, Balk E, Chew P, DeVine D, Lau J. Update on
Chemotherapy 2005;56(1):146–53.
acute bacterial rhinosinusitis. Evidence Report/Technology
Hickner 2001 Assessment No. 124. AHRQ Publication No. 05-E020-
Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman 2. Rockville, MD: Agency for Healthcare Research and
JR, Sande MA. Principles of appropriate antibiotic use Quality 2005. [: Prepared by Tufts–New England Medical
for acute rhinosinusitis in adults: background. Annals of Center Evidence–based Practice Center under Contract No.
Internal Medicine 2001;134:498–505. 290–02–0022]
Joki-Erkkilä 2000 Margolis 2005
Joki-Erkkilä VP, Pukander J, Laippala P. Alteration of Margolis DJ, Bowe WP, Hoffstad O, Berlin JA. Antibiotic
clinical picture and treatment of pediatric acute otitis media treatment of acne may be associated with upper respiratory
over the past two decades. International Journal of Pediatric tract infections. Archives of Dermatology 2005;141(9):
Otorhinolaryngology 2000;55(3):197–201. 1132–6.
Jousimies-Somer 1988 Maxwell 2002
Jousimies-Somer HR, Savolainen S, Ylikoski JS. Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics
Bacteriological findings of acute maxillary sinusitis in increase functional abdominal symptoms. American Journal
young adults. Journal of Clinical Microbiology 1988;26(10): of Gastroenterology 2002;97(1):104–8.
1919–25.
Meltzer 2004
Kilkkinen 2002 Meltzer E, Hamilos D, Hadley J, Lanza D, Marple B,
Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen Nicklas R, et al.Rhinosinusitis: establishing definitions for
P, Adlercreutz H. Use of oral antimicrobials decreases clinical research and patient care. Journal of Allergy and
serum enterolactone concentration. American Journal of Clinical Immunology 2004;114(Suppl):155–212.
Epidemiology 2002;155(5):472–7.
Meltzer 2006
Kristo 2009
Meltzer E, Hamilos D, Hadley J, Lanza D, Marple B,
Kristo A, Uhari M. Timing of rhinosinusitis complications
Nicklas R, et al.Rhinosinusitis: developing guidance for
in children. Pediatric Infectious Disease Journal 2009;28(9):
clinical trials. Otolaryngology - Head and Neck Surgery 2006;
769–71.
135(Suppl):31–80.
Lanza 1997
Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Odenholt 2003
Otolaryngology - Head and Neck Surgery 1997;117(Suppl): Odenholt I, Gustafsson I, Löwdin E, Cars O. Suboptimal
1–7. antibiotic dosage as a risk factor for selection of penicillin-
Lawson 2008 resistant Streptococcus pneumoniae: in vitro kinetic model.
Lawson W, Patel ZM, Lin FY. The development and Antimicrobial Agents and Chemotherapy 2003;47(2):518–23.
pathologic processes that influence maxillary sinus Puhakka 1998
pneumatization. Anatomical Record (Hoboken) 2008;291 Puhakka T, Mäkelä MJ, Alanen A, Kallio T, Korsoff L,
(11):1554–63. Arstila P, et al.Sinusitis in the common cold. Journal of
Lefebvre 2011 Allergy and Clinical Immunology 1998;102(3):403–8.
Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching
Puhakka 2000
for studies. In: Higgins JPT, Green S editor(s). Cochrane
Puhakka T, Heikkinen T, Mäkelä MJ, Alanen A, Kallio T,
Handbook for Systematic Reviews of Interventions. Version
Korsoff L, et al.Validity of ultrasonography in diagnosis of
5.1.0 [updated March 2011]. The Cochrane Collaboration.
acute maxillary sinusitis. Archives of Otolaryngology - Head
Available from www.cochrane-handbook.org. 5.1. Chichester,
and Neck Surgery 2000;126(12):1482–6.
UK: Wiley-Blackwell, 2011.
Lemiengre 2012 Rautakorpi 1999
Lemiengre MB, van Driel ML, Merenstein D, Young Rautakorpi U-M, Lumio J, Huovinen P, Klaukka T.
J, de Sutter AIM. Antibiotics for clinically diagnosed Indication-based use of antimicrobials in Finnish primary
acute rhinosinusitis in adults. Cochrane Database of health care. Description of a method for data collection and
Systematic Reviews 2012, Issue 10. [DOI: 10.1002/ results of its application. Scandinavian Journal of Primary
14651858.CD006089.pub4] Health Care 1999;17(2):93–9.
Lexchin 2003 RevMan 2012

Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical The Nordic Cochrane Centre, The Cochrane Collaboration.
industry sponsorship and research outcome and quality: Review Manager (RevMan). 5.2. Copenhagen: The Nordic
systematic review. BMJ 2003;326:1167–70. Cochrane Centre, The Cochrane Collaboration, 2012.
Linder 2003 Rosenfeld 2007

Linder JA, Singer DE, van den Ancker M, Atlas SJ. Rosenfeld RM, Singer M, Jones S. Systematic review of
Measures of health-related quality of life for adults with antimicrobial therapy in patients with acute rhinosinusitis.
acute sinusitis. Journal of General Internal Medicine 2003; Otolaryngology - Head and Neck Surgery 2007;137(Suppl):
18:390–401. 32–45.
Low 1997 SAHP 2004
Low DE, Desrosiers M, McSherry J, Garber G, Williams Sinus and Allergy Health Partnership. Antimicrobial
JW Jr, Remy H, et al.A practical guide for the diagnosis and treatment guidelines for acute bacterial rhinosinusitis 2004.
treatment of acute sinusitis. Canadian Medical Association Otolaryngology - Head and Neck Surgery 2004;130(Suppl 1):
Journal 1997;156(Suppl 6):1–14. 1–50.

Seppälä 1995 a comparison of symptoms, signs, ultrasound, and
Seppälä H, Klaukka T, Lehtonen R, Nenonen E, Huovinen radiography. Rhinology 2003;41(1):37–43.
P. Outpatient use of erythromycin: link to increased Velicer 2004
erythromycin resistance in group A streptococci. Clinical Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson
Infectious Diseases 1995;21(6):1378–85. CA, Taplin SH. Antibiotic use in relation to the risk of
Slavin 2005 breast cancer. JAMA 2004;291(7):827–35.
Slavin RG, Spector SL, Bernstein IL, Sinusitis Update Williams 1993
Workgroup. The diagnosis and management of sinusitis. A Williams JW Jr, Simel DL. Does this patient have sinusitis?.
practice parameter update. Journal of Allergy and Clinical JAMA 1993;270(10):1242–6.
Immunology 2005;116(Suppl):13–47.
Wu 2009
Smith 1997 Wu AW, Shapiro NL, Bhattacharyya N. Chronic
Smith HS, Hughes JP, Hooton TM, Roberts P, Scholes D, rhinosinusitis in children: what are the treatment options?.
Stergachis A, et al.Antecedent antimicrobial use increases Immunology and Allergy Clinics of North America 2009;29
the risk of uncomplicated cystitis in young women. Clinical (4):705–17.
Infectious Diseases 1997;25(1):63–8. Young 2008
Snow 2001 Young J, De Sutter A, Merenstein D, van Essen GA, Kaiser
Snow V, Mottur-Pilson C, Hickner JM. Principles of L, Varonen H, et al.Antibiotics for adults with clinically
appropriate antibiotic use for acute sinusitis in adults. diagnosed acute rhinosinusitis: a meta-analysis of individual
Annals of Internal Medicine 2001;134(6):495–7. patient data. Lancet 2008;371:908–14.
Stalman 1997b References to other published versions of this review
Stalman W, van Essen GA, van der Graaf Y, de Melker
RA. Maxillary sinusitis in adults: an evaluation of placebo- Ahovuo-Saloranta 2008
controlled double-blind trials. Family Practice 1997;14(2): Ahovuo-Saloranta A, Borisenko OV, Kovanen N, Varonen
124–9. H, Rautakorpi U-M, Williams Jr JW, et al.Antibiotics
Steinke 2001 for acute maxillary sinusitis. Cochrane Database of
Steinke D, Davey P. Association between antibiotic Systematic Reviews 2008, Issue 2. [DOI: 10.1002/
resistance and community prescribing: a critical review 14651858.CD000243.pub2]
of bias and confounding in published studies. Clinical Ahovuo-Saloranta 2011
Infectious Diseases 2001;33(Suppl 3):193–205. Ahovuo-Saloranta A, Rautakorpi U-M, Borisenko OV, Liira
Sterne 2011 H, Williams Jr JW, et al.Antibiotics for acute maxillary
Sterne JAC, Egger M, Moher D (editors). Chapter 10: sinusitis. Cochrane Database of Systematic Reviews 2011,
Addressing reporting biases. In: Higgins JPT, Green S Issue 3. [DOI: 10.1002/14651858.CD000243.pub2]
editor(s). Cochrane Handbook for Systematic Reviews of Williams 1999
Intervention. Version 5.1.0 [updated March 2011]. The Williams Jr. JW, Aguilar C, Makela M, Cornell J,
Cochrane Collaboration. Available from www.cochrane- Hollman DR, Chiquette E, et al.Antimicrobial therapy
handbook.org. Chichester, UK: Wiley-Blackwell, 2011. for acute maxillary sinusitis. Cochrane Database of
Unnebrink 2001 Systematic Reviews 1999, Issue 3. [DOI: 10.1002/
Unnebrink K, Windeler J. Intention-to-treat: methods for 14651858.CD000243.pub2]
dealing with missing values in clinical trials of progressively Williams 2003
deteriorating diseases. Statistics in Medicine 2001;20: Williams Jr JW, Aguilar C, Cornell J, Chiquette E. Dolor
3931–46. RJ, Makela M, et al.Antibiotics for acute maxillary sinusitis.
Varonen 2003b Cochrane Database of Systematic Reviews 2003, Issue 2.
Varonen H, Savolainen S, Kunnamo I, Heikkinen [DOI: 10.1002/14651858.CD000243.pub2]
R, Revonta M. Acute rhinosinusitis in primary care: ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Adelglass 1998a
Methods Randomised, single-blind study (investigator). Diagnosis of acute sinusitis confirmed

radiographically by at least 5 mm mucosal thickening, opacification or air-fluid level.
Outcomes assessed by an investigator; cure defined as disappearance of clinical signs and
symptoms without need for further antimicrobial therapy. Treatment compliance not
reported. Proportion of the participants without known or reported clinical outcome
12% on day 16 to 19
Participants The study setting was not described. Participants were 40 years old on average (range 18
to 83) and included 122 men and 69 women. ENT co-morbidity was assessed; about
50% of patients had hay fever. Country - USA
Interventions 2 treatment arms:

Group 1: levofloxacin 500 mg daily for 14 days
Group 2: clarithromycin 500 mg BID for 14 days
Acetaminophen and diphenhydramine were allowed
Outcomes Clinical outcomes were assessed in 190 out of 216 randomised patients (in 101 out of
108 patients in levofloxacin group and in 89 out of 108 patients in clarithromycin group)
. Outcomes were assessed on day 16 to 19. Second follow-up on 42 to 46 days
Notes Study supported by a pharmaceutical company. 5 of the authors were affiliated to a

pharmaceutical company
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk Quote: “The subject randomization list was
bias) computer-generated and stratified by site.
Equal numbers of subjects were assigned to
each treatment group”
Allocation concealment (selection bias) Low risk Quote: “To reduce potential bias during
data collection and evaluation of clinical
end points, a qualified third party assumed
responsibility for all procedures related to
the study drugs including dispensing”
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response, ad-
verse effects and quality of life
Comment: in the methods section it is
stated that repeat sinus X-rays were taken
at 16 to 19 days giving the impression that

Adelglass 1998a (Continued)
this was an outcome. However, the results

were not reported
Blinding? (Participant and investigator) High risk Quote: “Single-blinded (investigator)”
Incomplete outcome data addressed? High risk Missing data: 7/108 (6%) in levofloxacin
(Clinical efficacy outcomes) group and 19/108 (18%) in clarithromycin
group on day 16 to 19
Comment: imbalance in numbers of miss-
ing data across groups
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: no co-interventions included in

the protocol. In both groups the same con-
comitant medication was allowed and was
of such quality that it did not have an effect
on recovery (thus did not cause bias)
Free of other bias? Funding High risk Study supported by a pharmaceutical com-
pany. 5 of the authors were affiliated to a
Adelglass 1998b
Methods Randomised, unblinded trial. Diagnosis by clinical signs and symptoms (mean duration
of symptoms prior to enrolment 9 days) and radiograph showing at least 4 mm mucosal
thickening. Cure defined as absence of symptoms or a score of 1 or less on a 10-point
symptom scale. At least 80% of assigned doses were taken by 94% of participants.
Proportion of the participants without known or reported clinical outcome 21% on day
11 to 15
Participants The study setting was not described. Mean age approximately 37; 128 men and 150
women. About 40% of patients had ENT or eye diseases. Country - USA
Interventions 2 treatment arms

Group 1: cefprozil 500 mg twice daily for 10 days
Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 days
Mucolytics and decongestants allowed and taken by < 50%
Outcomes Clinical outcomes assessed at day 11 to 15 in 219 out of 278 randomised patients (in
108 out of 140 patients in cefprozil group and in 111 out of 138 patients in amoxicillin-
clavulanate group). Second follow-up 2 weeks post-treatment. Radiographic and bacte-
riological outcomes not reported

Adelglass 1998b (Continued)
Notes Study was supported by a grant from a pharmaceutical company
Risk of bias
Random sequence generation (selection Unclear risk No information provided

bias)
Allocation concealment (selection bias) Unclear risk No information provided
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Open-label study”
Incomplete outcome data addressed? High risk Missing data: 32/140 (22.9%) in cefprozil
(Clinical efficacy outcomes) group and 27/138 (19.6%) in amoxicillin-
clavulanate group on day 11 to 15. Total
missing data rate 21% on day 11 to 15 and
28% on day 24
Comment: total missing data rate over 20%

Free of other bias? Funding High risk Study was supported by a grant from a

Adelglass 1999
Methods Randomised, unblinded trial. Diagnosis by clinical symptoms and radiograph showing
at least 4 mm mucosal thickening, opacification or air-fluid level. Cure defined as dis-
appearance of symptoms and signs, and stabilisation or improvement of radiographic
findings. Treatment compliance not reported. Proportion of the participants included
in the clinically evaluable population was 87% on day 12 to 19
Participants Participants were recruited from community-based primary care and otolaryngology
clinics. Mean age 39 (range 18 to 85); 225 men and 390 women. Country - USA

Group 1: levofloxacin 500 mg daily for 10 to 14 days
Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 to 14 days
The use of antihistamines and decongestants was encouraged
Outcomes Study reported clinical responses for clinically evaluable patients only. Clinical outcomes
for clinically evaluable population were assessed on day 12 to 19 in 535 out of 615
randomised patients (in 267 out of 307 patients in levofloxacin group and in 268 out of
308 patients in amoxicillin-clavulanate group). (To be clinically evaluable, the patient
had to be evaluable for safety, have a confirmed clinical diagnosis of acute sinusitis, have
received at least 7 days of therapy, have followed the protocol, and have a clinical evalu-
ation within 2 to 10 days after ending therapy.) Radiographic outcomes not separately
reported. Long-term follow-up at 28 to 32 days after completion of therapy to assess
relapse
Notes Study was supported by a pharmaceutical company
Risk of bias

bias)
Selective reporting (reporting bias) Unclear risk Outcomes reported: overall clinical re-
sponse (clinical response + radiographic re-
sponse) and adverse effects
methods) were unclearly reported (3 anal-
yses groups for treatment comparison de-
fined in methods section but the role of
mITT and ITT populations in results re-
mains unclear)

Adelglass 1999 (Continued)
Incomplete outcome data addressed? Low risk Missing data: 40/307 (13%) in levofloxacin
(Clinical efficacy outcomes) group and 40/308 (13%) in amoxicillin-
clavulanate group on day 12 to 19
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity at baseline was insufficient to assess
whether the groups were comparable at
baseline or not (no information on severity
rating)
Free of other bias? Co-interventions Low risk Quote: “The use of antihistamines and de-
congestants was encouraged”
Comment: no co-interventions included in
Free of other bias? Funding High risk Study was supported by a pharmaceutical
company
Arndt 1994
Methods Randomised, unblinded study. Diagnosis = clinical evidence, an abnormal radiograph

and nasal swab. Radiographic criteria not described. Cure defined as “complete resolution
of clinical signs/symptoms of infection”; improvement as “clear regression of clinical
signs within 4 to 5 days without having entirely disappeared on completion of therapy.”
Treatment compliance was not reported. Proportion of the participants without known
or reported clinical outcome 20%
Participants Participants were recruited from academic, outpatient otolaryngology clinics. Partici-
pants were 33 years old on average (range 18 to 65) and included 25 men and 31 women.
Country - Germany

Group 1: brodimoprim 200 mg once daily for 8 to 12 days
Group 2: doxycycline 100 mg once daily for 8 to 12 days
Only non-specific medications were allowed (most patients received concomitant med-
ications, mainly nasal decongestants)
Outcomes Clinical and radiographic outcomes were assessed in 56 out of 70 randomised patients.
Outcomes were assessed on day 8 to 12 after randomisation. Bacteriological outcomes
were reported in 50 patients
Notes 1 of the authors was affiliated to a pharmaceutical company

Arndt 1994 (Continued)
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses; and adverse
effects
Blinding? (Participant and investigator) High risk Quote: “Open study”
Incomplete outcome data addressed? Unclear risk Quote: “In total 14 of 70 randomized par-
(Clinical efficacy outcomes) ticipants had to be excluded shortly after
the trial began due to negative culture at
baseline or because some of them did not
come back after the first visit”
Comment: the missing data rates not re-
ported by study group. It remains unclear
how many participants were excluded be-
cause of negative culture in each group

Free of other bias? Funding Unclear risk 1 of the authors was affiliated to a pharma-
ceutical company

Arrieta 2007
Methods Randomised, unblinded design. Diagnosis by clinical signs and symptoms lasting 7 to
28 days, confirmed by computed tomography or X-ray (criteria not specified). Culture
by sinus puncture or endoscopy of middle meatus, or both (51% of participants had at
least 1 causative organism identified before study entry). Clinical resolution was defined
as total resolution of signs and symptoms related to acute sinusitis and, at least, improve-
ment in the radiographic or computer tomographic scan appearance of the sinuses to the
extent that no additional or alternative antimicrobial therapy was necessary. Treatment
compliance unclearly reported. Proportion of the participants included in the per-pro-
tocol population was 80% on day 17 to 24 (there was no description of missing data)
Participants Multicentre (31 centres), multinational trial (Argentina, Brazil, Chile and Mexico). De-
mographic data reported for per-protocol population at baseline: 459 outpatients, 172
men and 287 women; mean age was 37 years. ENT co-morbidity was not assessed

Group 1: moxifloxacin 400 mg once daily for 7 days
Group 2: amoxicillin-clavulanate 500/125 mg 3 times daily for 10 days
Concomitant therapies were not reported
Outcomes Study reported clinical resolution rates for intention-to-treat and per-protocol popula-
tions. However, only per-protocol population could be used as basis for clinical outcome
calculating in this review because failure rates were not reported and there was no de-
scription of the reasons and amounts of missing data. Clinical outcomes for per-protocol
population (patients who completed the course of treatment) were assessed on day 17
to 24 in 459 out of 575 randomised participants (in 226 out of 289 participants in
moxifloxacin group and in 233 out of 286 participants in amoxicillin/clavulanate group)
. Bacteriological outcomes for per-protocol population were assessed in 234 participants
Notes Study supported by a pharmaceutical company but the authors stated that although
they received a grant from the company to conduct the study, results were in no way
modified in favour of the sponsor’s product. 4 of the authors were affiliated to the same
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiological findings), bacteriolog-
ical response in 234 participants and ad-
verse effects

Arrieta 2007 (Continued)
Incomplete outcome data addressed? Unclear risk Missing data: 63/289 (22%) in moxi-
(Clinical efficacy outcomes) floxacin group and 53/286 (19%) in amox-
icillin/clavulanate group on day 17 to 24
Comment: no description of reasons for
missing data
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Co-interventions Unclear risk No information provided
Free of other bias? Funding Unclear risk Study supported by a pharmaceutical com-
pany but the authors stated that although
they received a grant from the company to
conduct the study, results were in no way
modified in favour of the sponsor’s prod-
uct. 4 of the authors were affiliated to the
same pharmaceutical company
Axelsson 1970
Methods Randomised trial. Blinding was not reported. Patients with clinically suspected sinusitis
were radiologically examined; only patients with secretion were included. Secretion was
confirmed by a single diagnostic irrigation for those with completely opaque maxillary
sinuses. Clinical outcomes assessed by an investigator but “cure” and “improvement” were
not defined. Compliance with treatment was not reported. Proportion of the participants
without known or reported clinical outcome 7% on day 10
Participants The study setting was not described. It is unclear if participants were a convenience
sample or a consecutive series of eligible patients. Participants were 33 years old on
average (range 13 to 80) and included 62 men and 94 women. Patients with a history
of nasal allergy were excluded. Country - Sweden
Interventions 4 treatment arms: (only groups 1 and 3 used in the analysis)

Group 1: oxymetazoline only (no placebo control)
Group 2: oxymetazoline plus sinus irrigation
Group 3: oxymetazoline plus penicillin V 400 mg 3 times daily for 10 days
Group 4: oxymetazoline plus lincomycin 500 mg 3 times daily for 8 days
Outcomes Clinical outcomes were assessed in 142 out of 156 randomised participants (in 35 out
of 38 patients in penicillin group and in 32 out of 34 patients in oxymetazoline group)
. Outcomes were assessed on day 10 after randomisation. Radiographic outcomes were
reported as mean number of severity points per sinus (not by patient)

Axelsson 1970 (Continued)
Notes There was no identified funding source
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, radi-
ological response and adverse effects
Blinding? (Participant and investigator) Unclear risk No information provided
Incomplete outcome data addressed? Low risk Missing data: 8% (3/38) in penicillin group
(Clinical efficacy outcomes) and 6% (2/34) in oxymetazoline group
Comment: although the reasons for miss-
ing data were not stated, we decided to
judge this domain ’low’ risk of bias because
the missing data rates were equal and mar-
ginal in both groups
Free of other bias? Baseline comparability Low risk Comment: detailed description of radio-
logical sinusitis severity rating at baseline.
It appears that the groups were balanced
although the information on demographic
characteristics was scarce
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Free of other bias? Funding Unclear risk No information provided
Boezeman 1988
Methods Randomised, but unblinded trial. Diagnosis by clinical symptoms, confirmed by radio-
graph showing sinus opacity and positive culture taken near the ostium of, or by aspira-
tion from, maxillary sinus. Clinical outcomes assessed by an investigator but a definition
of clinical cure was not given. Treatment compliance was not reported. Proportion of
the participants without known or reported clinical outcome 18%
Participants The study setting was not described. Outpatients were 30 years old on average (range
13 to 76) and included 23 men and 10 women. Country - The Netherlands

Boezeman 1988 (Continued)

Group 1: spiramycin 1000 mg twice daily for 10 days
Group 2: doxycycline 200 mg on day 1 then 100 mg each day for 10 days
Nasal decongestants were allowed but were not given as part of the study treatment
Outcomes Clinical outcomes were assessed in 27 out of 33 randomised participants (in 15 out of
18 patients in doxycycline group and in 12 out of 15 patients in spiramycin group).
Outcomes were assessed on day 11 after randomisation. Radiographic and bacteriological
outcomes were reported for 27 out of 33 patients
Risk of bias

bias)
and bacteriological outcomes, and adverse
effects
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 3/15 in
spiramycin group and 3/18 in doxycycline
group; other missing data 0%
Comment: the absence of pathogen was
seen not to cause bias
Free of other bias? Baseline comparability High risk Comment: the severity rating at baseline
was different across the groups

Free of other bias? Funding Unclear risk There was no identified funding source

Buchanan 2003
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms lasting
at least 7 days, confirmed by radiograph showing at least 10 mm mucosal thickening,
opacification or air fluid level in a sinus radiograph or CT. Bacteriological specimens
were obtained by sinus puncture (in US sites) or endoscopy collection (non-US sites).
Clinical cure assessed by investigators and defined as dichotomous - either cure or failure.
Cure defined according to the following criteria: return to preinfection state, with no
ABMS-related signs and symptoms present, as determined on a scale of 0 to 3 points
in which 0 = absent, 1 = mild, and 3 = severe, supplemented by a sinus X-ray/CT scan
confirming no worsening of infection or the presence of only those residual symptoms
indicative of a normal course of clearance in the infection process, with no requirement
for additional antibiotic treatment. Compliance among available patients was in average
95% (assessed by unused capsule count). Proportion of the participants included in the
per-protocol clinically evaluable population was 72% on day 16 to 24
Participants Multicentre, multinational trial (USA, Argentina, France, South Africa). 148 men and
208 women, mean age about 40 years (range from 14 to 84)
ENT co-morbidity was not assessed

Group 1: telithromycin 800 mg once daily for 5 days
Group 2: cefuroxime axetil 250 mg twice daily for 10 days
Concomitant treatments were not described
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol evalu-
able populations. However, only per-protocol evaluable population could be used as
basis for clinical failure rate calculating in this review because true failures were not re-
ported and indeterminate responses were included in failures in mITT analyses. Clinical
outcomes for per-protocol evaluable population assessed on day 16 to 24 in 278 out of
385 randomised patients (in 189 out of 260 participants in telithromycin group and
in 89 out of 125 participants in cefuroxime axetil group). Per-protocol clinically evalu-
able population defined as patients who met the diagnostic criteria, and had no major
protocol violation. Bacteriologic outcomes assessed on day 16 to 24 in 149 patients.
Radiologic outcomes were not reported
Notes Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated
to pharmaceutical company
Risk of bias

bias)
cluding radiological findings) and bacteri-
ological response, and adverse effects

Buchanan 2003 (Continued)

Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “To ensure blind-
ing matched placebo capsules were used in
telithromycin group”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? High risk Missing data: 71/260 (27%) in
(Clinical efficacy outcomes) telithromycin group and 36/125 (29%) in
cefuroxime axetil group on day 16 to 24
Comment: total missing data rate 28%
Free of other bias? Baseline comparability Unclear risk Comment: information on comparability
of intervention and control groups at base-
line reported only for modified intention-
to-treat population, not for per-protocol
evaluable population which was used in the
analyses
Free of other bias? Funding High risk Study supported by a grant from a phar-
maceutical company. 1 of the authors was
affiliated to pharmaceutical company
Burke 1999
Methods Randomised, double-blind trial. Diagnosis by symptoms lasting 1 to 4 weeks and ra-
diograph showing air-fluid level, opacity or at least 6 mm mucosal thickening. Clini-
cal resolution was defined resolution or improvement of clinical symptoms and radio-
graphic findings and no need for additional antimicrobial treatment. To be included in
the efficacy-valid population the compliance had to be at least 80%. Proportion of the
participants without known or reported clinical outcome 16%
Participants Mixed otolaryngology and primary care. Mean age 40; 178 men, 279 women. Country
- USA

Group 2: moxifloxacin 400 mg daily for 10 days
Decongestants, antihistamines and phenylephrine drops were allowed; systemic or topical
corticosteroids not allowed

Burke 1999 (Continued)
Outcomes Study reported clinical cure rates for intention-to-treat and efficacy-valid populations but
clinical failure rates only for efficacy-valid population. Clinical outcomes were assessed
on day 17 to 24 in 457 out of 542 randomised patients (in 234 out of 275 participants
in cefuroxime axetil group and in 223 out of 267 participants in moxifloxacin group).
The efficacy-valid population defined as patients who met diagnostic criteria and were
without major protocol violations. Radiographic outcomes not reported. Long-term
follow-up on 37 to 41 days
Notes Study supported by a research grant from a pharmaceutical company. 3 of the authors
were affiliated to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Block-design random code”
bias) Comment: although the description of the
sequence generation was incomplete, this
domain was graded ’low’ risk of bias be-
cause description gives an impression of
computer-based method
cluding radiological findings) and adverse
effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Medica-
tions were encapsulated in gelatin for mask-
ing purposes. Placebo capsules used in
moxifloxacin group”
blinding was incomplete (regarding blind-
ing of investigator), this domain was graded
’low’ risk of bias because the study was
reported to be double-blind and blinding
method was partly described
Incomplete outcome data addressed? Low risk Missing data: 41/275 (15%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 44/267 (16%) in moxi-
floxacin group on day 17 to 24

Burke 1999 (Continued)
Free of other bias? Baseline comparability Low risk Comment: although the proportion of pa-
tients with severe sinusitis was 47/223
(21%) in moxifloxacin group and 36/234
(15%) in cefuroxime axetil group, this do-
main was graded ’low’ risk of bias

Free of other bias? Funding High risk Study supported by a research grant from a
pharmaceutical company. 3 of the authors
were affiliated to a pharmaceutical com-
pany
Calhoun 1993
Methods Randomised, single-blind trial (investigator). Diagnosis established by clinical symptoms

and abnormal radiograph (criteria not reported). Clinical outcomes were assessed by an
investigator. Clinical cure defined as signs and symptoms of infection resolved. Treatment
compliance not reported. Proportion of the participants without known or reported
clinical outcome 18%
Participants Consecutive patients were recruited from academic, primary care clinics. Mean age was
37 (range 14 to 77); 84 women and 58 men. ENT co-morbidity was not assessed.
Country - USA

Group 1: clarithromycin 500 mg twice daily for 7 to 14 days
Group 2: amoxicillin 500 mg 3 times daily for 7 to 14 days
Both groups received oxymetazoline 2 sprays twice daily for 3 days
70 patients in clarithromycin group and in 61 out of 72 patients in amoxicillin group)
. Outcomes were assessed on day 7 to 16 after randomisation. Radiographic outcomes
were assessed in 116 out of 142 patients randomised. Bacteriological outcomes were not
reported
Notes Study was supported in part by a grant from a pharmaceutical company
Risk of bias

Calhoun 1993 (Continued)

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses, and adverse effects
Blinding? (Participant and investigator) High risk Quote: “A third party dispensed the antibi-
otics and assessed compliance, ensuring the
single-blind (investigator-blind) nature of
the study. The single-blind design was nec-
essary because of the difficulty in packaging
the two drugs in identical capsules. Patients
were instructed not to discuss the dosing
schedule with their physicians”
Comment: no blinding of the participants
Incomplete outcome data addressed? Unclear risk Missing data: 15/70 (21.4%) in clar-
(Clinical efficacy outcomes) ithromycin group and 11/72 (15.3%) in
amoxicillin group
Comment: all reasons for missing data were
not reported by group
Free of other bias? Funding High risk Study was supported in part by a grant from
a pharmaceutical company

Camacho 1992
Methods Randomised, single-blind design (investigator). Clinical diagnosis of acute sinusitis and
an abnormal radiograph (mucosal thickening, opacity or air-fluid level). Sinus puncture
performed. Clinical outcomes assessed by an investigator; cure defined as “resolution
of clinical symptoms with radiographic evidence of sinus decongestion with no further
therapy required”. Improvement defined as “clinical symptoms substantially reduced but
radiographic evidence of residual sinus congestion”. Treatment compliance not reported.
11 to 38
Participants Patients were recruited from academic and community settings; probably otolaryngology
practices. Mean age = 35 (range 18 to 79); 171 men and 146 women. ENT co-morbidity
was not assessed. Countries - Brazil, Chile, Columbia, USA

Group 2: amoxicillin-clavulanate 500 mg 3 times daily for 10 days
Concomitant therapies were not described
Outcomes Clinical outcomes were assessed on day 11 to 38 in 239 out of 317 randomised par-
ticipants (in 115 out of 157 participants in cefuroxime axetil group and in 124 out
of 160 participants in amoxicillin-clavulanate group). Radiographic outcomes were not
reported. Bacteriological outcomes were assessed in 76 participants
Notes Study was supported in part by a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Computer-generated randomized

bias) code”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for a proportion of
participants, adverse effects
Blinding? (Participant and investigator) High risk Quote: “Investigator-blinded”
Incomplete outcome data addressed? High risk Missing data: 42/157 (27%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 36/160 (23%) in amoxi-
cillin-clavulanate group on day 11 to 38
Comment: total missing data over 20%

Camacho 1992 (Continued)
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding High risk Study was supported in part by a pharma-
ceutical company
Chatzimanolis 1998
Methods Randomised, unblinded design. Diagnosis of acute or recurrent sinusitis documented by

clinical and endoscopic findings, bacteriology (sinus puncture) and X-ray. Clinical cure
not defined. Treatment compliance not reported. Proportion of the participants without
known or reported clinical outcome 7%
Participants Study setting not described. Mean age 38; 34 men and 26 women. ENT co-morbidity
not assessed. Country - Greece

Group 1: roxithromycin 150 mg twice daily for 10 to 14 days
Group 2: amoxicillin-clavulanate (500 mg/ 125 mg) 3 times daily for 10 to 15 days
Concomitant treatments not reported
Outcomes Clinical outcomes reported on day 10 to 17 for 56 out of 60 randomised participants

(for 29 out of 31 participants in roxithromycin group and for 27 out of 29 participants
in amoxicillin-clavulanate group). Radiographic outcomes not reported by group
Notes Study funded by a pharmaceutical company
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects

Chatzimanolis 1998 (Continued)
Incomplete outcome data addressed? Low risk Missing data: 2/31 (6.5%) in rox-
(Clinical efficacy outcomes) ithromycin group and 2/29 (7%) in amox-
icillin-clavulanate group
Free of other bias? Funding High risk Study funded by a pharmaceutical com-
pany
Clement 1998
Methods Randomised, unblinded design. Clinical diagnosis of ethmoid or maxillary sinusitis con-
firmed by fibre-optic examination (purulent discharge from ostium of affected sinus) and
computed tomography (criteria not specified). Pus samples were collected endoscopically
for bacteriological culture. Clinical outcomes assessed by an investigator but were not
defined. Compliance with treatment was not reported. Proportion of the participants
without known or reported clinical outcome 8% on day 10 to 14
Participants Participants were recruited from otolaryngology clinics. Mean age 41; 103 men, 151
women. ENT co-morbidity not assessed. Country - Belgium

Group 1: azithromycin 500 mg daily for 3 days
Group 2: amoxicillin 500 mg/clavulanic acid 125 mg 3 times daily for 10 days
Concomitant therapies (decongestants, corticosteroids, mucolytics) were allowed but
not prescribed. 133 participants used a concomitant treatment
Outcomes Clinical outcomes were assessed on day 10 to 14 in 233 of 254 participants (in 151 out of
165 participants in azithromycin group and in 82 out of 89 participants in amoxicillin-
clavulanate group) and on day 21 to 28 in 210 of 254 participants. Bacteriological
outcomes were assessed in 100 participants
Notes Study funding provided by a pharmaceutical company
Risk of bias

bias)

Clement 1998 (Continued)
participants and adverse effects
Incomplete outcome data addressed? Low risk Missing data: 14/165 (8.5%) in azithromy-
(Clinical efficacy outcomes) cin group and 7/89 (7.9%) in amoxicillin-
clavulanate group on day 10 to 14. Total
missing data 8% on day 10 to 14 and 17%
on day 21 to 28
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data. Available case data given for both fol-
low-ups
Free of other bias? Co-interventions Unclear risk Comment: no co-interventions included in

comitant medication was allowed. Corti-
costeroids may have effect on recovery but
their use was not reported
Free of other bias? Funding High risk Study funding provided by a pharmaceuti-
cal company
Clifford 1999
Methods Randomised, double-blind trial. Participants with acute sinusitis and acute exacerbation
of chronic sinusitis included. Proportion of the participants with acute sinusitis 75% and
their results reported separately. Clinical diagnosis, confirmed by radiograph showing air-
fluid level, opacification or at least 6 mm mucosal thickening. Cure defined as symptom
resolution and radiographic improvement. Proportion of the participants without known
or reported clinical outcome 18% for the whole study population including participants
with acute sinusitis and participants with acute exacerbation of chronic sinusitis
Participants Study setting not described. Mean age approximately 41 (range 18 to 76); 187 men and
270 women. 25% of participants with acute exacerbation of chronic sinusitis in efficacy-
valid population. About 26% of participants had allergic rhinitis. Country - USA

Clifford 1999 (Continued)

Group 1: ciprofloxacin 500 mg twice daily for 10 days
Group 2: clarithromycin 500 mg twice daily for 14 days
Decongestants allowed. Nasal corticosteroids prohibited
Outcomes Clinical outcomes for participants with acute maxillary sinusitis were separately reported
only for efficacy-valid population (342 participants at day 14). Efficacy-valid population
was defined as participants who completed the course of treatment and did not use other
antimicrobial agents concomitantly with the study drug. Radiographic outcomes not
reported
Notes Study supported by a research grant from a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “The patients were randomly as-
bias) signed to 1 of 2 treatment groups by means
of a block design random code computer-
generated”
Allocation concealment (selection bias) Low risk Comment: central allocation (randomisa-
tion made at a pharmaceutical company)
cluding radiographic findings) and adverse
effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “The study drugs
were encapsulated in gelatin capsules for
blinding purposes. Matched placebos used”
Comment: although the description of
the blinding was incomplete (in respect
of investigator-blinding), this domain was
Incomplete outcome data addressed? Unclear risk Comment: missing data not described sep-
(Clinical efficacy outcomes) arately for the participants with acute si-
nusitis and participants with acute exacer-
bation of chronic sinusitis

Clifford 1999 (Continued)

Free of other bias? Funding High risk Study supported by a research grant from
Desrosiers 2008
Methods Randomised, unblinded trial. Diagnosis by clinical signs and symptoms lasting for 7 to
28 days (purulent nasal discharge; 1 additional major sign and symptom (facial pain/
pressure/tightness over the maxillary sinuses; nasal congestion/obstruction, hyposmia/
anosmia; fever) or 2 minor signs and symptoms (headache, halitosis, dental pain, ear
pressure/fullness, cough, fatigue)), confirmed by abnormal maxillary sinus X-rays or
limited sinus computed tomography scans or sinus ultrasound (at least 1 of the following:
air/fluid level, total opacification, mucosal thickening at least 10 mm). Samples for
microbiological analysis were taken by using rhinoscopic aspiration or micro-swabbing of
the maxillary sinus (middle meatus). Clinical outcome was defined as “success”, “failure”
or “indeterminate” (success was defined as cured or improved). Clinical failure was
recorded if at least on the following criteria was met: all signs/symptoms remained
unchanged or had worsened, at least 1 additional antibiotic had to be prescribed and/
or added to the study treatment for sinusitis, sinusitis-related complications occurred,
sinus puncture or drainage had been performed. Treatment compliance at least 80%
for those patients who were included in the per-protocol population. Proportion of the
participants included in the per-protocol population was 83% on day 17 to 21
Participants Multicentre (41 centres), multinational trial (Canada, Germany, Greece, Portugal and
Turkey). Demographic data reported for modified intention-to-treat population at base-
line: participants’ mean age was 39 years; 109 men and 181 women. ENT co-morbidity
was assessed; 1 participant had allergic rhinitis, 2 participants had chronic sinusitis and
5 participants had nasal septal deviation

Group 2: amoxicillin-clavulanate 875/125 mg twice daily for 10 days
Concomitant therapies were not clearly reported
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol pop-
ulations. However, only per-protocol population could be used as basis for clinical fail-
ure rate calculating in this review because true failures were not reported and it seemed
that indeterminate and missing responses were included in failures in mITT analyses.

Desrosiers 2008 (Continued)
Clinical outcomes for per-protocol population were assessed in 248 of 298 randomised
participants on day 17 to 21 and on day 41 to 49. Per-protocol population was defined
as all randomised participants with clinically and radiographically confirmed sinusitis,
and were without major protocol violations. Bacteriological outcomes reported for 103
participants on day 17 to 21. Health-related quality of life measured by SF-36 question-
naire completed by 278 participants at baseline, and on day 41 to 49
Risk of bias
Random sequence generation (selection Low risk Quote: “Centrally generated randomiza-
bias) tion list”
Allocation concealment (selection bias) Low risk Quote: “Centrally generated randomiza-
tion list”
participants, quality of life and adverse ef-
fects
Incomplete outcome data addressed? Low risk 8 out of 298 randomised participants were
(Clinical efficacy outcomes) excluded at the beginning of the study
because of the unconfirmed sinusitis. No
information provided how these partici-
pants were divided across the 2 groups.
Calculating missing data by group was
therefore based on the modified intention-
to-treat (mITT) population (290 partici-
pants) which was defined as all randomised
participants with clinically and radiograph-
ically confirmed sinusitis, and who received
at least 1 dose of study medication
Missing data: 21/144 (14.6%) in
telithromycin group and 21/146 (14.4%)
in amoxicillin-clavulanate group on day 17
to 21
Comment: groups appeared to be balanced
in numbers and reasons for missing data

Desrosiers 2008 (Continued)
Free of other bias? Co-interventions Unclear risk Concomitant therapies were not clearly re-
ported
cal company
Dubois 1993
Methods Randomised, single-blind (investigator) trial. Diagnosis established by symptoms, an

abnormal maxillary radiograph (minimum criteria were not given) and a positive cul-
ture of sinus fluid (collected by puncture or endoscopically). Clinical outcomes assessed
by an investigator; ”cure“ defined as pretreatment signs and symptoms resolved; ”im-
provement“ defined as improved but not resolved.” Treatment compliance not reported
but participants had to take at least 70% of prescribed treatment to be included in the
efficacy analysis. Total proportion of the participants without known clinical outcome
48%. Patients were excluded mostly due to negative culture; exclusions because of other
reasons marginal 3.4%
Participants Participants were recruited from outpatient ENT and primary care settings. It is unclear
if the study sample represents a consecutive series of participants or a convenience sample.
Country - Canada

Group 1: clarithromycin 500 mg every 12 hours for a maximum of 14 days
Group 2: amoxicillin-clavulanate 500 mg every 8 hours for a maximum of 14 days
Both groups received oxymetazoline 0.05% nasal sprays twice daily for the first 3 days
Outcomes Clinical, radiographic and bacteriological outcomes were assessed in 260 out of 497
randomise participants (in 132 out of 246 participants in clarithromycin group and in
128 out of 251 participants in amoxicillin-clavulanate group). Outcomes were assessed
on about day 15 after randomisation
Notes Study was supported in part by a grant from a pharmaceutical company
Risk of bias

bias)

Dubois 1993 (Continued)
and bacteriological responses, and adverse
effects
Blinding? (Participant and investigator) High risk Quote: “Investigators were blind to the
drug being administered”
Comment: no description of blinding of
the participants
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 103/246
in clarithromycin group and 117/251 in
amoxicillin-clavulanate group; other exclu-
sions 10 (4.1%) and 7 (2.8%) of partici-
pants in clarithromycin group and amoxi-
cillin-clavulanate group, respectively
seen not to cause bias. Other missing data
marginal
co-intervention during the first 3 days
Free of other bias? Funding High risk Study was supported in part by a grant from
Ferguson 2004
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed
by radiograph showing at least 10 mm mucosal thickening, total sinus opacity or air-
fluid level in a sinus radiograph. Pretreatment cultures of rhinoscopic aspirations or deep
nasal Calgiswab samples were compared with cultures taken at 17 to 24 days of follow-
up. Clinical success was defined: the patient was either cured or showed improvement
relative to baseline (including no worsening of radiological findings) without addition
of a new antibiotic. Treatment compliance reported as over 90% assessed by capsule
counts. Proportion of the participants included in the per-protocol population was 78%
on day 17 to 24
Participants Multicentre study, 41 sites in USA. Median age approximately 45 (range 18 to 85); 123
men and 199 women. ENT co-morbidity not described

Ferguson 2004 (Continued)

Outcomes Study reported clinical success rates for modified intention-to-treat and per-protocol
populations. However, only per-protocol population could be used as basis for clinical
response calculating in this review because true failures were not reported and all in-
stances of not completing the study were included in failures in mITT analyses. Clinical
outcomes for per-protocol population were assessed at days 17 to 24 in 272 of 349 ran-
domised participants (in 135 out of 173 participants in telithromycin group and in 137
out of 176 participants in moxifloxacin group). The per-protocol population was defined
as all randomised participants who received at least 1 dose of study medication and had
signs and symptoms of acute maxillary sinusitis and radiologic findings supporting the
diagnosis and were without major protocol violations. Long-term follow-up at 31 to 36
days. Bacteriological outcomes were assessed in 67 participants
Notes Study supported by a grant from a pharmaceutical company. 4 of the authors had received
research support/grants from and/or acted as consultants for the same pharmaceutical
company
Risk of bias

bias)
cluding radiologic findings), bacteriologi-
cal response in 67 participants and adverse
effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
capsules used”
Incomplete outcome data addressed? High risk Missing data: 38/173 (22%) in
(Clinical efficacy outcomes) telithromycin group and 39/176 (22%) in
moxifloxacin group on day 17 to 24
Comment: missing data over 20%, insuffi-

Ferguson 2004 (Continued)
cient description of reasons for missing data
(information given for mITT population,
not for per-protocol population)
maceutical company. 4 of the authors had
received research support/grants from and/
or acted as consultants for the same phar-
maceutical company

Garbutt 2012
Methods Randomised, placebo-controlled trial. Clinical diagnosis of acute sinusitis was based
on clinical findings, with history of maxillary pain or tenderness in the face or teeth,
purulent nasal secretions, and rhinosinusitis symptoms for 7 days or more and 28 days
or less that were not improving or worsening, or rhinosinusitis symptoms lasting for less
than 7 days that had significantly worsened after initial improvement. The symptoms
had to be moderate, severe or very severe. Mean duration of symptoms was 11 days in
both groups (median 10.0, interquartile range (25th to 75th percentile) 7.0 to 14.0).
Because the proportion of the participants with symptoms less than 7 days was small
(14%), and because the reason to include those patients was that patients’ symptoms
had significantly worsened, this study was included in this review
Clinical outcomes were assessed by telephone interview using a structured questionnaire.
Participants used a 6-point scale (a lot or a little worse or better, the same or no symp-
toms) to retrospectively assess symptom change since enrolment. Those reporting their
symptoms as a lot better or absent were categorised as significantly improved. In total, 23
participants (14%) (11 in the amoxicillin group and 12 in placebo group) did not com-
plete the 10-day course of treatment. Sixteen were treated with another antimicrobial (5
in the amoxicillin group and 11 in the placebo group). Proportion of the participants
without known or reported clinical outcome 7% on day 7; and 8% on day 10; and 4%
on day 28.
Follow-up time chosen for analyses of this review was 10 days. The 7-day follow-up
was not used because the treatments lasted for 10 days. The 28 day follow-up was not
considered because the outcome measure at this time point was recurrence or relapse and
did not include all failures, and thus the outcome is not in accordance with the outcome
definition of this review.
The study was not considered in the primary analysis of this review because it remained
unclear whether the patients who received rescue therapy were classified as non-improved
or not
The results, as reported in the original article, are presented in the Results section
Participants Participants recruited from 10 offices of primary care physicians. 60 men and 106 women;
mean age 32 (range 18 to 69) years. Allergic rhinitis in 32%, asthma in 11% and history
of sinus disease in 74% of participants in each group. Smokers 13% in amoxicillin and
26% in placebo group. Country - USA

Group 1: amoxicillin 500 mg 3 times daily for 10 days
Group 2: placebo 3 times daily for 10 days
Concomitant therapies
All patients received a 5 to 7-day supply of the following symptomatic treatments to
be used as needed: acetaminophen for pain or fever at a dose of 500 mg every 6 hours,
guaifenesin to thin secretions at a dose of 600 mg every 12 hours, 10 mg/5ml of dex-
tromethorphan hydrobromide and 100 mg/5 ml of guaifenesin for cough at a dose of 10
ml every 4 to 6 hours, pseudoephedrine-sustained action for nasal congestion at a dose
of 120 mg every 12 hours, and 0.65% saline spray using 2 puffs per nostril as needed
Concurrent use of symptomatic treatments was 92% and did not vary by study group.
No new nasal steroid use was reported

Garbutt 2012 (Continued)
Outcomes Clinical outcomes were assessed on day 7 in 155 of 166 randomised participants (in 80
out of 85 participants in amoxicillin group and in 75 out of 81 participants in placebo
group), on day 10 in 152 of 166 randomised participants (in 81 out of 85 participants
in amoxicillin group and in 71 out of 81 participants in placebo group), and on day 28
in 159 of 166 randomised participants (in 82 out of 85 participants in amoxicillin group
and in 77 out of 81 participants in placebo group)
Outcomes were assessed by telephone interview using a structured questionnaire. Par-
ticipants used a 6-point scale (a lot or a little worse or better, the same or no symptoms)
to retrospectively assess symptom change since enrolment
Analyses were based on the intention-to-treat principle (all of the eligible participants as
randomised)
Notes Study supported by a grant from the National Institute of Allergy and Infectious Diseases,
which did not have a role in the design and conduct of the study, management and
analysis of data, or in the preparation, review or approval of the manuscript
Risk of bias
Random sequence generation (selection Low risk Quote: “Using a blocked randomiza-
bias) tion scheme, computer-generated random
numbers were used to determine how the 2
study drugs were allocated to the consecu-
tively numbered study treatment packages”
Allocation concealment (selection bias) Low risk Quote: “Randomisation was performed in
advance by the investigational pharmacist
who did not participate in patient enrol-
ment or outcome assessment. Randomisa-
tion occurred when the research assistant
assigned the treatment package”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses,
quality of life and adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Placebo was similar in appearance
and taste and dispensed in the same fashion
than the antibiotic. Telephone interviews
were conducted by trained research assis-
tants blinded to group assignment”
Incomplete outcome data addressed? Unclear risk Missing data: in amoxicillin group 5/85 (5.
(Clinical efficacy outcomes) 9%) and in placebo group 6/81 (7.4%) on
day 7; 4/85 (4.7%) and 10/81(12.3%) on
day 10; and 3/85 (3.5%) and 4/81 (4.9%)

Garbutt 2012 (Continued)
on day 28, respectively

Total missing data rates 6.6% on day 7; and
8.4% on day 10; and 4.2% on day 28
Comment: although the authors gave addi-

tional information that participants simply
missed the interviews and there was prob-
ably not any systematic difference in rea-
sons for drop-outs between the groups, we
graded this domain ’unclear’ risk of bias at
day 10. Although the difference in drop-
out rates between groups was not statis-
tically significant (P value 0.077), differ-
ence in proportions of missing outcomes
(7.6%) compared to the difference of an-
ticipated failure risks (10% to 20%) may
be big enough to cause bias

Concurrent use of symptomatic treatments
was 92% and did not vary by study group.
No new nasal steroid use was reported
Free of other bias? Funding Low risk Comment: no pharmaceutical company

funding
Gehanno 1996a
Methods Randomised, unblinded study. Diagnosis established by clinical symptoms and radio-
graph showing sinus opacity or air-fluid level. Culture based on the sample from the
middle meatus; 79% of participants had positive cultures. Clinical outcomes assessed
by investigator; cure defined as resolution of facial pain, purulent discharge, air-fluid
level by radiograph and no recurrence of symptoms. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 7%
Participants Multicentre study, 284 outpatients; 136 men and 148 women. Mean age was 40. Fewer
than 25% of participants had concurrent allergic disease. Country - France

Gehanno 1996a (Continued)

Group 1: clarithromycin 500 mg daily for 8 days
Group 2: amoxicillin-clavulanic acid 500 mg 3 times daily for 8 days
Intranasal decongestants were allowed
Outcomes Clinical outcomes were assessed on about day 10 in 263 out of 284 randomised partici-
pants (in 134 out of 145 participants in clarithromycin group and in 129 out of 139 par-
ticipants in amoxicillin-clavulanate group). Radiographic and bacteriological outcomes
were not reported
Notes 2 of the authors were affiliated to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Central randomisation (computer-gener-

bias) ated?)
Allocation concealment (selection bias) Low risk Central random allocation
adverse effects
Incomplete outcome data addressed? Low risk Missing data: 11/145 (7.6%) in clar-
amoxicillin-clavulanate group on day 10
anced

Free of other bias? Funding Unclear risk 2 of the authors were affiliated to a phar-
maceutical company

Gehanno 1996b
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed
by radiograph (criteria not reported) and/or bacteriological culture of the middle meatus
aspirate (76% of participants had a positive culture). Clinical success defined as resolution
of all signs and symptoms. Treatment compliance was not reported. Total proportion
of the participants without known or reported clinical outcome 21%. Patients were
excluded mostly due to normal sinus X-ray and a negative bacteriological culture at
inclusion; exclusions because of other reasons 6%
Participants Multicentre study. 376 outpatients; 160 men and 216 women, mean age about 41 years.
ENT co-morbidity was not assessed. Country - France

Group 1: sparfloxacin 200 mg for 5 days
Outcomes Clinical outcomes were assessed on days 10 to 12 in 302 of 382 randomised participants
(in 153 out of 193 participants in the sparfloxacin group and in 149 out of 189 partici-
pants in the cefuroxime axetil group)
Notes There was no identified funding source. However, 2 pharmaceutical companies were
mentioned in the methods section
Risk of bias

bias)
Allocation concealment (selection bias) Low risk Central allocation by a pharmaceutical

company
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, over-
all response (included clinical, radiological
and bacteriological efficacy) and adverse ef-
fects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Blinding
was prepared by a pharmaceutical com-
pany and maintained throughout the study.
Placebo-tablets used”

Gehanno 1996b (Continued)
Incomplete outcome data addressed? Low risk Exclusions from analyses on day 10 to 12:
(Clinical efficacy outcomes) normal sinus X-ray and a negative bacteri-
ological culture at inclusion 28/193 in the
sparfloxacin group and 29/189 in the ce-
furoxime axetil group; other exclusions 12
(6%) and 11 (6%) of participants in the
sparfloxacin and cefuroxime axetil group,
respectively
Comment: exclusions because of lack of
inclusion criteria were seen not to cause
bias. The groups appeared to be balanced
in numbers and reasons for missing data
Free of other bias? Baseline comparability Unclear risk Comment: detailed description of demo-
graphic characteristics and sinusitis sever-
ity rating at baseline to assess the compara-
bility of the groups for whole randomised
population, not separately for the efficacy
evaluable population
Free of other bias? Funding Unclear risk There was no identified funding source.
However, 2 pharmaceutical companies
were mentioned in the methods section
Gehanno 1998
Methods Randomised, unblinded trial. Diagnosis by symptoms and radiograph showing > 5 mm
mucosal thickening, sinus opacity or air-fluid level. A causative pathogen was isolated
in the pus sample at study entry, in 51% of the 241 participants enrolled. Treatment
compliance not reported. Proportion of the participants without known or reported
clinical outcome 2% on day 10 to 12
Participants Participants recruited from community-based otolaryngology clinics. Mean age 42; 105
men and 136 women. Country - France

Group 1: cefatrizine 500 mg twice daily for 10 days
Vasoconstrictors and paracetamol allowed
Outcomes Clinical outcomes assessed on days 10 to 12 in 236 out of 241 randomised participants
(in 121 out of 123 participants in cefatrizine group and in 115 out of 118 participants
in amoxicillin-clavulanate group). Second follow-up on day 30. Radiographic outcomes
assessed in 214. Bacteriologic outcomes not reported
Notes 1 of the authors was affiliated to a pharmaceutical company

Gehanno 1998 (Continued)
Risk of bias
Random sequence generation (selection Low risk Quote: “Central random allocation” (com-
bias) puter-generated?)
Allocation concealment (selection bias) Low risk Quote: “Central random allocation”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radio-
graphic responses, and adverse effects
Incomplete outcome data addressed? Low risk Missing data: 2/123 (1.6%) in cefatrizine
(Clinical efficacy outcomes) group and 3/118 (2.5%) in amoxicillin-
clavulanate group on days 10 to 12. Total
missing data rate 2% on day 10 to 12 and
4.5% at day 30
Comment: marginal missing data rate

ceutical company
Gehanno 2004
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms, confirmed
by radiograph showing at least 5 mm mucosal thickening, opacity or air-fluid level.
A rhinoscopic bacteriologic sampling was made on the middle nasal meatus (cultures
were positive in 46% of participants). Clinical cure based on resolution of symptoms.
Treatment compliance for per-protocol population 98%. Proportion of the participants
without known or reported clinical outcome 11%

Participants Participants were recruited by otorhinolaryngologists. The mean age of the participants
was 43 years; women 60% and men 40%. Multinational trial (France, Tunisia, Poland,
Argentina)

Group 1: pristinamycin 1 g BID for 4 days
Group 2: cefuroxime axetil 250 mg BID for 5 days
Topical vasoconstrictors prescribed for 3 days. Anti-inflammatory analgesic allowed.
Corticosteroids and mucolytics prohibited
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol popu-
lations. However, only per-protocol population could be used as basis for clinical failure
rate calculating in this review because true failures were not reported in mITT popula-
tion. Clinical outcomes were assessed on day 12 to 19 in 434 out of 485 randomised
participants (in 220 out of 250 participants in pristinamycin group and in 214 out of
participants 235 in cefuroxime axetil group). The per-protocol population was defined
as participants who met the diagnostic criteria (radiologically confirmed) and had no
major protocol violation. Bacteriological outcomes reported in 199
Notes Study was supported by a pharmaceutical company. 3 of the authors were affiliated with
the same pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Comment: although the description of the
bias) sequence generation was incomplete, this
Allocation concealment (selection bias) Low risk Quote: “Central allocation in blocks of 4”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses, bac-
teriological response in 199 and adverse ef-
fects
tablets used”

Incomplete outcome data addressed? Low risk Missing data: 30/250 (12%) in pristi-
(Clinical efficacy outcomes) namycin group and 21/235 (9%) in ce-
furoxime axetil group on day 12 to 19
data

company. 3 of the authors were affiliated
with the same pharmaceutical company
Gwaltney 1997
Methods Randomised, investigator-blind design. Clinical diagnosis confirmed by radiograph (cri-

teria not specified). Bacterial cultures obtained by sinus aspirations. Cure and improve-
ment reported as combined outcome. Treatment compliance not reported. Proportion
of the participants without known or reported clinical outcome 19% on day 7 to 14
Participants Study setting not described. Median age 35; 789 men and 1009 women. ENT co-
morbidity not described. Countries - USA and Europe

Group 1: cefdinir 600 mg once daily for 10 days
Group 2: cefdinir 300 mg twice daily for 10 days
Group 3: amoxicillin-clavulanate (500 mg) 3 times daily for 10 days
Group 1 and Group 3 used in the analysis
Outcomes Clinical outcomes reported at day 7 to 14 in 1446 out of 1798 people randomised (in
474 out of 585 participants in cefdinir 600 mg once daily group and in 491 out of
603 participants in amoxicillin-clavulanate group). Long-term follow-up at 3 to 5 weeks
for participants cured or improved at the first follow-up. Radiographic outcomes not
reported. Bacteriological outcomes not reported by group
Notes 3 of the authors were affiliated with a pharmaceutical company

Gwaltney 1997 (Continued)
Risk of bias

bias)
Allocation concealment (selection bias) Low risk Quote: “Medications were dispensed by a
third party, and all records regarding study
medication were kept at a separate site”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logical responses, and adverse effects
Blinding? (Participant and investigator) High risk Quote: “Investigator-blind study”. “Pa-
tients were instructed to with-hold details
of study medication appearance and dosing
schedule”
Incomplete outcome data addressed? Low risk Missing data: 111/585 (19%) in cefdinir
(Clinical efficacy outcomes) 600 mg once daily group and 112/603
(19%) in amoxicillin-clavulanate group on
day 7 to 14
Quote: “The 3 groups were comparable in
the reasons for their non-evaluability”
data on day 7 to 14
Additional missing data at 3 to 5 weeks
compared to the first follow-up about 12%.
Data not used in the long-term follow-up
meta-analysis
Free of other bias? Funding Unclear risk 3 of the authors were affiliated with a phar-
maceutical company

Hadley 2010
Methods Randomised (2:1), double-blind, multicentre, phase III trial. Diagnosis by clinical signs
and symptoms present for at least 7 days (but less than 28 days) as defined by radiographic
and clinical criteria. Radiographic criteria included the presence of air-fluid levels and/or
opacification on a radiographic paranasal sinus film. Eligible patients had to be at least
18 years of age and had to have 2 major symptoms (purulent anterior or posterior nasal
discharge and unilateral facial pain or malar tenderness) or at least 1 major and 1 minor
symptom (frontal headache or fever). A sinus puncture for bacterial culture of the sinuses
was performed; only culture positive patients with target pathogen (S. pneumoniae, H.
influenzae, M. catarrhalis, Streptococcus pyogenes or Staphylococcus aureus) were included
in the analyses.
Clinical cure was defined as resolution or improvement in the signs and symptoms such
that no further therapy (antimicrobial, corticosteroid or irrigation) was required. Patients
who received rescue therapy were deemed clinical failures. Compliance not reported for
modified intention-to-treat population (which was used in the primary analyses) but
in the per-protocol population 80% compliance was required. Total proportion of the
participants without known clinical outcome 68%. Patients were excluded mostly due
to negative culture or non-target pathogen in it; exclusions because of other reasons 6%
on day 6 to 8
The study was not considered in the primary analysis because the way of reporting left
the exact numbers of failures somewhat unclear. Further, the data were not seen to be
comparable with the data from the other trials (the clinical response was measured already
at days 6 to 8 after start of therapy while other studies included in the meta-analyses did
it at days 10 to 14; unlike the other placebo-controlled trials, in this study isolation of
pathogenic bacteria from the sinus secretion was a prerequisite for inclusion)
The results at day 6 to 8, as reported in the original article, are presented in the Results
section
The study was, however, included in the analysis of “clinical failure defined as a lack of
full recovery or improvement at 16 to 60 days follow-up” (but not pooled)
Participants Participants recruited from 37 centres (ear, nose and throat practices, family practitioners
and general medical clinics). Mean age 39 years; 45 men and 73 women (in modified
intention-to-treat population; 118 out of 374 randomised). ENT co-morbidity was not
assessed. Country - USA

Group 2: placebo once daily for 5 days
The following concomitant medications were allowed: oral or nasal decongestants or

antihistamines, nasal sprays and nasal inhalants containing corticosteroids or corticos-
teroids used as broncho-inhalants if the patient had been on a stable dose for over 4
weeks prior to enrolment and there was no increase of their dose during the study period
Outcomes The modified intention-to-treat population was the main analysis population and con-
sisted of all patients who received at least 1 dose of study drug and whose initial quan-
titative culture was positive. Clinical outcomes were assessed on day 6 to 8 and on day
20 to 26 in 118 of 374 randomised participants (in 73 out of 251 participants in moxi-
floxacin group and in 45 out of 123 participants in placebo group). No radiological or

Hadley 2010 (Continued)
bacteriological outcomes
Notes Study supported by a pharmaceutical company. 3 of the 6 authors were employees of

Risk of bias
Random sequence generation (selection Unclear risk Quote: “multicenter, placebo-controlled,

bias) 2:1 randomized, double-blind, phase IIIb
clinical trial”
Comment: no detailed information pro-

vided
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response dur-
ing therapy and at follow-up, patient-re-
ported symptom improvement, question-
naire scores, assessment of activity impair-
ment via questionnaire and safety
Blinding? (Participant and investigator) Unclear risk Quote: “Double-blinded trial, matching
placebos”
Comment: no detailed information pro-

vided
Incomplete outcome data addressed? Low risk Exclusions from analyses: negative culture
(Clinical efficacy outcomes) or non-target pathogen 161/251 (64%) in
moxifloxacin group and 72/123 (58.5%)
in placebo group; other exclusions 17 (6.
8%) and 6 (4.9%) of participants in mox-
ifloxacin group and placebo group, respec-
tively, on day 6 to 8 and on day 20 to 26
Comment: non-target pathogen or absence
of pathogen was seen not to cause bias.
Other missing data were balanced in num-
bers and reasons across the groups
Free of other bias? Baseline comparability Unclear risk Comment: in the placebo group there were
9% more bilateral sinus infections than in
the moxifloxacin group (38% versus 29%)
and no by-group description was provided
on allowed concomitant medications (es-

Hadley 2010 (Continued)
pecially stable-use nasal corticosteroids)
Free of other bias? Co-interventions Unclear risk Comment: no detailed description of the
use of co-interventions (especially nasal
corticosteroids which may have also cura-
tive effect)
Free of other bias? Funding High risk Study supported by a pharmaceutical com-
pany. 3 of the 6 authors were employees of
Haye 1996
Methods Randomised, double-blind design. Diagnosis established clinically (symptoms lasting for
10 to 30 days) and radiograph showing at least 6 mm mucosal thickening. Culture was
not done. Clinical outcomes assessed by investigator; cure defined as “disappearance of
all pretreatment symptoms relevant to infection.” Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 0.9% on day
10 to 12
Participants Patients recruited from general practices in Norway; 150 men and 288 women. Mean
age 40 (range 19 to 71). ENT co-morbidity was not assessed. Country - Norway

Group 2: phenoxymethylpenicillin 1.3 g 3 times daily for 10 days
Outcomes Clinical outcomes were assessed on day 10 to 12 in 434 out of 438 randomised partic-
ipants and on day 23 to 27 in 436 out of 438 participants. Radiographic and bacterio-
logical outcomes were not reported
Notes 1 of the authors had affiliation to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were computer-ran-
bias) domised in blocks of six to one of two treat-
ment groups”
Allocation concealment (selection bias) Low risk Comment: although there is no exact in-
formation on how the randomisation re-
sult was concealed, the method of sequence
generation and information that placebo
tablets were used give the impression that
the concealment was real

Haye 1996 (Continued)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind, double-dummy

study. Placebo-tablets were used”
Incomplete outcome data addressed? Low risk Missing data: 4/438 on day 10 to 12 and
(Clinical efficacy outcomes) 2/438 participants on day 23 to 27
Comment: marginal missing data rates
Free of other bias? Co-interventions Low risk Quote: “In addition to the clinical assess-
ment, the amount of analgesics taken, com-
pliance, concomitant medication, and ad-
verse events were recorded”
Comment: although there was no informa-
tion on use of analgesics or concomitant
medication, this domain was graded ’low’
risk of bias, because the way of reporting
gives an impression that use of analgesics
and concomitant medication was allowed
for both groups but of such quality that
they would not cause bias
Free of other bias? Funding Unclear risk 1 of the authors had affiliation to a phar-
maceutical company

Haye 1998
Methods Randomised, double-blind, double-dummy design. Clinical diagnosis of acute sinusitis

was based on clinical findings, which had to include 1 or both of the following signs:
presence of nasal secretion (purulent at the time of examination) for > 10 and < 30 days,
and maxillary sinus tenderness and/or pain of < 30 days duration (87% had both signs).
Radiograph was taken to exclude participants with more than 6 mm mucosal thickening,
complete opacity or an air-fluid level. Samples of nasal secretions (cotton-tipped swabs)
were taken from the posterior part of the nasal cavity in 75 participants (only some
samples had the growth of pathogenic bacteria). Clinical failure defined as no change or
a worsening of the pretreatment symptoms and relapse if there was initial improvement
or disappearance of pretreatment symptoms followed by worsening (failure and relapse
figures are combined in the analyses in this review). Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 0.6% on day
10 to 12
Participants Patients recruited from Norwegian General Practices. 44 men and 125 women; mean
age 40 (range 21 to 70) years in the azithromycin group and 43 (range 18 to 68) years
in placebo group. ENT co-morbidity was not assessed. Country - Norway

Group 1: azithromycin 500 mg once daily for 3 days
Group 2: placebo once daily for 3 days
Outcomes Clinical outcomes were assessed on day 10 to 12 in 168 out of 169 participants ran-
domised (in 86 out of 87 patients in antibiotic group and in 82 out of 82 participants
in placebo group) and on day 23 to 27 in 169 participants
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were computer-ran-
bias) domised in blocks of six to either of the two
treatment groups”
generation and information that the tablets
were indistinguishable from each other give
the impression that the concealment was
real
adverse effects

Haye 1998 (Continued)

study. The azithromycin and placebo
tablets were indistinguishable”
was reported to be double-blind and dou-
ble-dummy, and blinding method was
partly described
Incomplete outcome data addressed? Low risk Missing data: 0.6% at 10 to 12 days, and
(Clinical efficacy outcomes) 0% at 23 to 27 days
Comment: minimal missing data rates
Free of other bias? Co-interventions Low risk Quote: “In addition to the clinical assess-
ment, the amount of analgesics taken, com-
pliance, concomitant medication, and ad-
verse events were recorded”
Comment: although there was no informa-
tion on use of analgesics or concomitant
medication, this domain was graded ’low’
risk of bias, because the way of reporting
gives an impression that use of analgesics
and concomitant medication was allowed
for both groups but of such quality that
they would not cause bias
maceutical company

Henry 2003
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms (presence
of either purulent nasal discharge or facial pain and/or pressure and/or tightness for 7
to 28 days), confirmed radiologically by presence of opacity or air-fluid level or mucosal
thickening of more than 6 mm. Mean duration of symptoms prior to enrolment about
13 days. Clinical response was assessed by investigator; cure was defined as resolution of
signs and symptoms to the level that existed prior to the occurrence of the acute illness;
improvement defined as partial but incomplete resolution of the signs and symptoms.
Compliance was measured by investigators reporting exact doses taken, reasons for missed
doses and the amounts of study medication returned by participants at the end of therapy
visit. Compliance was reported as 99% in the 3-day azithromycin group and 82% in
the amoxicillin-clavulanate group. Proportion of the participants included in the per-
protocol population was 85% on day 8 to 15
Participants Multicentre study. 936 outpatients, 381 men and 555 women; mean age was 41 years
(range 18 to 84). Allergic rhinitis was reported in 39% of participants. Country - USA

Outcomes Study reported clinical cure rates for intention-to-treat and per-protocol populations.
However, only per-protocol population could be used as basis for clinical failure rate
calculating in this review because true failures were not reported and there was unclear
description of missing data in the ITT population. Clinical outcomes for per-protocol
population were assessed at days 8 to 15 in 799 out of 941 randomised participants
(in 269 out of 316 patient in azithromycin for 3 days - group and in 259 out of 314
participants in co-amoxiclav group). Second follow-up at days 22 to 36. Radiographic
outcomes were not reported
Notes Study was supported by a grant from a pharmaceutical company
Risk of bias

bias)
adverse effects

Henry 2003 (Continued)
Blinding? (Participant and investigator) Unclear risk Quote: “Double-blind, double-dummy

study”
Comment: no description of the blinding
procedure
Incomplete outcome data addressed? Unclear risk Comment: there was not a clear statement
(Clinical efficacy outcomes) about missing data
Henry 2004
Methods Randomised, double-blind study. Clinical diagnosis (presence of facial pain/pressure/

tightness over 1 or both maxillary sinus areas, facial swelling or toothache, as well as pu-
rulent discharge for > 7 and < 21 days) was confirmed by radiograph or CT (opacification
or air/fluid level). Clinical response was assessed by investigator and cure was defined as
resolution of at least 1 of the acute signs and symptoms of the original infection, with
no worsening in the remaining symptoms or the radiographic appearance of the sinus.
Compliance was assessed by inspection of returned blister cards and by counting unused
study medication; to be clinically evaluable the patient had to have received at least 80%
of study medication. Proportion of the participants without known or reported clinical
outcome 11% on 19 to 24 days
Participants Multicentre, multinational study (USA, Poland). 271 ambulatory participants, 146
women and 95 men, mean age was about 41 years. ENT co-morbidity was not assessed

Group 1: cefdinir 600 mg once daily for 10 days
Group 2: levofloxacin 500 mg once daily for 10 days
There was no restriction on the use of medications for symptom relief (decongestants,
antihistamines)
Outcomes Clinical outcomes were reported for clinically evaluable population only and assessed in
241 out of 271 randomised participants on 19 to 24 days (in 123 out of 138 patients
in cefdinir group and in 118 out of 133 participants in levofloxacin group). Clinically
evaluable population defined as participants who met the study selection criteria, received
at least 80% of the intended amount of study drug, underwent an assessment at 19 to
24 days, and did not receive any other antibiotic before the assessment. Radiographic
outcomes were assessed in 239 participants at 19 to 24 days

Risk of bias
Random sequence generation (selection Low risk Quote: “Computer-generated randomiza-

bias) tion schedule that determined each pa-
tient’s treatment assignment by patient
number”
Allocation concealment (selection bias) Low risk Centralised randomisation

Quote: “Randomisation made by the statis-
tics department of a pharmaceutical com-
pany. Study personnel called a centralized
interactive voice response system to receive
a code/randomization number and the cor-
responding drug”
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Drugs were
over-encapsulated to achieve an identical
appearance. The drugs were prepackaged
and dispensed in blister cards in such a way
that each patient received the appropriate
quantity of active drug for 10 days of ther-
apy”
of investigator blinding), this domain was
Incomplete outcome data addressed? Low risk Missing data: 15/138 (11%) in cefdinir
(Clinical efficacy outcomes) group and 15/133 (11%) in levofloxacin
group on 19 to 24 days


maceutical company
Huck 1993
Methods Randomised, double-blind trial. Diagnosis established by symptoms of acute, recurrent

or chronic sinusitis with a positive radiograph showing, at a minimum, mucosal thick-
ening. Sinus puncture was performed. Clinical outcomes assessed by investigator; im-
provement defined as “the patient’s signs and symptoms had improved or resolved dur-
ing therapy.” No separate categories for “cured” and “improved.” Treatment compliance
reported as about 97% assessed by pills taken by participants. Proportion of the partici-
pants without known or reported clinical outcome 11% for the whole study population
Participants Patients were recruited from community-based otolaryngology clinics. Participants were
38.4 years old on average (range 16 to 73) and included 50 men and 58 women. ENT co-
morbidity was assessed: fewer than 25% of participants had chronic sinusitis. Country
- USA

Group 1: cefaclor 500 mg twice daily for 10 days
Outcomes Clinical outcomes were assessed in 96 out of 108 randomised participants overall. 56
participants with acute sinusitis and 25 participants with recurrent acute sinusitis with
more than 1 episode per year with clinical improvement between episodes were consid-
ered in this review (15 participants with chronic sinusitis were not included). Outcomes
were assessed on day 10 to 12 after randomisation. Radiographic and bacteriological
outcomes were not measured
Risk of bias

bias)

Huck 1993 (Continued)
adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “To maintain
blinding, drugs and placebo were placed in
identical capsules and given to participants
in identical bottles”
Incomplete outcome data addressed? Unclear risk Total amount of missing data 11%
(Clinical efficacy outcomes) Comment: no description of missing data
across intervention groups (when chronic
participants are excluded)
ity at baseline was insufficient to assess
whether the groups were comparable at
baseline or not (no information on severity
rating)
cal company
Jareoncharsri 2004
Methods Randomised, unblinded design. 80% of participants had acute maxillary sinusitis and
20% had acute exacerbation of chronic sinusitis. Diagnosis by clinical symptoms and
signs confirmed by the finding of mucopurulent discharge in the middle meatus or
maxillary ostium as seen by nasal endoscopy and abnormal radiograph (criteria not
specified); about 88% of patients had air-fluid level or opacity on X-ray. Bacteriological
specimens were collected by sinus aspiration. Clinical cure was assessed by investigators
using a 4-point scale; cure was defined as complete resolution of signs and symptoms
with no radiological evidence of remaining disease; improvement defined as incomplete
resolution of signs and symptoms and improvement of radiological findings. Treatment
compliance was not reported. Proportion of participants without known or reported
clinical outcome 2%
Participants Participants (n = 60) were recruited from 2 otolaryngologic centres. Mean age 36 (range
17 to 68); 23 men and 37 women. 20% of participants had acute exacerbation of chronic
sinusitis (n = 12). About 28% of participants had allergic rhinitis. Country - Thailand

Jareoncharsri 2004 (Continued)

Group 2: co-amoxiclav 625 mg 3 times a day for 14 days
Concomitant treatments were not described
Outcomes Clinical outcomes were assessed in 47 out of 48 randomised participants with acute
maxillary sinusitis. Outcomes were assessed on day 21 after the start of treatment. Bac-
teriological outcomes were assessed in 37 participants with acute maxillary sinusitis on
day 14. Radiological findings were not reported separately for participants with acute
maxillary sinusitis
Notes Study was financially supported by a pharmaceutical company
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported for participants with
acute maxillary sinusitis: clinical response
(including radiological findings), bacterio-
logical response and adverse effects
Incomplete outcome data addressed? Low risk Missing data: 2%

(Clinical efficacy outcomes) Comment: marginal missing data rate
Concomitant allergy was more frequent in
levofloxacin group than in co-amoxiclav
group, but this was seen not to cause bias
Free of other bias? Funding High risk Study was financially supported by a phar-
maceutical company

Karma 1991
Methods Randomised, single-blinded trial. Diagnosis was established by at least 1 symptom of

sinusitis plus an antral puncture showing fluid (study protocol required that pathogens
cultured from sinus fluid be susceptible to both the study antibiotics). Radiographs
showed findings “suggestive” of sinusitis. Clinical outcomes were assessed by an inves-
tigator. Clinical cure was defined as “pretreatment signs and symptoms of infection re-
solved.” Improvement was defined as “improvement but not complete resolution of the
infection.” Compliance with treatment was not reported. Total proportion of the partic-
ipants without known or reported clinical outcome 33% on day 11 to 13. Participants
were excluded mostly due to absence of appropriate pathogens in pretreatment cultures;
exclusions because of other reasons marginal (3%)
Participants Participants were recruited from academic, outpatient otolaryngology clinics. Mean age
was approximately 30 (range 17 to 69); 89 men and 11 women. Country - Finland and
Sweden

Group 2: amoxacillin 500 mg every 8 hours for 9 to 11 days
Both groups received oxymetazoline 0.05% twice daily for the first 3 days
50 participants in clarithromycin group and in 35 out of 50 participants in amoxicillin
group) on day 11 to 13. Radiographic and bacteriological outcomes were assessed in 68
participants
Risk of bias

bias)
effects
Blinding? (Participant and investigator) High risk Quote: “Single-blinded study”
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of appro-
(Clinical efficacy outcomes) priate pathogens in pretreatment cultures
16/50 in clarithromycin group and 14/50
in amoxicillin group; other exclusions 2
(4%) and 1 (2%) of participants in clar-

Karma 1991 (Continued)
ithromycin group and amoxicillin group,

respectively
marginal
Klapan 1999
Methods Randomised, unblinded design. Diagnosis based on symptoms (lasting on average 7 days)
and radiograph showing at least 4 mm mucosal thickening, opacity or air-fluid level. Sinus
puncture performed in a subset of participants. Cure defined as complete disappearance
of signs and symptoms; improvement as partial disappearance of symptoms without need
for further antibiotics. Treatment compliance not reported. Proportion of the participants
Participants The study setting not described. Mean age approximately 33 years old (range 15 to 50)
; 77 men and 23 women. Coexisting allergic rhinitis in 30%. Country - Croatia

Group 2: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 days
Outcomes Clinical outcomes assessed on day 10 to 12 in 94 out of 100 randomised participants

(in 47 out of 50 participants in azithromycin group and in 47 out of 50 participants
in amoxicillin-clavulanate group); and 4 weeks after the initiation of treatment in 89
participants. Bacteriological cure assessed in 47 participants. Radiographic outcomes not
reported
Notes 1 of the authors had affiliation to a pharmaceutical company. Copyright by pharmaceu-

tical company
Risk of bias

Klapan 1999 (Continued)

bias)
Incomplete outcome data addressed? Low risk Missing data: 3/50 (6%) in azithromycin
(Clinical efficacy outcomes) group and 3/50 (6%) in amoxicillin-clavu-
lanate group on day 10 to 12. Missing data
6% on day 10 to 12 and 11% at 4 weeks
numbers and reasons for missing data.
Available case data given for both follow-
ups
Free of other bias? Funding High risk 1 of the authors had affiliation to a phar-
maceutical company. Copyright by phar-
maceutical company

Lari 2010
Methods Randomised, single-blinded design. Outpatients, both genders, 18 years or older. Diag-
nosis of acute sinusitis was based on clinical symptoms of postnasal discharge and facial
pain and tenderness in maxillary sinus area for at least 7 and at last 28 days. Cure defined
as complete disappearance of signs and symptoms to the level that existed prior to the
occurrence of the acute illness and without requirement for other antibiotics; improve-
ment (applicable only at the end of the treatment) as partial disappearance of symptoms
without need for further antibiotics. Treatment compliance not reported. Proportion of
the participants without known clinical outcome not reported (results give, however, an
impression that at least at 10 days there are drop-outs)
Data not used in the meta-analysis in this review because exact data and participant
numbers remain unclear at follow-ups (results given only as percentages)
Participants Setting not described. In total 76 patients; detailed demographic characteristics not given.
Patients with chronic sinusitis were excluded (chronic sinusitis was defined as sinusitis 3
or more times during the past 6 months). Country - Iran

Group 1: azithromycin 250 mg (500 mg single dose on the first day and 250 mg once
daily for 4 days)
Group 2: co-amoxiclav 625 mg, 3 times daily for 10 days
Outcomes Clinical outcomes assessed on day 10 and 30 but the numbers of participants are missing
and the results are given only as percentages
Notes There was no identified funding source. 2 authors were employees of a pharmaceutical
company
Risk of bias
Random sequence generation (selection Unclear risk Quote: “This was a single blind random-
bias) ized clinical trial”
No further information provided
Selective reporting (reporting bias) High risk Outcomes reported: clinical responses
Comment: in conclusions it was stated that
“results revealed that azithromycin has less
side effects, and patients were able to tol-
erate the medications better with a higher
compliance and less economic cost than co-
amoxiclav regimen”.
However, any results for adverse effects
were not reported

Lari 2010 (Continued)
Blinding? (Participant and investigator) High risk Quote: “This was a single blind random-
ized clinical trial”
Comment: single-blinded trial
Incomplete outcome data addressed? Unclear risk Comment: the numbers of participants at
(Clinical efficacy outcomes) follow-ups are missing and the results give
an impression that at least at 10 days there
are drop-outs
Free of other bias? Baseline comparability Unclear risk Quote: “Signs and symptoms of patients
in both groups were more or less similar.
Symptoms and signs prevalence and du-
ration of symptoms before treatment were
similar in both therapy groups. Participants
also had similar age distribution”
Comment: no detailed information on the
severity of symptoms and demographic
characteristics
Free of other bias? Funding Unclear risk There was no identified funding source. 2
of the authors had affiliation to a pharma-
ceutical company
Lasko 1998
Methods Randomised, double-blind design. Clinical diagnosis confirmed by radiograph showing >
5 mm mucosal thickening, opacity or air-fluid level. Cure defined by symptom resolution.
Treatment compliance not reported. Proportion of the participants without known or
reported clinical outcome 19%
Participants Setting not described. Mean age 40; 102 men and 134 women. Country - Canada

Group 1: levofloxacin 500 mg daily for 10 to 14 days
Antihistamines and decongestants prohibited
Outcomes Clinical outcomes reported at day 12 to 19 in 191 out of 236 participants randomised
(in 98 out of 119 participants in levofloxacin group and in 93 out of 117 participants
in clarithromycin group). Radiographic and bacteriological outcomes not reported
Notes Study funding provided by a pharmaceutical company. 2 of the authors affiliated to the
same pharmaceutical company
Risk of bias

Lasko 1998 (Continued)
Random sequence generation (selection Low risk Quote: “Patients were assigned either to
bias) levofloxacin 500 mg once daily or to clar-
ithromycin 500 mg twice daily, based on a
computer-generated randomization sched-
ule”
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response and
adverse effects
Comment: in the methods section it is
stated that repeat sinus X-rays were taken
at 42 to 46 days giving the impression that
this was an outcome. However, the results
were not reported
Blinding? (Participant and investigator) Low risk Quote: “Double-blinding was accom-
plished by encapsulation of tablets. The size
of the capsule necessitated the use of the
250 mg tablet and each dose was therefore 2
capsules morning and evening”. “Identical
morning and evening bottles”. “Placebo-
tablets used”
blinding was incomplete (in respect of in-
vestigator), this domain was graded ’low’
risk of bias because the study was reported
to be double-blind and blinding method
was partly described
Incomplete outcome data addressed? Low risk Missing data: 21/119 (18%) in levofloxacin
(Clinical efficacy outcomes) group and in 24/117 (21%) in clar-
ithromycin group
Free of other bias? Co-interventions Low risk No co-interventions allowed
cal company. 2 of the authors affiliated to

Lindbaek 1996
Methods Randomised, double-blind design. Clinical diagnosis of acute sinusitis (> 7 and < 30
days), confirmed by computed tomography (the criteria for confirming the diagnosis
were presence of fluid level or total opacification in any sinus). Bacteriological specimens
were obtained from the nasopharynx of 125 participants (42% had “normal nasal flora”)
. Participants assessed response as “restored”, “much better”, “somewhat better”, “unim-
proved” or “worse”
Treatment compliance was not reported. In total, 12 participants (9%) (5 in the amoxi-
cillin group and 7 in placebo group) did not complete the 10-day course of treatment. 9
were treated with another antimicrobial (2 in the amoxicillin group and 7 in the placebo
group)
10
Participants Participants recruited from Norwegian General Practices. 45 men and 85 women; mean
age 39 (range 16 to 74) years. ENT co-morbidity was not assessed. Country - Norway

Group 1: penicillin V 1320 mg 3 times daily for 10 days
Groups 1 and 2 were combined in the analyses
Nasal decongestants and analgesics were allowed but not prescribed
Outcomes Clinical and radiographic outcomes were assessed on day 10 in 127 out of 130 partici-
pants randomised (in 83 out of 86 participants in antibiotic groups and in 44 out of 44
participants in placebo group)
Notes Study was funded by governmental sources
Risk of bias
Random sequence generation (selection Low risk Quote: “The randomization was per-
bias) formed in blocks of three within each of
the six subgroups (3 subgroups by CT and
2 subgroups by a severity scale) by using a
dice to generate the random allocations”
Comment: randomisation was done by a
statistician (information obtained from the
author)
Allocation concealment (selection bias) Low risk The statistician sent the randomisation list
to the company who produced the med-
ication boxes with numbers according to
the list. The author received the numbered
boxes for each of the subgroups from the
company. The randomisation codes were

Lindbaek 1996 (Continued)
broken after the whole study was finished

Comment: information obtained from the
author
Blinding? (Participant and investigator) Low risk Quote: “The trial was double blind; neither
the patients, the general practitioner, nor
the radiologists were aware of the allocation
of treatment”
Comment: the randomisation codes were
(information obtained from the author)
Incomplete outcome data addressed? Low risk Missing data: 2% on day 10

(Clinical efficacy outcomes) Comment: marginal missing data rate
rating at baseline but actual numbers are
not given
Free of other bias? Co-interventions Low risk Quote: “Nasal decongestants and mild
analgesics allowed in both groups”
Free of other bias? Funding Low risk Study was funded by governmental sources
Lindbaek 1998
Methods Same study as Lindbaek 1996 but separate randomised population.

Randomised, double-blind design. Clinical diagnosis of acute sinusitis (> 7 and < 30
days), confirmed by computed tomography showing mucosal thickening of 5 mm or
more in any sinus without fluid level or total opacification. Patients assessed response
as “restored”, “much better”, “somewhat better”, “unimproved” or “worse”. Treatment
compliance was not reported. Proportion of the participants without known or reported
clinical outcome 7.4% on day 10
Participants Patients recruited from Norwegian General Practices. 27 men and 43 women; mean age
40 (range 16 to 83) years. ENT co-morbidity was not assessed. Country - Norway


Group 1: penicillin V 1320 mg 3 times daily for 10 days
Groups 1 and 2 combined in the analyses.
Nasal decongestants and analgesics were allowed but not prescribed
Outcomes Clinical outcomes (based on patient diary) were assessed on day 10 in 63 out of 68
participants randomised (no information for drop-outs per group)
Notes Study was funded by governmental sources
Risk of bias
Random sequence generation (selection Low risk A dice

bias) Comment: information obtained from the
author
Allocation concealment (selection bias) Low risk The statistician sent the randomisation re-
sults to the company who produced the
medication boxes. The author received the
numbered boxes from the company. The
randomisation codes were broken after the
whole study was finished
Comment: information obtained from the
author
adverse effects
Blinding? (Participant and investigator) Low risk Quote: “The trial was double-blind: Nei-
ther the patients, the general practitioner,
nor the radiologists were aware of the treat-
ment allocation”
Comment: the randomisation codes were
(information obtained from the author)
Incomplete outcome data addressed? Low risk Total drop-out rate 5/68 (7.4%)
(Clinical efficacy outcomes) Comment: although there were no exact
numbers on the drop-out rates across the 3
groups, this domain was graded ’low’ risk
of bias. The total drop-out rate was seen

as marginal. Further, the author gave in-

formation that there were drop-outs in all
groups
Free of other bias? Co-interventions Low risk Quote: “Nasal decongestants and mild
analgesics allowed in both groups”
Free of other bias? Funding Low risk Study was funded by governmental sources
Luterman 2003
Methods Randomised, double-blind trial. Diagnosis by clinical symptoms and by radiograph

showing air-fluid level, opacity or at least 6 mm mucosal thickening. Sinus puncture
performed in a small subset of participants. About 60% of participants had had symp-
toms for longer than 7 days before enrolment to the study. Clinical cure defined as dis-
appearance of infection, clinical improvement or a return to the preinfection state with
regard to all signs and symptoms and sinus X-ray findings that were normal, improved
or at least not worse. Treatment compliance was reported with over 90% of participants
in each group taking at least 70% of their doses. Proportion of the participants without
known or reported clinical outcome 44% on day 17 to 24 and therefore data are not
used in the meta-analyses in this review
Participants Multicentre, multinational trial (USA, Canada, South Africa, Argentina and Chile). De-
mographic data reported for modified intention-to-treat population at baseline: partic-
ipants’ mean age was 39 years (range 16 to 84); 248 men and 359 women. ENT co-
morbidity was not assessed

Outcomes Results reported for per-protocol population only. Clinical outcomes were assessed on
day 17 to 24 in 423 out of 754 randomised participants; and on day 31 to 45 in
399 participants. The per-protocol population was defined as participants who met the
diagnostic criteria and had no major protocol violation. Bacteriological outcomes were
assessed in 24 participants

Luterman 2003 (Continued)
Notes Study funded by an unrestricted grant from a pharmaceutical company
Risk of bias

bias)
cluding radiological findings) and bacteri-
ological response for a small proportion of
the participants, adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “The iden-
tity of all drugs was concealed by placing
them in identical opaque capsules. Placebo-
capsules were also used”
Incomplete outcome data addressed? High risk Total missing data 44% on day 17 to 24
(Clinical efficacy outcomes)
Free of other bias? Baseline comparability Unclear risk Comment: the demographic and severity
rating reported only on modified inten-
tion-to-treat population, not on the per-
protocol population used in analysis of the
study
Free of other bias? Funding Unclear risk Study funded by an unrestricted grant from

Marple 2010
Methods Randomised, open-label study. Clinical diagnosis of acute sinusitis was based on signs
and symptoms lasting for between 7 and 30 days (pain, pressure and/or tightness as-
sociated with 1 or both maxillary sinuses that worsened with movement or percussion,
and discoloured (yellow-green) nasal discharge or discoloured drainage in the posterior
pharynx or from the maxillary sinus orifice, together with 2 or more of fever, frequent
coughing, nasal congestion or postnasal drainage). Treatment success by day 28 (the
only time point eligible in this review) was defined as resolution of symptoms within the
study period, no unscheduled sinusitis visits and no additional antibiotics prescribed for
sinusitis. Treatment compliance not reported. Proportion of the participants included
in the per-protocol population was 62% on day 28; data not used in the meta-analyses
of this review
Participants Multicentre study, participants were recruited in primary care settings by 70 study inves-
tigators. Demographic data for per-protocol population at baseline: participants’ mean
age was 46 years; 151 men and 323 women. ENT co-morbidity was assessed; about 37%
of participants had history of allergic rhinitis. Country - USA

Group 1: azithromycin extended release (2 g), single dose
Group 2: amoxicillin-clavulanate potassium 875 mg/125 mg 2 times daily for 10 days
Outcomes Clinical responses on day 28 were reported for per-protocol population only. Clinical
responses (based on follow-up telephone interviews) were assessed on day 28 in 462 out
of 751 participants randomised (in 231 out of 380 participants in azithromycin group
and in 231 out of 371 participants in amoxicillin-clavulanate group). The per-protocol
population was defined as all eligible randomised participants who completed the diary
and first telephone interview (at day 5) and reported taking at least 1 dose of the study
medication
Notes The study was sponsored by a pharmaceutical company. 3 of the authors had affiliation
to, and other 3 of the authors were paid consultants of, the same pharmaceutical company
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses,
quality of life, satisfaction with treatment
and adverse effects

Marple 2010 (Continued)
Incomplete outcome data addressed? High risk Missing data: 149/380 (39%) in azithro-
(Clinical efficacy outcomes) mycin group and 140/371 (38%) in amox-
icillin-clavulanate group on day 28
Comment: total missing data over 20%
rating for per-protocol population to assess
the comparability of the groups at baseline
Free of other bias? Funding High risk The study was sponsored by a pharmaceu-
tical company. 3 of the authors had affili-
ation to, and other 3 of the authors were
paid consultants of, the same pharmaceu-
tical company
Matthews 1997
Methods Randomised, unblinded design. Diagnosis by clinical symptoms and signs, confirmed by
radiograph showing opacity, clouding or air-fluid level. Bacteriological specimens were
obtained by antral puncture. Acute and chronic sinusitis included (acute reported sepa-
rately). Success defined as cure or improvement. Proportion of the participants without
known or reported clinical outcome 24% among participants with acute sinusitis. Data
not used in the meta-analyses of this review because time points for outcome measure
were not clearly reported
Participants Participants recruited from otolaryngology clinics. Mean age of 42 (range 18 to 78). 93
of 182 participants had acute sinusitis. Country - USA
Interventions 2 treatment groups

Group 1: cefixime 400 mg once daily for 10 to 14 days
Aspirin prohibited. Acetaminophen, antacids and nasal decongestants were permitted
Outcomes Clinical outcomes reported in 71 out of 93 randomised participants with acute sinusitis
(in 37 out of 49 participants in cefixime group and in 34 out of 44 participants in amox-
icillin group). Bacteriological outcomes assessed in 32 participants with acute sinusitis.
Drop-outs due to adverse events reported for acute and chronic sinusitis combined
Notes Study funding not stated
Risk of bias

Matthews 1997 (Continued)
Random sequence generation (selection Low risk Quote: “Patients were randomized by a
bias) computer-generated schedule to receive
oral doses of either 400 mg of cefixime
once daily or 500 mg of amoxicillin every
8 hours”
logic responses, and adverse effects
Blinding? (Participant and investigator) High risk Quote: “Open label study”
Incomplete outcome data addressed? High risk Missing data: 12/49 (24%) in cefixime
(Clinical efficacy outcomes) group and 10/44 (23%) in amoxicillin
group
Comment: missing data over 20%
was insufficient to assess whether the in-
tervention groups with acute sinusitis were
comparable at baseline or not

Free of other bias? Funding Unclear risk Study funding not stated
Mattucci 1986
Methods Randomised trial; unblinded. Diagnosis was established by a clinical diagnosis of acute
sinusitis plus a radiograph showing “clouding” of the nasal sinus and a positive culture
from or near the sinus ostium. Clinical outcomes were assessed by an investigator; clinical
cure was not defined. Compliance with treatment was not reported. Proportion of the
participants without known or reported clinical outcome 19%
Participants Patients were recruited from outpatient otolaryngology clinics. Participants were 40 years
old on average (range 12 to 76) and included 23 men and 35 women. ENT co-morbidity
was not assessed. Country - USA

Group 1: minocycline 100 mg twice daily for 10 to 20 days (mean 11.6)
Group 2: amoxicillin 250 mg every 8 hours for 10 to 20 days (mean 11.4)
Mattucci 1986 (Continued)
Both groups were allowed to take decongestants or analgesics but these were not pre-
scribed by the investigators (all of the participants took decongestants during the trial)
Outcomes Clinical outcomes were assessed in 47 out of 58 randomised participants (in 25 out of 29
participants in minocycline group and in 22 out of 29 participants in amoxicillin group)
. Outcomes were assessed on day 10 to 20 after randomisation. Radiographic outcomes
were assessed in 42 participants and bacteriological in 46
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, radi-
ological response for 42 participants, bacte-
riological response for 46 participants and
adverse effects
Incomplete outcome data addressed? Unclear risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 3/29 in
minocycline group and 3/29 in amoxicillin
group; other exclusions 1 (3.4%) and 4 (13.
8%) of participants in minocycline group
and amoxicillin group, respectively
seen not to cause bias. Other missing
data in numbers not balanced between the
groups
Free of other bias? Baseline comparability High risk Quote: “The proportion of participants
with severe sinusitis 68% in minocycline
group and 43% in amoxicillin group”


Mattucci 1986 (Continued)
Meltzer 2005
Methods Randomised, double-blind, double-dummy, placebo-controlled study. Clinical diagno-

sis of acute sinusitis was based on clinical findings with signs and symptoms of acute
rhinosinusitis lasting at least 7 but less than 29 days. In addition, the major symptom
score (MSS) had to be at least 5 but less than 13 at screening and baseline visits with no
more than 3 of the 5 symptoms rated severe. MSS was defined as sum of the scores for
rhinorrhoea, postnasal drip, nasal congestion/stuffiness, sinus headache and facial pain/
pressure/tenderness on palpation over the paranasal sinuses (each scaled from 0 (none)
to 3 (severe)). Duration of symptoms at enrolment 6 to 14 days in 61% of participants in
amoxicillin group and 58% in placebo group (out of the total 981 randomised patients
9 were enrolled with 6 days’ duration of symptoms instead of the originally specified
minimum of 7 days). Participants were excluded if they had signs or symptoms suggestive
of fulminant bacterial rhinosinusitis.
Clinical failure defined by worsening or no improvement of symptoms by day 3 to 4 or
thereafter jointly evaluated by the investigator and the participant. Protocol noncom-
pliance 1% in amoxicillin and placebo groups. Proportion of the participants without
known or reported clinical outcome 1.8% by day 15
Participants Participants recruited from 71 medical centres in 14 countries. Study population con-
sisted of a total of 981 randomised patients in 4 groups: 243 in mometasone furoate nasal
spray (MFNS) 200 µg once daily, 235 in MFNS 200 µg twice daily, 251 in amoxicillin
and 252 in placebo. 338 men and 643 women; mean age 35 years (4% of participants
were 12 to 17 years of age in amoxicillin group and 6% in placebo group). ENT co-
morbidity: 42% of participants had either seasonal or perennial allergic rhinitis in amox-
icillin and placebo groups

Group 1: MFNS 200 µg in the morning with placebo spray in the evening for 15 days
plus placebo capsules 3 times daily for 10 days
Group 2: MFNS 200 µg in the morning and evening for 15 days plus placebo capsules
3 times daily for 10 days
Group 3: Amoxicillin 500 mg 3 times daily for 10 days plus placebo nasal spray twice
daily for 15 days
Group 4: Placebo capsules 3 times daily for 10 days plus placebo nasal spray twice daily
for 15 days
Groups 3 and 4 considered in this review.
Concomitant medications that would interfere with study evaluations were not permit-
ted, including nasal saline, nasal cromolyn sodium, ipratropium bromide, corticosteroids
(excluding oral inhaled corticosteroids for mild to moderate persistent asthma), antihis-
tamines, decongestants and leukotriene pathway modifiers. Analgesics and nonsteroidal
anti-inflammatory drugs were prohibited for the treatment of acute rhinosinusitis
Outcomes The original article reported the total failure rates during the 15-day treatment phase per
group but exact numbers of the assessed participants were not given (only numbers and
reasons for discontinued participants per group). It remains unclear whether all other

Meltzer 2005 (Continued)
discontinued participants than those lost to follow-up were assessed or not. The original
article used intention-to-treat principle in the analyses. We decided to exclude in our
analyses those randomised participants who were reported to be lost to follow-up (1 in
antibiotic group and 4 in placebo group) and those 4 participants in placebo group who
did not meet the protocol criteria for entry. Thus clinical failures were assessed during
the 15-day treatment phase in 494 out of 503 randomised participants (in 250 out of
251 participants in amoxicillin group and in 244 out of 252 participants in placebo
group). Figures for failures at the follow-up phase (days 16 to 29) not given
Notes Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated
to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Randomisation was performed ac-
bias) cording to a computer-generated code,
stratified on the basis of duration of rhi-
nosinusitis symptoms before baseline (7-14
days and 15-28 days)”
generation of this multicentre study (71
centres in 14 countries) and information
that placebo nasal sprays and placebo cap-
sules were used, give the impression that
the concealment was real
adverse effects

study. Those receiving amoxicillin a match-
ing placebo nasal spray twice daily; patients
randomized to placebo received placebo
capsules 3 times daily and placebo nasal
spray twice daily”
was reported to be double-blind and dou-
ble-dummy, and blinding method was
partly described

Meltzer 2005 (Continued)
Incomplete outcome data addressed? Low risk Missing data: 1/251 (0.4%) in amoxicillin
(Clinical efficacy outcomes) group and in 8/252 (3.2%) in placebo
group
Free of other bias? Co-interventions Low risk Quote: “Concomitant medications that
would interfere with study evaluations were
not permitted”
Comment: medications that might cause
bias were prohibited
maceutical company. 1 of the authors was
affiliated to a pharmaceutical company
Merenstein 2005
Methods Randomised, double-blind design. Clinical diagnosis of acute sinusitis was based on
clinical findings, which had to include at least 1 of the following: purulent nasal discharge
predominating on 1 side, facial pain on 1 side, purulent nasal discharge on both sides,
pus in the nasal cavity, lasting for at least 7 days. About 50% of participants had at least
2 of these signs at baseline (the study did not report any subjective symptoms); mean
duration of symptoms prior to enrolment 11 days. Clinical cure defined as dichotomous
- either “completely improved” or “not improved”. Treatment compliance not reported.
14
Participants Participants recruited from a suburban primary care office. 42 men and 93 women; mean
age 34 years. ENT co-morbidity was not assessed. Country - USA

Group 1: amoxicillin 500 mg twice daily for 10 days
Group 2: placebo twice daily for 10 days
Over-the-counter medications were allowed in both groups (information obtained from
the authors)
Outcomes Clinical outcomes (based on follow-up telephone interviews of participants) were assessed
on day 14 in 116 out of 135 participants randomised (in 56 out of 67 participants in
antibiotic group and in 60 out of 68 participants in placebo group)
Notes Study was funded mostly by academic sources

Risk of bias
Random sequence generation (selection Low risk Quote: “Permuted block randomization
bias) stratified for the 3 participating clinicians
was used to determine treatment assign-
ment”
Comment: computer-generated by a statis-
tician who gave the authors a list to follow
(information obtained from the authors)
Allocation concealment (selection bias) Low risk Comment: a statistician made the ran-
domisation and gave the authors a list that
they followed (information obtained from
the authors)
Selective reporting (reporting bias) Low risk Outcomes reported: several clinical re-
sponses and adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Patients were given an enve-
lope containing either a placebo medicine
taken twice daily for 10 days or antibiotic
medicine taken twice daily for 10 days. The
envelopes were opaque, and each had 40
identical-appearing pills”
Comment: the authors followed the ran-
domisation list without knowing which
medicine was given to each patient (infor-
mation obtained from the authors)
Incomplete outcome data addressed? Low risk Missing data: 16.4% (11/67) in antibiotic
(Clinical efficacy outcomes) group and 11.8% (8/68) in placebo group
at 14 days
data
comparability of the groups at baseline.
The groups appeared to be balanced at
baseline


Merenstein 2005 (Continued)
Free of other bias? Funding Low risk Funded mostly by academic sources
Murray 2005
Methods Randomised, double-blind trial. Clinical diagnosis of acute sinusitis (> 6 and < 29 days)
, confirmed by radiograph (the criteria for confirming the diagnosis were presence of air-
fluid level or total or partial opacification). Sinus puncture for all participants. Clinical
outcomes were assessed by an investigator. Clinical failure was defined as the persistence
or worsening of signs and symptoms requiring additional antibiotics or development
of new signs and symptoms requiring antibiotics. Treatment compliance reported over
96%. Proportion of the participants without known or reported clinical outcome 6%
Participants Multicentre study; 81 outpatient centres in the United States, India, Europe and Latin
America. 225 men and 313 women; mean age 38 (range 18 to 88) years. ENT co-
morbidity was assessed; about one-third of participants suffered from allergic rhinitis

Group 1: azithromycin-microspheres 2 g single dose
Outcomes Clinical outcomes were assessed at days 17 to 24 in 507 out of 541 participants ran-
domised. Bacteriologic outcomes assessed in 213 participants
Notes Study funded by a pharmaceutical company. 2 of the authors were affiliated to a phar-
maceutical company
Risk of bias

bias)
logic responses, clinical response by base-
line pathogen and adverse effects

trial”. “Placebo medication used”
Murray 2005 (Continued)

Incomplete outcome data addressed? Low risk Missing data: 14/270 (5%) in azithromy-
(Clinical efficacy outcomes) cin group and 17/268 (6%) in levofloxacin
group
The information on number of randomised
participants across groups was insuffi-
ciently reported. In calculating the missing
data, the population who received at least
1 dose of study medication was used as the
baseline population (missing only 3 partic-
ipants from the total randomised popula-
tion)
Comment: although reasons for missing
data across groups were not reported, this
cause missing data were marginal and bal-
anced in numbers
Although the information was provided
only for the whole treated population (not
for clinically evaluable population which
was the primary efficacy endpoint) this do-
main was graded ’low’ risk of bias because
the missing data rate was small
Free of other bias? Funding High risk Study funded by a pharmaceutical com-
pany. 2 of the authors were affiliated to a

Nyffenegger 1991
Methods Randomised, unblinded study. Diagnosis was established by a clinical diagnosis of acute
sinusitis, confirmed by a radiograph (criteria were not specified), transillumination and
a positive bacterial culture obtained from samples of discharge from the sinuses. Clinical
outcomes were assessed by an investigator. Clinical cure was defined as complete disap-
pearance of clinical symptoms at completion of treatment; improvement was defined as
a clear regression of the clinical symptomatology. Compliance with treatment was not
reported. Proportion of the participants without known or reported clinical outcome
0%
Participants Participants were recruited from an outpatient otolaryngology clinic. Participants repre-
sented a convenience sample, not a consecutive series. Participants were 37.8 years old
on average (range 18 to 75) and included 30 men and 50 women. ENT co-morbidity
was not assessed. Country - Switzerland

Group 1: brodimoprim 200 mg once daily for 7 to 10 days
Mucolytic nose drops and steam inhalations were allowed but not prescribed as part of
the intervention
Outcomes Clinical outcomes were assessed in 80 out of 80 randomised participants. Outcomes were
assessed on day 7 to 10 after randomisation. Radiographic outcomes were not reported.
Bacteriological outcomes were reported for 40 participants
Notes 2 of the authors were affiliated to pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “According to a computer-gener-

bias) ated list, the patients were randomly as-
signed to receive 200 mg of brodimoprim
once daily or 750 mg of amoxicillin three
times daily for seven to 10 days”
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response, bac-
teriological response for 40 patients and ad-
verse effects
Comment: it remains unclear why only a
proportion of the population was included
in the bacteriological response and how
were they selected
Blinding? (Participant and investigator) High risk Quote: “Unblinded study”

Nyffenegger 1991 (Continued)
Incomplete outcome data addressed? Low risk Missing data rate 0%

graphic characteristics. However, no infor-
mation on the severity rating across the
groups

Free of other bias? Funding Unclear risk 2 of the authors were affiliated to pharma-
ceutical company
O’Doherty 1996
Methods Randomised, unblinded design. Participants with otitis media, pharyngitis/tonsillitis

or sinusitis included. Sinusitis diagnosis was established clinically and confirmed by
a radiograph (criteria not given). Throat swabs, nasopharyngeal swabs or exudates, as
appropriate, were collected for bacterial culture. Clinical outcomes were assessed by
an investigator; clinical cure defined as “disappearance of all signs and symptoms of
infection”. Compliance with treatment was not reported. Proportion of the participants
Participants Recruitment settings were not described. Mean age was 35 for all diagnoses. ENT co-
morbidity was not assessed. Countries - UK, Ireland

Group 2: cefaclor 250 mg 3 times daily for 10 days
Adjuvant treatments were not described
Outcomes Clinical outcomes were assessed on day 11 to 15 and reported separately for 78 out of
91 randomised participants with sinusitis (in 41 out of 48 participants in azithromycin
group and in 37 out of 43 participants in cefaclor group). Radiographic outcomes were
not reported. Bacteriological outcomes were assessed in 18 participants
Risk of bias

O’Doherty 1996 (Continued)

bias)
teriological response for 18 participants
and adverse effects
Incomplete outcome data addressed? Unclear risk Missing data: 7/48 (15%) in azithromycin
(Clinical efficacy outcomes) group and 6/43 (14%) in cefaclor group on
day 11 to 15
Comment: no information on reasons for
missing data separately for sinusitis partic-
ipants across groups
(information not stated separately for par-
ticipants with sinusitis)
Olmo 1994
Methods Randomised, obviously unblinded design. Diagnosis was established by clinical symp-
toms and a radiograph showing sinus opacity or air-fluid level. 66% of participants had
positive culture. Clinical outcomes were assessed by an investigator; clinical cure was
“remission of symptoms within the treatment time”. Compliance with treatment was
not reported. Proportion of the participants without known or reported clinical outcome
0% on day 24 to 26
Participants Participants were recruited from emergency rooms. Mean age was not reported (>= 20
for inclusion); 28 men and 19 women. ENT co-morbidity was not assessed. Country -
Spain

Adjuvant therapies were not described

Olmo 1994 (Continued)
Outcomes Overall clinical outcomes (including also radiological response and bacteriological re-
sponse for those participants with positive culture at baseline) were assessed in 48 out of
48 randomised participants on day 24 to 26. Bacteriological outcomes were also reported
separately for the 31 participants with positive culture at baseline
Risk of bias
Random sequence generation (selection Low risk Quote: “Random numbers table”
bias)
teriological response and adverse effects
Incomplete outcome data addressed? Low risk No missing data

Otte 1983
Methods Randomised, double-blind design. Diagnosis based on symptoms and abnormal radio-
graph (criteria not given). Bacteriological culture was performed. Clinical cure based on
resolution of symptoms and normal radiograph. Treatment compliance was not reported.
10
Participants Patients recruited from outpatient otolaryngology clinics. Mean age was 32 (range 17 to
56); 12 men and 19 women. ENT co-morbidity was not assessed. Country - Chile

Otte 1983 (Continued)

Group 1: sulfamethopyrazin 200 mg/ trimethoprim 250 mg, 2 doses on day 1, then 1
dose per day for 10 days
Group 2: tetracycline 500 mg 4 times daily for 10 days
Outcomes Clinical outcomes were assessed on day 10 in all 31 participants randomised. Radiolog-
ical outcomes reported on day 20 in 31 participants, bacteriological outcomes for 27
participants
Risk of bias

bias)
ical responses for all participants, bacterio-
logical response for a proportion of the par-
ticipants and adverse effects
tables were used; antibiotics and placebo
tablets were identical. Tablets were deliv-
ered in numbered envelopes”
Incomplete outcome data addressed? Low risk Missing data rate 0%


Pessey 1996
Methods Randomised, open design. Diagnosis established clinically and by a radiograph showing
at least 5 mm mucosal thickening, sinus opacity or fluid-level. Clinical outcomes were
assessed by an investigator and clinical cure was defined as resolution of clinical symptoms
and radiographic cure or improvement. Compliance with treatment was not reported.
10 to 15
Participants Participants were recruited from community, otolaryngology clinics. Mean age = 43; 99
men and 143 women. Country - France

Group 1: cefixime 200 mg twice daily for 4 days (+ placebo for 6 days)
Group 2: cefixime 200 mg twice daily for 10 days
Group 3: amoxicillin clavulanic acid 500 mg 3 times daily for 10 days
All groups received prednisolone 40 mg daily and oxymetazoline 3 sprays daily for 4
days
ipants (in 85 out of 87 participants in cefixime for 10 days group and in 77 out of 82
participants in amoxicillin clavulanic acid group). Second follow-up on day 33. Radio-
graphic outcome was not reported separately
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: overall response in-
cluding clinical and radiological responses,
and adverse effects
Blinding? (Participant and investigator) High risk Quote: “Open study” (when comparing
group 2 to group 3)
Incomplete outcome data addressed? Low risk Missing data: 2/87 (2.3%) in cefixime
(Clinical efficacy outcomes) group and 5/82 (6.1%) in amoxicillin
clavulanic acid group on day 10 to 15. To-
tal missing data 4% on day 10 to 15 and
9% on day 33
Comment: missing data rate marginal on
day 10 to 15. The judgement on day 33 was

Pessey 1996 (Continued)
’unclear’ because the study did not report

the reasons for missing data by study groups
Free of other bias? Co-interventions Low risk Comment: groups received the same co-
interventions during the trial
maceutical company(?)
Pessey 2001
Methods Randomised, double-blind design. Diagnosis based on clinical signs and symptoms con-
firmed by radiograph (total opacity of sinus or air-fluid level). Culture based on an as-
pirate from the middle meatus; 52% of participants had positive cultures. Clinical cure
based on resolution of symptoms. Treatment compliance over 90%. Proportion of the
participants without known or reported clinical outcome 0.6% on day 10 to 12
Participants Multicentre study; 47 community-based ENT specialists in 10 regions. Mean age = 43

years; men 141 and 167 women. ENT co-morbidity was not assessed. Country - France

Group 1: pristinamycin 1000 mg 2 times daily for 8 days
Nasal decongestants prescribed for 3 days. Corticosteroids prohibited
ipants (in 160 out of 161 participants in pristinamycin group and in 148 out of 149
participants in cefuroxime axetil group). Follow-up (29 to 36 days) for those participants
who were cured at the end of treatment. Participant-related radiographic and bacterio-
logical outcomes were not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Treatment was allocated by means
bias) of a randomization code. The randomiza-
tion was balanced in each center by blocks
of 4 participants”

Pessey 2001 (Continued)

Allocation concealment (selection bias) Low risk Quote: “Sealed individual envelopes con-
taining the identification of the treatment
to be administered to each patient were
handed to each investigator”
allocation concealment was incomplete,
this domain was graded ’low’ risk of bias
because the way of reporting the blinding
also gives an impression of adequate alloca-
tion concealment
adverse effects

study”. “Sealed individual envelopes con-
taining the identification of the treatment
to be administered to each patient were
handed to each investigator. The code
number of each patient was noted on each
of the envelopes. The treatments had to be
assigned by the investigator in ascending
order of the numbers on the envelopes”
Incomplete outcome data addressed? Low risk Missing data: 1/161 (0.6%) in pristi-
(Clinical efficacy outcomes) namycin group and 1/149 (0.7%) in ce-
Free of other bias? Co-interventions Low risk Comment: in both groups the same con-
comitant medication was prescribed

Rakkar 2001
Methods Randomised, unblinded design. Diagnosis of acute sinusitis was based on clinical findings
(purulent nasal discharge, nasal congestion, postnasal drainage, frequent coughing or
throat clearing, frontal headache, malar tenderness/pain); lasting for at least 7 days.
Clinical response was assessed by investigator and it was defined as disappearance of
acute signs and symptoms related to the infection or sufficient improvement such that
additional or alternative antimicrobial therapy was not required. Treatment compliance
not reported but to be included in the per-protocol population the patient had to have
received at least 80% of study medication. Proportion of the participants included in
the per-protocol population was 72% on day 24 to 31
Participants Multicentre study; primary care participants. 156 men and 315 women; mean age ap-
proximately 42 (range 18 to 87) years. ENT co-morbidity was not assessed. Country -
USA

Group 2: amoxicillin clavulanate 875 mg twice daily for 10 days
Use of oral or nasal decongestants or antihistamines was permitted; systemic or topical
corticosteroids were not allowed
Outcomes Available case data were basically possible to extract for per-protocol population only.
However, the way of reporting does not enable identification of clinical failure rates
because of inconsistent description of clinical response in results (it remains unclear in
which outcome group improvements are included). Clinical outcomes for per-protocol
population on day 24 to 31 were reported in 341 out of 475 randomised participants (in
170 out of 238 participants in moxifloxacin group and in 171 out of 237 participants in
amoxicillin clavulanate group). (The per-protocol population included all participants
with no major protocol violation who had received a study antibiotic for at least 72 hours
if a clinical failure, had completed the evaluation at 14 to 21 days post-treatment, and had
adequate compliance documented with at least 80% of study medication administered)
Notes Study supported by a research grant from a pharmaceutical company. 2 of the authors
were affiliated to the same pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Block design random code”
bias) Comment: although the description of the
adverse effects

Rakkar 2001 (Continued)

Blinding? (Participant and investigator) High risk Quote: “Non-blinded”
Incomplete outcome data addressed? High risk Missing data: 68/238 (29%) in moxi-
(Clinical efficacy outcomes) floxacin group and 66/237 (28%) in amox-
icillin clavulanate group
Comment: missing data rate over 20%

Free of other bias? Funding High risk Study supported by a research grant from a
were affiliated to the same pharmaceutical
company
Riffer 2005
Methods Randomised, investigator-blinded design. Diagnosis by clinical symptoms and opacifi-

cation or an air/fluid level in a sinus radiograph or CT. Sinus fluid samples were obtained
by aspiration or fibreoptic endoscopy. Clinical cure defined as resolution or improvement
in purulent nasal discharge and at least 1 additional sinusitis sign or symptom observed
at baseline. Treatment compliance at least 80% for those participants who were included
in the clinically evaluable population. Proportion of the participants without known or
reported clinical outcome 16% on day 16 to 18
Participants Multicentre, multi-country trial. Mean age was 37 (range 13 to 79); 194 men and 243
women. ENT co-morbidity was not assessed

Group 1: clarithromycin ER 1000 mg once daily for 14 days
Group 2: amoxicillin/clavulanate 875/125 mg twice daily for 14 days
Oral sympathomimetic agents, nasal decongestants and antihistamines were used by 23.
8%, 8.9% and 6.9% of participants, respectively
Outcomes Study reported clinical cure rates for intention-to-treat and clinically evaluable popu-
lations. However, only clinically evaluable population could be used as basis for clin-
ical failure rate calculation in this review because true failures were not reported and

Riffer 2005 (Continued)
it seemed that indeterminate and missing responses were included in failures in ITT
analyses. Clinical outcomes were assessed on day 16 to 18 in 373 of 437 randomised
participants (in 188 out of 221 participants in clarithromycin group and in 185 out of
216 participants in amoxicillin-clavulanate group) and on day 24 to 31 in 361 partic-
ipants. The clinically evaluable population was defined as all randomised participants
with clinically and radiographically confirmed sinusitis, and were without major protocol
violations. Bacteriological outcomes assessed on day 16 to 18 in 109 of 218 participants.
Radiographic outcomes assessed on day 24 to 31 in 366 of 423 participants. Quality of
life measured by symptom assessment and the SNOT-16 test
Notes The study was supported by a grant from a pharmaceutical company
Risk of bias

bias)
and bacteriological responses, adverse ef-
fects and quality of life
Blinding? (Participant and investigator) High risk Quote: investigator-blinded study. To

maintain the study blind, participants were
instructed not to discuss the appearance of
study drug or any aspect of dosing with the
investigator
Incomplete outcome data addressed? Low risk Missing data: 33/188 (17.5%) in clar-
amoxicillin-clavulanate group on day 16 to
18. Total missing data 16% on day 16 to
18 and 17% day 24 to 31
data

Riffer 2005 (Continued)

Free of other bias? Funding High risk The study was supported by a grant from a
Russell 1997
Methods Randomised trial. Blinding not stated. Diagnosis by clinical signs and symptoms, con-
firmed by X-ray or CT (opacification, air/fluid level or mucosal thickening). Clinical
outcomes were assessed by an investigator; clinical cure defined as all clinical signs and
symptoms were resolved and no new clinical signs and symptoms were present and/or the
follow-up radiograph showed resolution/improvement. Approximately 80% of partici-
pants received the prescribed antibiotic course. Proportion of the participants without
known or reported clinical outcome 12% on day 20 to 35
Participants Study setting not described. Mean age was approximately 38 (range 13 to 79); 172
men and 256 women. 84% of participants had a history of ENT or eye-related medical
conditions. Country - USA
Interventions 3 treatment arms: (groups 1 and 3 used in the analysis)

Group 1: cefprozil 250 mg twice daily for 10 to 15 days
Group 2: cefprozil 500 mg twice daily for 10 to 15 days
Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily for 10 to 15 days
Adjuvant therapies permitted but not described
Outcomes Clinical outcomes were assessed on day 20 to 35 in 428 out of 479 participants (in 146
out of 158 participants in cefprozil 250 mg group, in 147 out of 160 participants in
cefprozil 500 mg group and in 135 out of 161 participants in amoxicillin-clavulanate
group). Radiographic and bacteriological outcomes not reported
Notes Study was supported by a pharmaceutical company. 3 of the authors were affiliated to
Risk of bias

bias)

Russell 1997 (Continued)
adverse effects
Incomplete outcome data addressed? High risk Missing data: 12/158 (8%) in cefprozil 250
(Clinical efficacy outcomes) mg group and 26/161 (16%) in amoxi-
cillin-clavulanate group on day 20 to 35
Comment: the groups were imbalanced in
numbers of missing data
company. 3 of the authors were affiliated to
Sher 2002
Methods Randomised, investigator-blinded design. Diagnosis by clinical signs and symptoms last-
ing at least 7 days, confirmed by radiograph showing at least 5 mm mucosal thickening,
opacification or air fluid level in a sinus radiograph. Clinical outcomes were assessed by
an investigator and clinical cure was defined as improvement in or resolution of all acute
signs and symptoms of the original infection, with no need for further antimicrobial
therapy. Treatment compliance for clinically evaluable population over 80% by counting
unused study medication. Proportion of the participants without known or reported
clinical outcome 9%
Participants Multicentre study; 30 centres. Participants were 42 years old on average (range 18 to
89); 159 men and 286 women. ENT co-morbidity was assessed; for example, 60% of
participants had a history of allergic rhinitis. Country - USA
Interventions 3 treatments arms

Group 1: gatifloxacin 400 mg once daily for 5 days
Group 2: gatifloxacin 400 mg once daily for 10 days
Group 3: amoxicillin/clavulanate 875 mg twice daily for 10 days
Medications for symptom relief (for example, decongestants and antihistamines) were
allowed

Sher 2002 (Continued)
Outcomes Study reported results for clinically evaluable participants only. Clinical outcomes were
assessed on day 10 to 13 and on day 17 to 24 in 405 out of 445 randomised participants
(in 137 out of 149 participants in 5-day gatifloxacin group, in 127 out of 141 participants
in 10-day gatifloxacin group and in 141 out of 155 participants in amoxicillin-clavulanate
group). Clinically evaluable participants were those who met the inclusion criteria and
had received at least 80% of the intended amount of study drug, had undergone the test-
of-cure assessment (7 to 14 days after the completion of treatment), and had not received
any other antibiotic during the study or before the test-of-cure visit for an infection other
than sinusitis. Long-term follow-up on day 31 to 38 by telephone
Radiographic and bacteriological outcomes not reported
Notes 2 of the authors were affiliated with a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were randomized to treat-
bias) ment by means of a centralized telephone
system. A permuted block design was used
to minimize imbalance in treatment arms
at each site and in the study overall”
Allocation concealment (selection bias) Low risk Quote: “Patients were randomized to treat-
ment by means of a centralized telephone
system. A permuted block design was used
to minimize imbalance in treatment arms
at each site and in the study overall”
adverse effects
Blinding? (Participant and investigator) Unclear risk Quote: “Investigator-blinded trial”.

“Matching placebo-tablets were used, and
drugs and placebos were supplied by the re-
spective manufacturers”
Comment: although blinding of partici-
pants was also described, this domain was
graded ’unclear’ because the study was re-
ported to be only investigator-blinded
Incomplete outcome data addressed? Low risk Missing data: 12/149 (8%) in 5-day gat-
(Clinical efficacy outcomes) ifloxacin group, 14/141 (10%) in 10-day
gatifloxacin group and 14/155 (9%) in
amoxicillin/clavulanate group
Quote: “The 40 unevaluable participants

Sher 2002 (Continued)
were distributed evenly between groups

and between reasons for non-evaluability”
Comment: although there was no detailed
description of the reasons for missing data,
this domain was graded ’low’ risk of bias be-
cause the study stated that the groups were
balanced
rating at baseline to assess the comparability
of the groups for whole randomised pop-
ulation, not separately for clinically evalu-
able population

comitant medication was allowed and of
such quality that it does not have effect on
recovery (thus not cause bias)
Free of other bias? Funding Unclear risk 2 of the authors were affiliated with a phar-
maceutical company
Siegert 2000
Methods Randomised, double-blind trial. Diagnosis by clinical signs and symptoms, confirmed
by radiograph (mucosal thickening, opacification or air-fluid level) or bacteriologically
(either by a swab collected under endoscopic view, cannulation of the middle meatus
or a sinus puncture; positive cultures were obtained in 52% of participants). Clinical
cure was not defined. Treatment compliance not reported. Proportion of the participants
Participants Multicentre (60 centres), multinational trial (Finland, France, Germany, Greece, Israel,
Spain, Sweden). Mean age 40; 220 men, 273 women. ENT co-morbidity not reported

Group 1: cefuroxime axetil 250 mg twice daily, 10 days
Group 2: moxifloxacin 400 mg daily, 7 days
Nasal decongestants and mucolytic drugs allowed; systemic or topical corticosteroids not
allowed
Outcomes Clinical outcomes assessed on day 14 in 468 out of 493 randomised (in 241 out of 251
participants in cefuroxime axetil group and in 227 out of 242 participants in moxifloxacin
group). Bacteriological outcomes in 224; radiographic outcomes not assessed

Siegert 2000 (Continued)
Risk of bias

bias)
teriological response for 224 participants
and adverse effects
capsules used”
Incomplete outcome data addressed? Low risk Missing data: 10/251 (4%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 15/242 (6%) in moxi-
floxacin group on day 14
Free of other bias? Baseline comparability Unclear risk Comment: it appears that the groups were
imbalanced in respect of severity of the si-
nusitis (more participants with severe dis-
ease in moxifloxacin group)

maceutical company

Siegert 2003
Methods Randomised, double-blind trial. Diagnosis by clinical symptoms and radiograph show-
ing at least 6 mm mucosal thickening, opacification or air-fluid level. Sinus material
for bacteriological culture by puncture or by middle meatus swab under endoscopic
guidance. Clinical cure defined as disappearance of signs and symptoms or significant
improvement and no further therapy required. Treatment compliance was not reported.
14 to 23
Participants Multicentre, multinational trial. Participants were enrolled by otolaryngologists at 43

centres in 7 countries: France, Germany, Greece, Israel, Lithuania, Spain and Sweden.
Participants were 42 years old on average and included 193 men and 259 women. ENT
co-morbidity was not assessed

Group 1: faropenem daloxate 300 mg twice daily for 7 days
Decongestants, antihistamines and mucolytics were allowed. Intranasal or oral corticos-
teroids were not permitted
Outcomes Study reported clinical responses for clinically evaluable patients only. Clinical outcomes
assessed on day 14 to 23 in 452 out of 558 randomised participants (in 228 out of
279 participants in faropenem daloxate group and in 224 out of 279 participants in
cefuroxime axetil group). Clinically evaluable population was defined as patients who
had clinically and radiologically confirmed diagnosis, did not receive any concomitant
antimicrobials and/or corticosteroids, and were assessed on day 14 to 23. Bacteriological
outcomes were assessed in 136 participants
Notes Study was supported by a grant from a pharmaceutical company. 2 of the authors were
affiliated to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were randomly assigned
bias) 1:1 to one of two treatment groups using a
block design computer-generated random
code”
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “For blind-
ing purposes, matched placebos were used
in one group and encapsulated tablets in

Siegert 2003 (Continued)
the other group”

Incomplete outcome data addressed? Unclear risk Missing data: 51/279 (18%) in faropenem
(Clinical efficacy outcomes) daloxate group and 55/279 (20%) in ce-
Comment: reasons for missing data across
groups insufficiently described

were affiliated to a pharmaceutical com-
pany
SSG 1993
Methods Randomised, double-blind trial. Diagnosis was established by purulent rhinorrhoea, a

radiograph consistent with sinusitis or a sinus puncture and that isolated a bacterial
pathogen (about 50% of participants had a pathogen). Clinical outcomes were assessed
by an investigator. Clinical cure was defined as resolution of pretreatment signs and
symptoms and no recurrence within 72 hours post-treatment; improvement was defined
as a reduction in the number or severity of signs and symptoms but without complete
resolution. Compliance with treatment was not reported. Proportion of the participants
Participants Participants were recruited from outpatient otolaryngology clinics. Demographic data
reported only for evaluable participants (defined as participants with isolated bacterial
pathogen plus no protocol violations): mean age approximately 35 (range 16 to 73);
186 men and 152 women. ENT co-morbidity was not assessed. Countries - Sweden,
Finland, Iceland

Group 1: loracarbef 400 mg twice daily for 10 days

SSG 1993 (Continued)
Group 2: doxycycline 200 mg first dose followed by 100 mg daily for 10 days
Outcomes Clinical outcomes were assessed in 648 out of 662 randomised participants (in 323 out
of 330 participants in doxycycline group and in 325 out of 332 participants in loracarbef
group). Outcomes were assessed on day 7 to 13 after randomisation. Radiographic
outcomes were not reported. Bacteriological outcomes were assessed in 324 participants
Notes Study was financially supported by a pharmaceutical company
Risk of bias

bias)
teriological response for those participants
who had positive culture at baseline and ad-
verse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “Participants in

the doxycycline group also received a cap-
sule containing a placebo in order to en-
sure blinding of both the participants and
observers”
Incomplete outcome data addressed? Low risk Missing data: 7/332 (2%) in loracarbef
(Clinical efficacy outcomes) group and 7/330 (2%) in doxycycline
group
Comment: minimal missing data rate
of intervention and control groups at base-
line reported only from evaluable partici-
pants which was half of the enrolled popu-
lation

SSG 1993 (Continued)
maceutical company
Stefansson 1998
Methods Randomised, double-blind trial. Diagnosis by symptoms and sinus opacity or air-fluid
level on radiograph. Cure defined as clinical signs and symptoms improved or resolved
at post-treatment (11 to 13 days) and radiographically confirmed absence at follow-up
(38 to 45 days). Treatment compliance was not reported. Proportion of the participants
Participants Study setting not described. Mean age 37; 157 men and 213 women. ENT co-morbidity
was not assessed. Countries - 8 European, Middle Eastern and African

Group 2: clarithromycin 250 mg twice daily for 10 days
Nasal corticosteroids prohibited; other adjuvant treatments not described
Outcomes Clinical outcomes were assessed on day 11 to 13 in 354 out of 370 randomised partici-
pants. Second follow-up on day 38 to 45 in 310 participants
Risk of bias

bias)
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response (in-
cluding also radiological findings at second
follow-up) and adverse effects
Comment: the radiological responses are
reported also separately. It remains unclear
whether radiological response was an inde-
pendent outcome or not
tablets used”

Stefansson 1998 (Continued)

Incomplete outcome data addressed? Low risk Missing data: 10/185 (5%) in cefurox-
(Clinical efficacy outcomes) ime axetil group and 6/185 (3%) in clar-
ithromycin group at 11 to 13 days (primary
outcome)
Comment: this assessment has been based
on the numbers given in a table. Although
the corresponding exact numbers given in
the text were slightly different, this domain
was graded ’low’ risk of bias because the
missing data rate is marginal

ceutical company
Sterkers 1997
Methods Randomised, unblinded design. Diagnosis by symptoms (duration not described) and
fluid or opacity on radiograph. Clinical cure defined as disappearance of purulent nasal
discharge. Treatment compliance not reported. Proportion of the participants without
known or reported clinical outcome 13%
Participants Multicentre, but settings not described. Mean age approximately 41; 178 men and 280
women. Country - France
Interventions 3 treatment arms: (only group 1 - the standard dosing and group 3 used in the analysis)
Group 1: ceftibuten 400 mg once daily for 8 days
Group 2: ceftibuten 200 mg twice daily for 8 days
Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily
Adjuvant treatments not described
Outcomes Overall, clinical and radiographic outcomes reported on day 10 in 400 out of 458
randomised participants (in 134 participants out of 152 in ceftibuten 400 mg once daily
group; 138 out of 157 in ceftibuten 200 mg twice daily group and 128 out of 149

Sterkers 1997 (Continued)
participants in amoxicillin-clavulanate group); 50 excluded post-randomisation due to

negative radiograph. Second follow-up on day 40 after randomisation
Notes Funding source not identified
Risk of bias

bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radio-
graphic responses, and adverse affects
Incomplete outcome data addressed? Unclear risk Total missing data 13% on day 10 and 14%
(Clinical efficacy outcomes) on day 40
Comment: no description of reasons for
missing data across groups
Free of other bias? Funding Unclear risk Funding source not identified

Steurer 2000
Methods Randomised, investigator-blinded trial. Diagnosis by clinical signs and symptoms, con-
firmed by a radiograph (criteria not specified). Sinus aspirate and culture (1 or more
pathogens were isolated from the maxillary sinus aspirates of 66% participants). Clinical
cure defined dichotomously - “cure” or “failure”. Compliance not reported. Proportion
of randomised participants without known clinical outcome was not reported. Study
reported only clinical cure rates for intention-to-treat population (all randomised partic-
ipants) and for “evaluable” population (participants all of whose clinical and microbial
data were available). The data from this study were not used in the meta-analyses of this
review because all non-cures in the ITT population (11%) were categorised as failures
in analyses (it remains unclear how many responses were true failures in each group and
how much was missing data); the missing data in the “evaluable” population was high
(52%)
Participants Participants recruited from 16 medical centres throughout Europe. Setting not described.
Mean age 31; 336 men, 233 women. ENT co-morbidity not reported

Group 1: cefdinir 600 mg daily, 10 days
Group 2: cefdinir 300 mg twice daily, 10 days
Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily, 10 days
Topical nasal decongestants with xylomethazoline, oxymethazoline or naphazoline were
permitted but not prescribed
Outcomes Study did not report description of missing data. Study reported only clinical cure rates for
intention-to-treat population and all clinical responses were known only for “evaluable”
populations. Clinical outcomes for “evaluable population” were reported on day 17 to
25 and on day 31 to 35 in 295 out of 569 randomised participants (in 93 participants
out of 182 in cefdinir 600 mg once daily group, in 96 out of 198 in cefdinir 300 mg
twice daily group and in 106 out of 189 participants in amoxicillin-clavulanate group)
. Radiographic outcomes reported on day 17 to 25 for 295. Bacteriological outcomes
reported in 248
Notes Study sponsored by a pharmaceutical company
Risk of bias
Random sequence generation (selection Unclear risk Quote: “For each study centre an indepen-
bias) dent randomized schedule was prepared”
Allocation concealment (selection bias) Low risk Quote: “Study monitored by a pharmaceu-
tical company. Medication was dispensed
by a third person and all records concern-
ing medications were kept in a separate lo-
cation”

Steurer 2000 (Continued)
effects
Blinding? (Participant and investigator) High risk Quote: “Participants were given consecu-
tive patient numbers after screening. As
this was investigator-blinded study, medi-
cation was dispensed by a third person and
all records concerning medications were
kept in a separate location. The participants
were instructed not to reveal the type of
medication to the investigator”
Incomplete outcome data addressed? High risk Missing data: 89/182 (49%) in cefdinir
(Clinical efficacy outcomes) 600 mg once daily group, 102/198 (52%)
in cefdinir 300 mg twice daily group, and
83/189 (44%) in amoxicillin-clavulanate
group on day 17 to 25

Free of other bias? Funding High risk Study sponsored by a pharmaceutical com-
pany

Sydnor 1992
Methods Randomised, single-blind (investigator). Diagnosis was confirmed by a clinical diagnosis

of acute sinusitis and a radiograph consistent with sinusitis (showing mucosal thickening
at a minimum). A bacteriologic culture of aspirated maxillary sinus fluid; evaluable
patients were required to have positive cultures of pathogens susceptible to both study
antibiotics. Clinical cure was not defined. Compliance with therapy was not reported.
Total proportion of the participants without known clinical outcome 62%. Participants
were excluded mostly due to bacteriologic reasons; exclusions because of other reasons
marginal 2%
Participants The study setting was not well described. Participants’ mean age was approximately 38
(range 18 to 78); 39 men and 74 women. Country - USA

Group 1: loracarbef 400 mg twice daily for 7 to 10 days
Group 2: amoxicillin clavulanate 500 mg/125 mg 3 times daily for 7 to 10 days
No information provided on symptomatic medication for sinusitis
Outcomes Clinical outcomes were assessed on day 7 to 13 in 43 of 113 randomised participants

(in 22 out of 59 participants in loracarbef group and in 21 out of 54 participants in
amoxicillin-clavulanate group). Second follow-up at 1 to 2 weeks after the conclusion of
therapy for those participants with favourable symptomatic responses at the first follow-
up. Radiographic outcomes were not reported; bacteriological outcomes were reported
for 28 participants
Notes Study supported by grants from a pharmaceutical company. 1 of the authors was affiliated
to the same pharmaceutical company
Risk of bias

bias)
logic responses, and adverse effects
Blinding? (Participant and investigator) High risk Quote: “Investigator-blinded”
Incomplete outcome data addressed? Low risk Exclusions from analyses: bacteriologic rea-
(Clinical efficacy outcomes) sons 36/59 in loracarbef group and 32/
54 in amoxicillin clavulanate group; other
exclusions 1 (2%) and 1 (2%) of par-
ticipants, respectively. (Bacteriologic rea-
sons included resistant causative organ-
Sydnor 1992 (Continued)
isms, negative pre-therapy cultures for

pathogens, and no or low colony counts on
pre-therapy isolates)
Comment: the bacteriologic reasons were
marginal
Free of other bias? Funding High risk Study supported by grants from a pharma-
ceutical company. 1 of the authors was affil-
iated to the same pharmaceutical company
Upchurch 2006
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms > 7 days
but < 28 days, confirmed by radiograph showing air fluid level, opacification and/or at
least 6 mm mucosal thickening. Clinical outcomes were assessed by an investigator and
clinical cure was defined as resolution or improvement of clinical symptoms and signs
such that no additional antimicrobial treatment was necessary. Treatment compliance
91%. Proportion of the participants included in the efficacy-valid population was 78%
on day 17 to 31
Participants Multicentre trial (57 centres) in USA and Canada. 1099 outpatients, 481 male and 618
women. Participants were 43 years old on average (range 15 to 90). 37% of participants
had a history of allergic rhinitis

Group 1: faropenem medoxomil 300 mg twice daily for 7 days
Group 2: faropenem medoxomil 300 mg twice daily for 10 days
Oral or nasal decongestants or antihistamines were allowed; systemic or topical corticos-
teroids not permitted
Outcomes Study reported clinical cure rates for intention-to-treat and efficacy-valid populations.
However, only efficacy-valid population could be used as basis for clinical failure rate
calculating in this review because true failures were not reported and both indeterminate
and missing responses were included in failures in ITT analyses. Clinical outcomes for
efficacy-valid population were assessed on day 17 to 31 in 861 out of 1106 randomised
participants (in 295 out of 370 participants in faropenem medoxomil for 7 days group, in
280 out of 365 participants in faropenem medoxomil for 10 days group, and in 286 out
of 371 participants in cefuroxime axetil group). Efficacy-valid population was defined
as participants who met inclusion criteria, had radiologically confirmed sinusitis, study

Upchurch 2006 (Continued)
drug given for a minimum of 72 hours for participants considered treatment failures
and a minimum of 5 days to be a treatment success, adequate adherence documented
with over 80% of medication, absence of any protocol violation influencing treatment
efficacy, and no essential data missing or indeterminate. Second follow-up 28 to 38 days
post-treatment. Radiographic outcomes not reported
Notes Funding for trial provided by a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Participants were randomly as-
bias) signed in a 1:1:1, double-blind fashion by
using a computer-generated random code
to one of three oral-treatment groups”
adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Because
faropenem medoxomil could not be encap-
sulated, a double-dummy design was used
to maintain blinding”. “Matching placebo-
capsules used”
blinding was incomplete (no description
Incomplete outcome data addressed? High risk Missing data: 75/370 (20%) in faropenem
(Clinical efficacy outcomes) medoxomil for 7 days group, 85/365
(23%) in faropenem medoxomil for 10
days group and 85/371 (23%) in cefurox-
ime axetil group on day 17 to 31
Free of other bias? Baseline comparability Low risk Quote: “Demographic and baseline medi-
cal characteristics for the efficacy-valid pop-
ulation were generally consistent with those
of the intent-to-treat population”
Comment: although data on baseline com-

Upchurch 2006 (Continued)
parability were only shown for the ITT

population (not separately for efficacy-
valid population), this domain was graded
’low’ risk of bias because the authors stated
that also the efficacy-valid groups were
comparable

Free of other bias? Funding High risk Funding for trial provided by a pharmaceu-
tical company
van Buchem 1997
Methods Randomised, double-blind design. Diagnosis made clinically (the mean duration of
the symptomatic period before treatment was 2.2 weeks), confirmed by radiograph
showing > 5 mm mucosal thickening, opacity or air-fluid level. Clinical cure was not
defined. Treatment compliance reported as 98% assessed by pills taking by participants.
14
Participants Participants were recruited from community-based, general medical practices. Mean age
was 34; 79 men and 135 women. ENT co-morbidity was assessed; approximately 12%
had allergic disease. Country - The Netherlands

Adjuvant therapy with oxymetazoline steam inhalation (duration not specified). Parac-
etamol as needed
Outcomes Clinical and radiographic outcomes were assessed on day 14 for 206 out of 214 partici-
pants randomised (in 105 out of 108 participants in antibiotic group and in 101 out of
106 participants in placebo group). Long-term relapse rates during 1 year. Bacteriological
outcomes were not assessed
Risk of bias
Random sequence generation (selection Low risk Quote: “The randomization of allocation
bias) of the amoxycillin or placebo (distributed

van Buchem 1997 (Continued)
in identical bottles) was computer gener-

ated”
Allocation concealment (selection bias) Low risk Quote: “Randomisation of patients was
carried out and capsules were provided by
the hospital pharmacy in the hospital were
patients were to see the ENT specialist. The
code of the allocation schedule was kept in
the office of the head of the hospital phar-
macy, and was broken prematurely only if
a severe clinical development or severe ad-
verse effects occurred”
Comment: central allocation
ical responses, relapses, chronic evolution
and adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Neither the pharmacist’s assistant
who distributed the bottles (identical bot-
tles for both groups), the patient, nor the
ENT specialist was aware of the nature of
the medication”
Incomplete outcome data addressed? Low risk Missing data: 2.7% (3/108) in antibiotic
(Clinical efficacy outcomes) group and 4.7% (5/106) in placebo group
at 14 days
Free of other bias? Funding Unclear risk No information provided

von Sydow 1995
Methods Randomised, double-blind design. Diagnosis based on clinical symptoms and radiograph
showing air-fluid level or opacity (verified by sinus aspiration). Failure defined as clinical
signs and sinus X-ray points unchanged or worsened. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 10%
Participants Participants recruited from academic affiliated, otolaryngology practices. Mean age 33
(range 18 to 78); 149 men and 137 women. ENT co-morbidity was not assessed. Coun-
tries - Sweden, Finland, Norway

Group 1: cefpodoxime proxetil 200 mg twice daily for 10 days
Group 2: amoxicillin 750 mg twice daily for 10 days
All participants received xylometazoline (nasal decongestant) for up to 7 days
Outcomes Clinical outcomes were assessed on day 11 to 20 in 258 out of 286 participants ran-
domised (in 130 out of 143 participants in cefpodoxime proxetil group and in 128 out
of 143 participants in amoxicillin group). Bacteriological outcomes reported in 150 par-
ticipants
Notes Study was financially supported by a pharmaceutical company. 1 of the authors had
affiliation to pharmaceutical company
Risk of bias

bias)
Selective reporting (reporting bias) High risk Outcomes reported: clinical response (in-
cluding radiological findings), bacteriolog-
ical response for 150 participants and ad-
verse effects
Comment: in the protocol it is stated that
the second follow-up would be at days 28 to
35. Those results are, however, not reported
Blinding? (Participant and investigator) Unclear risk Quote: “Double-blind, double-dummy

study”
Comment: no description of the blinding
procedure
Incomplete outcome data addressed? Low risk Missing data: 13/143 (9.1%) in cefpo-
(Clinical efficacy outcomes) doxime proxetil group and 15/143 (10.5%)
in amoxicillin group
Comment: although description of the rea-
sons for the missing data by group was un-

von Sydow 1995 (Continued)
clear this domain was graded ’low’ risk of

bias because the total missing data rate was
moderate and balanced
maceutical company. 1 of the authors had
affiliation to a pharmaceutical company
ABMS: acute bacterial maxillary sinusitis

BID: twice daily
CT: computerised tomography (scan)
ENT: ear, nose and throat
ITT: intention-to-treat
mITT: modified intention-to-treat
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Agbim 1974 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before
study entry not reported). Results not reported separately for participants with acute sinusitis
Alvart 1992 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Axelsson 1971 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes
Axelsson 1973 Antibiotic versus antibiotic - study design. Not randomised study
Axelsson 1975 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes, only radiological
outcomes
Axelsson 1981 Antibiotic versus antibiotic - study design. Not randomised study
Bandak 1999 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
study entry not reported)

(Continued)
Beatson 1985 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition
reported for acute sinusitis)
Bockmeyer 1994 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
study entry not reported; bacteriological specimens taken from nasal discharge)
Brodie 1989 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis mainly by clinical signs and symptoms but the minimum duration of those
before study entry not reported)
Brook 2006 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes
Bucher 2003 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; only 32% of participants had symptoms for 7
days or longer before study entry)
Carenfelt 1975 Antibiotic versus antibiotic - study design. Random allocation not stated
Casiano 1991 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute sinusitis
Correa 1986 Antibiotic versus antibiotic - study design. Clinical outcomes measured are clinical plus bacteriological; they
are not separated individually
De Abate 1992 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition
reported for acute sinusitis)
De Sutter 2002 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; about 50% of participants with symptoms less
than 7 days at study entry). The information obtained from the authors
Edelstein 1993 Antibiotic versus antibiotic - study design. Approximately 50% of participants with acute exacerbation of
chronic sinusitis. Results not reported separately for acute maxillary sinusitis
Ekedahl 1987 Antibiotic versus antibiotic - study design. No clinical outcomes

Insufficient information on intervention groups
Elies 2001 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled; proportion of
included complicated cases (frontal sinusitis or pansinusitis) was not reported
Falser 1988 Antibiotic versus antibiotic - study design including participants with otitis and sinusitis. Results not reported
separately for participants with sinusitis
Federspil 1983 Antibiotic versus antibiotic - study design. Mixed ENT infections. Sample size for acute sinusitis < 30

(Continued)
Felstead 1991 Antibiotic versus antibiotic - study design. The criteria for diagnosis of acute maxillary sinusitis not clearly
stated
Fiscella 1991 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30 (the total number
of the participants was > 30, but about 50% of participants had acute exacerbation of chronic sinusitis)
Freche 1988 Antibiotic versus antibiotic - study design. The definition of acute maxillary sinusitis unclear
Gananca 1973 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (definition of sinusitis by clinical signs and symptoms or by X-ray not reported;
bacteriological specimens taken from purulent nasal discharge, site not specified)
Gananca 1977 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings without detailed description of signs and symp-
toms and duration)
Garcia 1998 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Gladkov 1979 Antibiotic versus dexamethazone and formaldehyde - study design. Randomisation not stated. Sample size
for acute sinusitis < 30
Goumas 1997 Antibiotic versus antibiotic - study design. Quasi-randomised design
Gurdogan 2001 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Gwaltney 1981 Antibiotic versus antibiotic - study design. Randomised trial for some of the participants. Out of 113 partic-
ipants randomised only 32 had outcomes reported. Uncertain if outcomes relate only to those randomised
Hansen 2000 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; at least 50% of participants had symptoms
lasting for 6 days or less at study entry)
Hebblethwaite 1987 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis insufficiently
stated
Henry 1999a Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (the duration of symptoms before study entry not reported; the diagnosis in 30% of
participants not confirmed by X-ray)
Henry 1999b Antibiotic versus antibiotic - study design. Unclear data, contradictory results in table and text
Husfeldt 1993 Antibiotic versus antibiotic - study design. Random allocation not stated
Jeppesen 1970 Antibiotic versus placebo - study design. Quasi-randomised design. Puncture and irrigation (every second
day) used as co-intervention. Sample size for acute maxillary sinusitis < 30
Johnson 1999 Antibiotic versus antibiotic - study design. Approximately 30% of participants had acute exacerbation of

(Continued)
Karpov 1998 Antibiotic versus antibiotic - study design

Puncture used as co-intervention
Klein 1998 Antibiotic versus antibiotic - study design. Approximately 60% of participants had acute exacerbation of
Lacroix 2002 Study mainly designed to identify signs to predict the presence of bacteria in acute rhinosinusitis (including
common cold and acute sinusitis). Inclusion criteria for the study did not fulfil the inclusion criteria for this
review (69% of patients had other URTIs than sinusitis confirmed by X-ray; median duration of clinical
symptoms 4 days for all randomised patients; data not reported separately for patients with acute sinusitis)
Li 2000 Antibiotic versus antibiotic - study design. Approximately 67% of participants had chronic sinusitis. Ran-
domisation unclear
Lopez 1975 Sample size for acute sinusitis < 30 (7 participants)
Luchikhin 2005 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30
Mannhardt 1980 Antibiotic versus antibiotic - study design. Mixed sample of acute (n = 30) and chronic (n = 22) sinusitis.
Only combined results are reported
Manzini 1993 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary
sinusitis
Marchi 1990 Antibiotic versus antibiotic - study design. Random allocation not stated
Marcolino 1999 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (clinical symptoms lasting at least 4 weeks)
Mesure 1973 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (no definition of acute maxillary sinusitis). Sample size for acute sinusitis < 30
Mira 2001 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30. Insufficient information on
diagnostic criteria for acute maxillary sinusitis
Miyamoto 2005 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)
Moorhouse 1985 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
Norrelund 1978 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
Olsson 1976 Antibiotic versus antibiotic - study design. Questionable random allocation. Sample size for acute sinusitis
< 30
Osman 1983 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis not stated

(Continued)
Pallestrini 1995 Antibiotic versus antibiotic - study design. Approximately 27% of participants had acute exacerbation of
Panosetti 1992 Antibiotic versus antibiotic - study design. Hospitalised participants, ENT ward
Peyramond 1991 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; duration of symptoms before study entry not stated)
Piragine 1988 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30 (7 participants)
Podvinec 1982 Antibiotic versus antibiotic - study design. Mixed sample of acute (< 80%) and chronic sinusitis. Results
not reported separately
Polonovski 2006 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis, median duration of symptoms 4 days before study entry)
Quick 1973 Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis <
30
Quick 1975 Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis <
30
Rantanen 1973 Antibiotic versus no antibiotic - study design. Study design not suitable for this review because weekly
irrigation was used as co-intervention. Random allocation not stated
Rechtweg 2004 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Riedel 1987 Study design comparing antibiotic + serrapeptase versus serrapeptase. Not a randomised study
Rimmer 1997 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for sinusitis
Roenning 1987 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review
Overall clinical outcomes not reported
Sabater 1995 Antibiotic versus antibiotic - study design. Assessment of the study was based on the abstract. Additional
information was requested from the authors to assess the adequacy of the study for this review but the
authors were not able to deliver the necessary information
Salmi 1986 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Salmi 1993 Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Sample size for acute sinusitis
< 30. Insufficient information on diagnostic criteria for acute maxillary sinusitis
Schering-Plough 2003 Unpublished study (assessment of the study based on the study synopsis which was obtained from the
pharmaceutical company). The study was a randomised clinical trial comparing intranasal corticosteroid
with antibiotic and placebo. In the synopsis, definition of outcome and data were not in a usable form for
this review
(Continued)
Serra 2007 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (sinusitis not defined by clinical signs and symptoms; microbiological evaluation
reported to be based on specimens taken by swab without specification of where they were taken from)
Spindler 1985 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (criteria for acute
sinusitis not reported)
Stahl 1989 Antibiotic versus antibiotic - study design. Included also other URTI than sinusitis. Inclusion criteria for
this review not fulfilled: criteria for acute sinusitis not reported, the proportion of participants with chronic
sinusitis > 20% and clinical outcomes for acute sinusitis not reported separately
Stalman 1997a Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; duration of symptoms reported to have lasted at
least 5 days). Additional information was requested from the authors about the proportion of the participants
with symptoms for less than 7 days but the authors were not able to deliver the information
Strachunskii 1993 Antibiotic versus antibiotic - study design. Not randomised study
Sydnor 1989 Antibiotic versus antibiotic - study design. No clinical outcomes
Söderström 1991 Antibiotic versus antibiotic - study design. Clinical outcomes not measured for sinusitis (included also other
URTI)
Taub 1967 RCT comparing bromelains + antibiotics to antibiotics

Diagnostic criteria for sinusitis not stated. Sample size for acute maxillary sinusitis < 30
Varonen 2003a Antibiotics versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (about 27% of participants with symptoms for less than 6 days at study entry.
Ultrasound positive about 50% of participants)
von Sydow 1984 Antibiotic versus antibiotic - study design. Insufficient information (for example, the follow-up time and
duration of the therapy were not stated)
Wallace 1985 Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Insufficient information on
diagnostic criteria for acute maxillary sinusitis
Weis 1998 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
study entry not reported)
Westerman 1975 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary
sinusitis
Williamson 2007 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; only 57% of participants had symptoms for 7
days or longer at study entry). The information was obtained from the authors

(Continued)
Young 2003 The study design mainly intended to examine the diagnostic indicators for acute bacterial rhinosinusitis
than comparing antibiotic versus placebo. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms; median duration of symptoms 4 days)
Zbären 1983 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30
RCT: randomised controlled trial

URTI: upper respiratory tract infection

DATA AND ANALYSES
Comparison 1. Antibiotics versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Clinical failure defined as a lack 5 1058 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.47, 0.94]
of full recovery or improvement
at 7 to 15 days of follow-up
2 Clinical failure defined as a lack 2 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
of full recovery at 7 to 15 days
of follow-up
4 Clinical failure defined as a lack 1 169 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.38, 1.05]
of full recovery at 16 to 60 days
of follow-up
5 Relapse rates after 60 days 1 214 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.72, 2.19]
6 Drop-outs due to adverse effects 9 1818 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.40 [0.60, 3.25]
Comparison 2. Cephalosporin/macrolide versus amoxicillin-clavulanate
No. of No. of
1 Ceph versus amox-clav; clinical 6 1887 Risk Ratio (M-H, Random, 95% CI) 1.37 [1.04, 1.80]
failure defined as a lack of full
recovery or improvement at 7
to 15 days of follow-up
2 Ceph versus amox-clav; clinical 7 1415 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.85, 1.37]
failure defined as lack of full
recovery or improvement at 16
to 60 days of follow-up
(cephalosporins)
4 Macrolides versus amox-clav; 7 1807 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.62, 1.13]
clinical failure defined as a lack
5 Macrolides versus amox-clav; 4 908 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.57, 1.27]
clinical failure defined as a lack
(macrolides)

Comparison 3. Non-penicillin antibiotics versus beta-lactamase sensitive penicillins
No. of No. of
2 Clinical failure defined as a lack 1 436 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.37, 1.20]
Comparison 4. Tetracyclines versus mixed classes of antibiotics
No. of No. of

Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Clinical failure defined as a lack of full
recovery or improvement at 7 to 15 days of follow-up.
Review: Antibiotics for acute maxillary sinusitis in adults
Comparison: 1 Antibiotics versus placebo
Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Study or subgroup Antibiotics Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Haye 1998 6/86 9/82 12.3 % 0.64 [ 0.24, 1.71 ]
Lindbaek 1996 2/83 5/44 4.7 % 0.21 [ 0.04, 1.05 ]
Lindbaek 1998 5/42 3/21 6.8 % 0.83 [ 0.22, 3.16 ]
Meltzer 2005 18/250 27/244 37.0 % 0.65 [ 0.37, 1.15 ]
van Buchem 1997 18/105 23/101 39.3 % 0.75 [ 0.43, 1.31 ]
Total (95% CI) 566 492 100.0 % 0.66 [ 0.47, 0.94 ]

Total events: 49 (Antibiotics), 67 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 2.29, df = 4 (P = 0.68); I2 =0.0%
Test for overall effect: Z = 2.33 (P = 0.020)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours antibiotics Favours placebo
recovery or improvement at 16 to 60 days of follow-up.
Study or subgroup Antibiotics Placebo Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Hadley 2010 19/73 19/45 0.62 [ 0.37, 1.03 ]
Haye 1998 9/87 10/82 0.85 [ 0.36, 1.98 ]
0.01 0.1 1 10 100


recovery at 7 to 15 days of follow-up.
Outcome: 3 Clinical failure defined as a lack of full recovery at 7 to 15 days of follow-up

M- M-
n/N n/N CI CI
Haye 1998 36/86 55/82 21.3 % 0.62 [ 0.47, 0.84 ]
Lindbaek 1996 51/83 39/44 35.4 % 0.69 [ 0.57, 0.85 ]
Lindbaek 1998 27/42 12/21 11.1 % 1.13 [ 0.73, 1.74 ]
Merenstein 2005 24/56 35/60 14.6 % 0.73 [ 0.51, 1.06 ]
van Buchem 1997 37/105 48/101 17.6 % 0.74 [ 0.53, 1.03 ]
Total (95% CI) 372 308 100.0 % 0.73 [ 0.63, 0.85 ]

Heterogeneity: Tau2 = 0.01; Chi2 = 5.18, df = 4 (P = 0.27); I2 =23%
0.01 0.1 1 10 100


recovery at 16 to 60 days of follow-up.
Outcome: 4 Clinical failure defined as a lack of full recovery at 16 to 60 days of follow-up

Haye 1998 18/87 27/82 100.0 % 0.63 [ 0.38, 1.05 ]
Total (95% CI) 87 82 100.0 % 0.63 [ 0.38, 1.05 ]

Heterogeneity: not applicable
0.01 0.1 1 10 100

Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days.
Outcome: 5 Relapse rates after 60 days

van Buchem 1997 23/108 18/106 100.0 % 1.25 [ 0.72, 2.19 ]
Total (95% CI) 108 106 100.0 % 1.25 [ 0.72, 2.19 ]

0.01 0.1 1 10 100


Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 Drop-outs due to adverse effects.
Outcome: 6 Drop-outs due to adverse effects
Peto Peto
Study or subgroup Antibiotics Placebo Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Axelsson 1970 0/35 0/32 0.0 [ 0.0, 0.0 ]
Garbutt 2012 1/85 0/81 7.05 [ 0.14, 355.67 ]
Hadley 2010 3/251 1/123 1.43 [ 0.18, 11.64 ]
Haye 1998 0/87 0/82 0.0 [ 0.0, 0.0 ]
Lindbaek 1996 3/86 0/44 4.64 [ 0.42, 51.71 ]
Lindbaek 1998 3/46 0/22 4.59 [ 0.39, 53.49 ]
Meltzer 2005 5/251 6/252 0.83 [ 0.25, 2.75 ]
Merenstein 2005 0/67 0/68 0.0 [ 0.0, 0.0 ]
van Buchem 1997 0/105 1/101 0.13 [ 0.00, 6.56 ]
Total (95% CI) 1013 805 1.40 [ 0.60, 3.25 ]

Heterogeneity: Chi2 = 4.64, df = 5 (P = 0.46); I2 =0.0%
0.001 0.01 0.1 1 10 100 1000


Analysis 2.1. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 1 Ceph
versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up.
Comparison: 2 Cephalosporin/macrolide versus amoxicillin-clavulanate
Outcome: 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Study or subgroup Cephalosporins Amox-clav Risk Ratio Weight Risk Ratio

M- M-
n/N n/N CI CI
Adelglass 1998b 15/108 9/111 12.3 % 1.71 [ 0.78, 3.75 ]
Gehanno 1998 13/121 6/115 8.7 % 2.06 [ 0.81, 5.24 ]
Gwaltney 1997 49/474 44/491 50.5 % 1.15 [ 0.78, 1.70 ]
Pessey 1996 8/85 5/77 6.6 % 1.45 [ 0.50, 4.24 ]
Sterkers 1997 23/134 14/128 19.8 % 1.57 [ 0.85, 2.91 ]
Sydnor 1992 2/22 2/21 2.2 % 0.95 [ 0.15, 6.17 ]
Total (95% CI) 944 943 100.0 % 1.37 [ 1.04, 1.80 ]

Total events: 110 (Cephalosporins), 80 (Amox-clav)
0.01 0.1 1 10 100

Favours ceph Favours amox-clav

Analysis 2.2. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 2 Ceph
versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up.
Outcome: 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up
Study or subgroup Cephalosporins Amox-clav Risk Ratio Weight Risk Ratio

M- M-
n/N n/N CI CI
Adelglass 1998b 18/100 16/99 14.9 % 1.11 [ 0.60, 2.06 ]
Camacho 1992 17/115 22/124 16.6 % 0.83 [ 0.47, 1.49 ]
Gehanno 1998 21/119 13/111 13.6 % 1.51 [ 0.79, 2.86 ]
Olmo 1994 1/26 0/22 0.6 % 2.56 [ 0.11, 59.75 ]
Pessey 1996 15/85 12/77 11.6 % 1.13 [ 0.57, 2.27 ]
Russell 1997 27/146 30/135 25.9 % 0.83 [ 0.52, 1.32 ]
Sterkers 1997 25/133 16/123 16.8 % 1.45 [ 0.81, 2.57 ]
Total (95% CI) 724 691 100.0 % 1.08 [ 0.85, 1.37 ]

0.01 0.1 1 10 100


Analysis 2.3. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 3 Drop-outs
due to adverse effects (cephalosporins).
Outcome: 3 Drop-outs due to adverse effects (cephalosporins)
Peto Peto
Study or subgroup Cephalosporins Amox-clav Odds Ratio Odds Ratio
Adelglass 1998b 3/140 9/138 0.35 [ 0.11, 1.10 ]
Camacho 1992 1/157 2/160 0.52 [ 0.05, 5.05 ]
Gehanno 1998 2/123 1/118 1.88 [ 0.19, 18.24 ]
Gwaltney 1997 8/585 30/603 0.31 [ 0.16, 0.60 ]
Olmo 1994 0/25 0/22 0.0 [ 0.0, 0.0 ]
Pessey 1996 0/87 6/82 0.12 [ 0.02, 0.61 ]
Russell 1997 1/158 7/161 0.22 [ 0.05, 0.89 ]
Sterkers 1997 3/152 5/149 0.59 [ 0.14, 2.39 ]
Sydnor 1992 1/59 6/54 0.20 [ 0.04, 0.92 ]
Total (95% CI) 1486 1487 0.32 [ 0.21, 0.49 ]

Test for overall effect: Z = 5.18 (P < 0.00001)
0.01 0.1 1 10 100


Analysis 2.4. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 4 Macrolides
Outcome: 4 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Study or subgroup Macrolides Amox-clav Risk Ratio Risk Ratio

M- M-
n/N n/N CI CI
Chatzimanolis 1998 2/29 3/27 0.62 [ 0.11, 3.43 ]
Clement 1998 19/151 6/82 1.72 [ 0.72, 4.14 ]
Dubois 1993 4/132 9/128 0.43 [ 0.14, 1.36 ]
Gehanno 1996a 19/134 19/129 0.96 [ 0.53, 1.73 ]
Henry 2003 30/269 39/259 0.74 [ 0.47, 1.15 ]
Klapan 1999 0/47 0/47 0.0 [ 0.0, 0.0 ]
Riffer 2005 4/188 6/185 0.66 [ 0.19, 2.29 ]
Total (95% CI) 950 857 0.83 [ 0.62, 1.13 ]

Total events: 78 (Macrolides), 82 (Amox-clav)
0.01 0.1 1 10 100

Favours macrolide Favours amox-clav

Analysis 2.5. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 5 Macrolides
Outcome: 5 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up
Study or subgroup Macrolide Amoxicillin-clavulan Risk Ratio Weight Risk Ratio

M- M-
n/N n/N CI CI
Clement 1998 17/136 12/74 34.8 % 0.77 [ 0.39, 1.53 ]
Desrosiers 2008 14/123 14/125 33.3 % 1.02 [ 0.51, 2.04 ]
Klapan 1999 1/43 4/46 3.5 % 0.27 [ 0.03, 2.30 ]
Riffer 2005 12/184 13/177 28.3 % 0.89 [ 0.42, 1.89 ]
Total (95% CI) 486 422 100.0 % 0.85 [ 0.57, 1.27 ]

Total events: 44 (Macrolide), 43 (Amoxicillin-clavulan)
0.01 0.1 1 10 100


Analysis 2.6. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 6 Drop-outs
due to adverse effects (macrolides).
Outcome: 6 Drop-outs due to adverse effects (macrolides)
Peto Peto
Study or subgroup Macrolides Amox-clav Odds Ratio Odds Ratio
Chatzimanolis 1998 0/31 3/29 0.12 [ 0.01, 1.18 ]
Clement 1998 0/165 2/89 0.06 [ 0.00, 1.05 ]
Desrosiers 2008 5/145 9/148 0.56 [ 0.19, 1.64 ]
Dubois 1993 7/246 7/251 1.02 [ 0.35, 2.95 ]
Gehanno 1996a 5/145 4/139 1.20 [ 0.32, 4.53 ]
Henry 2003 7/312 28/313 0.28 [ 0.14, 0.56 ]
Klapan 1999 0/50 0/50 0.0 [ 0.0, 0.0 ]
Riffer 2005 4/221 6/216 0.65 [ 0.19, 2.27 ]
Total (95% CI) 1315 1235 0.47 [ 0.30, 0.72 ]

Total events: 28 (Macrolides), 59 (Amox-clav)
Heterogeneity: Chi2 = 9.91, df = 6 (P = 0.13); I2 =39%
0.001 0.01 0.1 1 10 100 1000


Analysis 3.1. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome
1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up.
Comparison: 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins
Study or subgroup Non-penicillin Penicillin class Risk Ratio Weight Risk Ratio
M- M-
n/N n/N CI CI
Calhoun 1993 5/55 7/61 14.0 % 0.79 [ 0.27, 2.35 ]
Haye 1996 6/220 11/214 17.4 % 0.53 [ 0.20, 1.41 ]
Huck 1993 11/44 8/37 26.0 % 1.16 [ 0.52, 2.57 ]
Karma 1991 3/32 3/35 7.1 % 1.09 [ 0.24, 5.04 ]
Mattucci 1986 0/25 1/22 1.7 % 0.29 [ 0.01, 6.89 ]
Nyffenegger 1991 2/40 7/40 7.3 % 0.29 [ 0.06, 1.29 ]
von Sydow 1995 9/130 15/128 26.6 % 0.59 [ 0.27, 1.30 ]
Total (95% CI) 546 537 100.0 % 0.70 [ 0.47, 1.06 ]

Total events: 36 (Non-penicillin), 52 (Penicillin class)
0.01 0.1 1 10 100

Favours non-pen Favours pen-class

2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up.
Study or subgroup Non-penicillin Penicillin class Risk Ratio Weight Risk Ratio
Haye 1996 17/220 25/216 100.0 % 0.67 [ 0.37, 1.20 ]
Total (95% CI) 220 216 100.0 % 0.67 [ 0.37, 1.20 ]

0.01 0.1 1 10 100


3 Drop-outs due to adverse effects.
Peto Peto
Study or subgroup Non-penicillin Penicillin class Odds Ratio Odds Ratio
Calhoun 1993 2/70 3/72 0.68 [ 0.12, 4.04 ]
Haye 1996 0/221 0/217 0.0 [ 0.0, 0.0 ]
Huck 1993 0/54 1/54 0.14 [ 0.00, 6.82 ]
Karma 1991 0/50 1/50 0.14 [ 0.00, 6.82 ]
Mattucci 1986 2/29 2/29 1.00 [ 0.13, 7.49 ]
Nyffenegger 1991 0/40 0/40 0.0 [ 0.0, 0.0 ]
von Sydow 1995 4/140 7/142 0.58 [ 0.17, 1.92 ]
Total (95% CI) 604 604 0.58 [ 0.25, 1.35 ]

0.001 0.01 0.1 1 10 100 1000


Analysis 4.1. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 1 Clinical failure
defined as a lack of full recovery or improvement at 7 to 15 days of follow-up.
Comparison: 4 Tetracyclines versus mixed classes of antibiotics
Study or subgroup Tetracyclines Mixed group Risk Ratio Weight Risk Ratio
M- M-
n/N n/N CI CI
Arndt 1994 1/26 1/28 2.7 % 1.08 [ 0.07, 16.35 ]
Boezeman 1988 5/15 3/12 13.7 % 1.33 [ 0.40, 4.49 ]
Mattucci 1986 0/25 1/22 2.0 % 0.29 [ 0.01, 6.89 ]
Otte 1983 6/17 4/14 18.3 % 1.24 [ 0.43, 3.53 ]
SSG 1993 23/323 22/325 63.3 % 1.05 [ 0.60, 1.85 ]
Total (95% CI) 406 401 100.0 % 1.09 [ 0.70, 1.71 ]

Total events: 35 (Tetracyclines), 31 (Mixed group)
0.01 0.1 1 10 100

Favours tetracycline Favours mixed group

Analysis 4.2. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 2 Drop-outs due to
adverse effects.
Comparison: 4 Tetracyclines versus mixed classes of antibiotics
Peto Peto
Study or subgroup Tetracycline Mixed group Odds Ratio Odds Ratio
Arndt 1994 0/35 3/35 0.13 [ 0.01, 1.27 ]
Boezeman 1988 0/18 0/15 0.0 [ 0.0, 0.0 ]
Mattucci 1986 2/29 2/29 1.00 [ 0.13, 7.49 ]
Otte 1983 0/17 0/14 0.0 [ 0.0, 0.0 ]
SSG 1993 9/330 10/332 0.90 [ 0.36, 2.25 ]
Total (95% CI) 429 425 0.73 [ 0.33, 1.60 ]

Total events: 11 (Tetracycline), 15 (Mixed group)
Heterogeneity: Chi2 = 2.52, df = 2 (P = 0.28); I2 =21%
0.001 0.01 0.1 1 10 100 1000

Favours tetracycline Favours mixed group
ADDITIONAL TABLES
Table 1. Collected information from placebo-controlled studies
Study Compari- Diagnos- Day Missing FR1 con- FR1 an- FR + I2 FR + I2 Side
son tic assessed data trol tibiotics control antibi- effects
method otics
Axelsson Penicillin Patients 10 7% 31% 46% 72% 83% Penicillin:

1970 V (400 with clin- 8%
(Sweden) mg 3 times ically sus- Control:
daily for 10 pected si- 6%
days) nusitis
+ nasal de- were radio-
congestant logi-
(oxymeta- cally exam-
zo- ined; only
line) versus partic-
oxymeta- ipants with
zoline secretion

Table 1. Collected information from placebo-controlled studies (Continued)
included
Garbutt Amox- Clin- 10; 8%; Infor- Infor- 80%; 78%; Amoxi-
2012 icillin (500 ical symp- 28 4% mation not mation not 92% 85% cillin: 16%
(USA) mg 3 times toms > 7 available available Placebo:
daily for 10 days, puru- 14%
days) ver- lent nasal
sus placebo discharge,
Ac- facial pain
etaminophen,
guaifen-
esin, dex-
tromethor-
phan
hydro-
bromide
and pseu-
doephedrine
prescribed
to be used
as needed
Hadley Moxi- Isolation 6 to 8; 6%; Infor- Infor- 67%; 78%, Moxi-

2010 floxacin of 20 to 26 6% mation not mation not 58% 74% floxacin:
(USA) (400 mg pathogenic available available 14%
once daily bacteria Placebo:
for 5 days) from the 7%
versus sinus se-
placebo cretion was
Oral a prerequi-
or nasal de- site
conges-
tants or an-
tihis-
tamines,
corticos-
teroid
nasal
sprays and
broncho-
inhalants
(if in sta-
ble use) al-
lowed
Haye 1998 Azithro- Clinical 10 to 12; 0.6%; 33%; 58%; 89%; 93%; Azithro-
(Norway) mycin symptoms 23 to 27 0% 67% 79% 88% 90% mycin:
(500 mg lasting 11 28%
once daily to 29 days Placebo:
for 3 days) (symp-

versus toms: 18%

placebo purulent
secretion,
maxillary
sinus
tenderness
and/or
pain);
radiograph
taken to
exclude
patients
with more
than 6 mm
mucosal
thick-
ening,
complete
opacity or
air-fluid
level
Lindbaek Penicillin Clin- 10 2% 11% Penicillin: 89% Penicillin: Penicillin:

1996 V (1320 ical symp- 31%, 97%, 59%
(Norway) mg 3 times toms last- Amoxi- Amoxi- Amoxi-
daily for 10 ing at least cillin: cillin: cillin: 56%
days) 8 days; 45% 98% Placebo:
, or amox- computer 36%
icillin (500 tomogra-
mg 3 times phy show-
daily for 10 ing opac-
days) ver- ity or fluid-
sus level
placebo.
Nasal de-
conges-
tants
and anal-
gesics were
al-
lowed but
not pre-
scribed in
all groups
Lindbaek Penicillin Clin- 10 7% 43% Penicillin: 86% Penicillin: Infor-

1998 V (1320 ical symp- 30% 91% mation not
(Norway) mg 3 times toms last- Amoxi- Amoxi- available
daily for 10 ing at least cillin: cillin:
days)
, or amox- 8 41% 86%

icillin (500 days; com-
mg 3 times puter to-
daily for 10 mography
days) ver- showing
sus mucosal
placebo. thickening
Nasal de- of 5 mm
conges- or more in
tants any
and anal- sinus with-
gesics were out opac-
al- ity or fluid-
lowed but level
not pre-
scribed in
all groups
Meltzer Amox- Clinical During the 1.8% Infor- Infor- 89% 93% Treat-
2005 icillin (500 signs 15-day mation not mation not ment-
(14 coun- mg 3 times and symp- treatment available available emergent
tries, not daily for 10 toms last- phase adverse ef-
specified) days) ver- ing at least fects
sus placebo 7 but less Amoxi-
Concomi- than 29 cillin: 34%
tant medi- days Placebo:
cations not (rhinor- 38%
allowed rhoea,
postnasal
drip, nasal
conges-
tion/stuffi-
ness, sinus
headache,
and facial
pain/
pressure/
tender-
ness on
palpation
over the
paranasal
sinuses)
Meren- Amox- Clin- 14 14% 42% 57% Infor- Infor- Amoxi-

stein icillin (500 ical symp- mation not mation not cillin: 23%
2005 mg twice toms > 7 available available Placebo:
(USA) daily for 10 days, puru- 12%
days) ver- lent nasal

sus placebo discharge,

Over-the- facial pain
counter
medica-
tions were
allowed in
both
groups
van Amox- The mean 14 4% 52% 65% 77% 83% Amoxi-

Buchem icillin (750 duration of cillin: 28%
1997 (the mg 3 times the symp- Placebo:
Nether- daily for 7 tomatic 9%
lands) days) ver- period be-
sus placebo fore treat-
Adju- ment
vant ther- 2.2 weeks;
apy with radiograph
oxymeta- showing >
zo- 5 mm mu-
line steam cosal
inhala- thicken-
tion (dura- ing, opac-
tion not ity or air-
specified) fluid level
. Paraceta-
mol as
needed
1 FR = full recovery.
2 FR + I = full recovery + improvement.

APPENDICES
Appendix 1. MEDLINE (Ovid) search strategy

1. exp Sinusitis/
2. sinusit*.tw.
3. or/1-2
4. exp Anti-Bacterial Agents/
5. antibiotic*.tw,nm.
6. or/4-5
7. 3 and 6
8. randomized controlled trial.pt.
9. controlled clinical trial.pt.
10. randomized.ab.
11. placebo.ab.
12. clinical trials as topic.sh.
13. randomly.ab.
14. trial.ti.
15. 8 or 9 or 10 or 11 or 12 or 13 or 14
16. (animals not (humans and animals)).sh.
17. 15 not 16
18. 7 and 17
Appendix 2. Embase.com search strategy

#11. #7 AND #10
#10. #8 OR #9
#9. random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR ’cross-over’:ab,ti OR factorial*:ab,ti OR (doubl*
NEAR/1 blind*):ab,ti OR (singl* NEAR/1 blind*):ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti
#8. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp
#7. #3 AND #6
#6. #4 OR #5
#5. antibiotic*:ab,ti
#4. ’antibiotic agent’/exp
#3. #1 OR #2
#2. sinusit*:ab,ti
#1. ’sinusitis’/exp
Appendix 3. SIGLE search strategy

keyword: sinusit* AND Subject collection: 06 - Biological and medical sciences

Appendix 4. Search strategy for ongoing trials
acute maxillary sinusitis AND antibiotics
Appendix 5. Details of previous searches
Review update 2011

In the 2011 review update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010,
Issue 1), which contains the Cochrane Acute Respiratory Infections Group’s Specialised Register, MEDLINE (2007 to March Week
2, 2010) and EMBASE (2007 to March 2010) and the System for Information on Grey Literature in Europe (SIGLE) (1976 to
August 2009). We used the following search terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with
the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision- maximising
version (2008 revision); Ovid format (Lefebvre 2011). The search terms were adapted to search EMBASE (Appendix 2). To locate
unpublished literature, the search of SIGLE was carried out on the OpenSIGLE (http://opensigle.inist.fr/) (Appendix 3).
MEDLINE (Ovid)
1. exp Sinusitis/
2. sinusit*.tw.
3. or/1-2
4. exp Anti-Bacterial Agents/
5. antibiotic*.tw,nm.
6. or/4-5
7. 3 and 6
8. randomized controlled trial.pt.
9. controlled clinical trial.pt.
10. randomized.ab.
11. placebo.ab.
12. clinical trials as topic.sh.
13. randomly.ab.
14. trial.ti.
15. 8 or 9 or 10 or 11 or 12 or 13 or 14
16. (animals not (humans and animals)).sh.
17. 15 not 16
18. 7 and 17
We used the function for finding related articles in PubMed for those already identified placebo-controlled trials to track down additional,
relevant articles. We reviewed reference lists of the identified new trials and four systematic reviews considering placebo-controlled
study designs (Falagas 2008a; Gwaltney 2004; Rosenfeld 2007; Young 2008) for additional, appropriate studies.
There were no language or publication restrictions.
Review update 2008

In the review version 2008, we used a revised, more specific strategy (compared to review version 2003) to search for trials in the
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); MEDLINE (1950 to May 2007)
and EMBASE (1974 to June 2007). In the revised strategy “antibiotics” was used as an additional keyword and “anti-bacterial agents” as
an exploded MeSH term in addition to “sinusitis”. The MEDLINE search terms were run over CENTRAL and adapted for EMBASE.
MEDLINE (OVID)
1 exp SINUSITIS/
2 sinusitis.mp.
3 or/1-2
4 exp Anti-Bacterial Agents/
5 antibiotic$.mp.
6 or/4-5
7 3 and 6
8 RANDOMIZED CONTROLLED TRIAL.pt.
9 CONTROLLED CLINICAL TRIAL.pt.
10 RANDOMIZED CONTROLLED TRIALS.sh.
11 RANDOM ALLOCATION.sh.
12 DOUBLE BLIND METHOD.sh.
13 SINGLE-BLIND METHOD.sh.
14 or/8-13
15 Animals/
16 human.sh.
17 15 not 16
18 14 not 17
19 CLINICAL TRIAL.pt.
20 exp Clinical Trials/
21 (clin$ adj25 trial$).ti,ab.
22 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
23 PLACEBOS.sh.
24 placebo$.ti,ab.
25 random$.ti,ab.
26 or/19-25
27 26 not 17
28 18 or 27
29 7 and 28
The function for finding related articles in PubMed was used for those already identified placebo-controlled trials so as to track down
additional, relevant articles. Reference lists from the already identified trials and nine systematic reviews considering placebo-controlled
study designs (Benninger 2000; de Bock 1997; de Ferranti 1998; Ioannidis 2001; Ioannidis 2002; Ip 2005; Linder 2003; Low 1997;
Stalman 1997b) were reviewed for additional, appropriate studies. Included and excluded trials in the previous version were rechecked
by using the revised inclusion criteria for this review. A search of the database ’System for Information on Grey Literature in Europe
(SIGLE)’ was intended, but the database was not available via the Internet in November 2005.
For the review version 2003 pharmaceutical companies that manufacture antibiotics used in the treatment of acute sinusitis had been
contacted and data and references from all published and unpublished trials on acute sinusitis were requested. Further, three experts in
the field had been contacted and asked to review the bibliography of the initial review (1999) for completeness.
Appendix 6. Results of the earlier searches
Review update 2011

In the 2011 update, the total number of the records considered from all updates was 2209 including 2036 records from the earlier
searches and 173 records from the 2010 update search. Of the total 2209 records, we rejected 1923 records as definitely not meeting
the inclusion criteria simply on the basis of title or abstract or because they were duplicates. Altogether 286 full-text reports were
obtained. From these 286 reports, 128 were clearly irrelevant for this review leaving 158 reports for final assessment. The main reasons
for irrelevance were: trials without control group, studies with treatments other than antibiotic, studies comparing same classes of
antibiotics and studies regarding children.
Over all updates, there were in total 158 reports to be considered in detail. Additional information was needed from four studies with
antibiotic versus placebo comparisons to assess whether they meet the inclusion criteria for this review (Meltzer 2005; Schering-Plough
2003; Stalman 1997a; Williamson 2007). Finally we considered 62 reports representing 59 individual studies eligible for inclusion
in the review. Compared to the 2008 update, two new antibiotic versus antibiotic studies were included. Eighty-nine studies with 96
reports were excluded.
Review update 2008

The electronic search based on the revised search strategy in the update 2008 produced 2030 records, many of which were duplicates.
Of these, 1761 records were rejected as definitely not meeting the inclusion criteria simply on the basis of title or abstract. Duplicates
were omitted. Checking the lists of the included and excluded studies in the previous version of the review (version 2003), reviewing
reference lists from the already identified trials and systematic reviews and using the function for finding related articles in PubMed
yielded six more appropriate trials. Altogether 269 full-text reports were obtained. All non-English language reports were translated to
assess the studies. The review authors could read reports in German, Russian and Scandinavian languages. Outside translators were
consulted to identify and assess the reports in Portuguese, Spanish, French, Chinese and Japanese. From these 269 reports, 117 were
clearly irrelevant for this review. The main reasons for exclusion were: trials without control group, studies with other treatment than
antibiotic, studies comparing same classes of antibiotics and studies regarding children.
In total there were 152 reports to be considered in detail. From these, 60 reports representing 57 individual studies were considered
eligible for inclusion in the review. Six of the 57 included studies compared antibiotic treatment to placebo. The remaining 51 studies
compared different classes of antibiotics.
FEEDBACK
Antibiotics for acute maxillary sinusitis
Summary
There are 4 primary questions to be answered by this systematic review:
1) Is antibiotic therapy effective for acute sinusitis?
2) Which antibiotic is most effective?
3) What is the best duration for antibiotic therapy?
4) Is there a change in the efficacy of antibiotics over time?
Question 1
Firstly, all 4 questions are clinically important. But it is paramount to recognize the interrelationships of all 4 questions, such that, if
the answer to the first question is negative, the value of the other answers is significantly diminished. It is therefore essential to include
all the evidence unless the exclusion is completely justified.
On the efficacy of antibiotics for acute sinusitis, there are only 6 published randomised clinical trials with control groups: Axelsson
1970, Gananca 1973, Wald 1986, Lindbaek 1996, van Buchen 1997, and Stalman 1997.
I agree that the Wald study involving children and the Gananca study from Brazil should be excluded. Gananca trial had only 50
subjects, with 50% more patients in the antibiotic group after randomisation. It also had extreme differences in cure rates between
antibiotic and placebo groups (15/30 versus 0/20).
The last 3 trials on this list, according to the recent meta-analysis by de Ferranti et al (BMJ 1998;317:632-7), received a quality score
of 5 by the Jadad scale (a maximum score indicating highest quality). The Axelsson study had a score of 1. The Williams et al answered
this first question, “Is antibiotic therapy effective?”, by excluding Stalman 1997 (with quality score of 5) and by doubling the control
group populations in Axelsson 1970 (n=34) and in Lindbaek 1996 (n=44). This artificially created population of 156 controls from 78
real controls would inflate the contributions of those 2 trials on the outcome. The exclusion of those true placebo-controls in Stalman
1997 (n=94), while adding 78 phantom controls, is not a reasonable approach to answer the antibiotic efficacy question for sinusitis.
The Stalman study was excluded, according to the author’s, because it did not use radiographic images for diagnosis. The same is
true however for the included Axelsson study. Though Axelsson et al took several different radiographic views of sinuses, they did not
describe a radiographic criteria for diagnosis.
Moreover, the relationship between radiograms, even the more advanced images of paranasal sinuses obtained by computed tomography
(CT scan), and the clinical description of sinusitis is extremely poor. The 1997 study of Bhattaharyya et al involving 586 patients (the
largest published data set) failed to find any correlation between CT scan results and patient described symptoms of sinusitis (See Arch.
Otolaryngol. 1997;123:1189-92). Also note that Williams et al argue that the cure rate differences between Lindbaek and van Buchem
were probably related to the diagnostic criteria. That is, a diagnosis confirmed by CT scan is more likely associated with bacterial
sinusitis than a diagnosis by radiography. This new theory of differential diagnosis of bacterial sinusitis however is not supported by
any published data.
To be consistent, either both Axelsson and Stalman should be included, or both should be excluded. If they are both excluded, then the
meta-analysis of Williams et al on the efficacy of antibiotics for sinusitis would depend on only 2 placebo controlled trials - Lindbaek
1996 and van Buchem 1997 - with opposite conclusions.
The Lindbaek study was terminated early with 130 patients instead of the original sample size of 180 subjects. This was done without
correction and without predefined stopping rules. Also, the randomisation was in a most unusual fashion for a modern clinical trial
using dice. Lindbeak et al do not provide a table, as customary, showing the baseline patient characteristics at entry indicating their
randomisation was effective. In contrast to those deficits, van Buchem reports this baseline information about randomisation and an
analysis of prognostic factors on the outcome. It shows that initial severity of sinusitis does not change the results. The van Buchem study
has a much higher quality and reliability than the Lindbaek trial. If the entire evidence has to be based on combining or contrasting
only those 2 trials, then conclusion has to follow the van Buchem results.
Most important, the Stalman trial which was published 9 months later completely supports the van Buchem results. Among the 3
trials with Jadad score of 5, reasonable people can easily conclude that van Buchem and Stalman clearly show that antibiotics for acute
sinusitis are not effective; and, Lindbaek et al is an outlier. Lindbaek’s efficacy claim based on one endpoint (cure) is not sustained by
his second endpoint (improvement). This inconsistent outcome and those basic problems associated with early termination and poor
randomisation perhaps is why Lindbaek results are not replicated by the last 2 trials (van Buchem and Stalman).
I suggest however that we include all 4 clinical trials to combine results and estimate a pooled efficacy. As such, even this would yield
still a meager sample size, a total of 648 subjects with only 278 controls. Consequently, this is the entire dataset we have to establish the
scientific evidence-base in justifying 15 million antibiotic prescriptions in the U.S. for sinusitis. Instead of finding excuses to exclude
the few controls in this limited database, we should savor them.
The answer to the first question, then, is a simple pooling of the results from those 4 clinical trials: Axelsson 1970 (n=112), Lindbaek
1996 (n=130), van Buchem 1997 (n=214), and Stalman 1997(n=192).
In all sinusitis trials the primary outcome measures of at 10-14 days are subjective. Outcomes are not based on some “Gold Standard”
but study-variant definitions of cure and success (cure/improvement) by each investigator. Those primary data unfortunately are not
based on objective endpoints. A well defined diagnostic criteria, such as combining radiographs with symptoms, validated against a
standard is lacking.
I argue that if the entry includes radiograms to make the diagnosis of sinusitis, then to be consistent for at least in defining cure,
the primary endpoint should also include both measures (e.g.. combination of normal radiograph with symptom free status). If both
measures are not negative, then improvement (or scaled improvement) is the only logical alternative. Without a normal radiogram,
cured diagnosis would be in contradiction with the entry criteria.
Regardless of these problems associated with an objective and study invariant outcome, the combined results from 4 trials are as follows:
Cure
Controls: 10/34 + 5/44 + 53/106 + 56/94 = 124/278 or 44.6%
Antibiotics: 27/78 + 32/86 + 68/108 + 59/98 = 186/370 or 50.3%
Success
Controls: 23/34 + 39/44 + 78/106 + 80/94 = 220/278 or 79.1%
Antibiotics: 51/78 + 81/86 + 87/108 + 83/98 = 302/370 or 81.6%
Antibiotic-placebo rate difference in cure is 5.7% (OR=1.26) and the rate difference in success is 2.5% (OR=1.17). These marginal
differences, neither statistically nor clinically significant, indicate the lack of efficacy of antibiotic therapy for the treatment of acute
paranasal sinusitis.
The methods used by Williams et al in their meta-analysis therefore must be re-examined. Relying on magical statistical packages, with
interesting inclusions and exclusions, can sometimes lead to positively misleading results. As in this case, claiming antibiotic efficacy
for sinusitis is not a reasonable conclusion but perhaps an artifact of meta-analysis.
The answer to this first question, “Are antibiotics for acute sinusitis effective?”, therefore is negative.
Question 2
Now the second question, which antibiotic is most effective, is a less important scientific issue. Notwithstanding, in real life clinical
practice, this question continues to be a primary issue because of the ongoing campaign of promoting newer, wider spectrum antibiotics
for sinusitis with higher costs.
Though there is no clinical trial which exclusively has focused on bacterial sinusitis caused by resistant bacteria, and which has shown the
benefit of such drugs, the emergence of multi-drug resistant bacteria is always cited to advocate those wide spectrum drugs. Therefore,
the second part of the Williams meta-analysis is clinically most significant.
Using a large sample size, Williams et al (n=7330 patients in 32 trials) show that there is no superior antibiotic. This result supports
the earlier findings of de Bock 1997 (n=3358 patients in 16 trials) and de Ferranti 1998 (n=2717 patients in 27 trials) meta-analyses.
The ineffectiveness of wide spectrum drugs are based on a wide collection of clinical trials. In fact, among those 3 meta-analyses,
the inclusion of the same trials are not common. The number of trials commonly inclusive between meta-analyses are: Williams -
de Ferranti (13/47), Williams - de Bock (3/45), and de Ferranti - de Bock (5/39). This diversity in inclusion/exclusion indicates the
arbitrary nature of selection of trials included in meta-analyses while supporting the robustness of conclusions.
Note also that this result, ineffectiveness of wide spectrum antibiotics for sinusitis, is consistent with the meta-analysis findings in acute
otitis media. It is a logical result since acute otitis media in general has the same pathogenic bacterial spectrum as acute sinusitis.
There is however an interesting point to consider. If the antibiotics are not better than placebo, then it is logical not to find a superior
antibiotic for sinusitis. Unless each new antibiotic is concurrently matched with a placebo control in the primary clinical trial, it would
be impossible to show the usefulness of new, wide spectrum antibiotics. Without such data, I think it is irresponsible to advocate wide
spectrum antibiotics for sinusitis.
I hope that Williams et al would reduce the complexity of their presentation to make this point by decreasing the number of figures and
by selecting a single primary endpoint to display. I suggest success (cure/improvement) as the measure of choice as I discussed above.
The remaining measures can be simply stated as not being different with some odds ratios or rate differences. Also, those redundant
figures with confidence intervals all over the place, are they necessary? It only illustrates that poor evidence is being included in the
meta-analysis.
I suggest that their Summary figure should also include sample sizes, exclude tetracycline’s, include duration of therapy analysis (short
versus long), and finally include some cumulative meta-analysis to indicate change in efficacy over time.
Question 3
Authors conclude in recommending 10-days of amoxicillin therapy for acute sinusitis but do not provide evidence-based arguments for
selecting this particular duration of therapy. This is not scientific and somewhat odd, because a few years ago, Dr.Williams published
arguably the best study showing that 3-days of antibiotic therapy is as good as the standard 10-days of therapy (See JAMA 1995;273:
1015-21).
A recent review by Pichichero and Cohen (Pediatr Infect Dis J 1997;16:680-95) indicates that there are at least 5 published studies
involving adult patients which show that short duration therapy is as effective as long duration therapy. I suggest Williams et al provide
a meta-analysis to answer this question or explain why such combination of data is not possible. This part on duration of therapy I
think is extremely important.
Question 4
The recent increase in the prevalence of multi-drug resistant bacteria is clearly shown to be changing rapidly and is caused by the misuse
or overuse of antibiotics. However, the research about the change of efficacy of antibiotics in vivo for common respiratory diseases is
lacking. This is an important question. I am not sure how it can be answered. The approach taken by Williams et al seems a reasonable
one, but I doubt that it can really answer the question of changing antibiotic efficacy for sinusitis.
The change in efficacy over time perhaps can be best approached by using a cumulative meta-analysis (See N Eng J Med 1992;327:248-
54, JAMA 1992;268:240-8). Williams et al state that they have performed such a cumulative meta-analysis as well as a meta-regression.
However, they do not show those results. I think the cumulative meta-analysis involving 32 trials in some chronological order (by the
date of the trial, and not the publication date) would be an excellent figure to make the point.
We must also keep in mind another possibility. The lack of change in efficacy over time, suggesting that the emergence of drug resistant
bacteria had no effect, could be simply untrue but related to the ineffectiveness of antibiotics for sinusitis in general.
With $2 billion over the counter medications, 15 million antibiotic prescriptions, 17 million office visits, 300,000 endoscopic sinus
surgeries, and 37 million Americans suffering from chronic sinus disease, this is not a trivial healthcare issue. If the Cochrane is going
to enter a systematic review in it’s library, it should be based on the best evidence and analysis. William et al require many changes and
much improvement before it is suitable for the Cochrane database.
I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter
of my criticisms.
Reply
Dr. Cantekin identifies the question - “are antibiotics more effective than placebo for acute sinusitis” as critically important but disagrees
with a number of our methods for answering this question. We will address each point.
First, it is stated that the control populations are double counted. This is an important and difficult methodological issue that occurs
when trials have more than two treatment arms. It was only problematic for the Lindbaek trial, which had amoxicillin, penicillin and
placebo arms. To avoid “double counting,” we analysed the amoxicillin and penicillin trials separately, thereby including the control
populations only once in each of these separate analyses.
Second, it is argued that the Stalman trial should be included in the analysis. We agree that the Stalman study is high quality, but it was
excluded because it lacked a diagnostic radiographic or sinus puncture. Our review was restricted to studies enrolling adult subjects with
sinusitis as determined by clinical symptoms and either an abnormal radiographic or sinus aspiration (the Stalman study used neither).
Because clinical symptoms alone lead to relatively high rates of misclassification, we thought the requirement for an objective measure
(x-ray or aspiration) was important. Studies with high rates of misclassification may include large proportions of subjects without
bacterial sinusitis, leading to a negative result because antibiotics are unlikely to help allergic or viral rhinosinusitis. These criteria were
applied to all studies considered for inclusion. Although we excluded studies without a diagnostic criterion standard, authors of other
literature syntheses on this topic have used more liberal inclusion criteria by dropping the requirement for an objective measure of
sinusitis. Their results were consistent with our findings (risk ratio to prevent clinical failure 0.54, 95% CI 0.37 to 0.79)1 .
Third, simple pooling is suggested as an appropriate method for combining trial results. We disagree. Simple pooling (as opposed to
meta-analytic techniques), can lead to biased results for a variety of reasons. These include bias if there is imbalance in the number of
subjects in treatment arms, underestimation of the variance, and inappropriate weighting of small and large trials. Further, it is not
possible to evaluate heterogeneity through simple pooling.
Next, the reviewer reaches the conclusion that antibiotics are no more effective than placebo. Although the trials are few, and the results
limited to patients with maxillary sinusitis confirmed radiographically or by aspiration, we interpret the current evidence as showing
that penicillin is more effective than placebo and that there are similar, but more heterogeneous findings for amoxicillin.
The reviewer asks for a single endpoint to simplify the presentation. We agree that it increases the complexity of the presentation to
consider both clinical cure and clinical cure or improvement. However, we think that these two clinical outcomes give information that
is worth the additional complexity. As clinicians, we think it is useful to be able to tell patients that on average 50% will be well and
75% will feel substantially better within the next 10 days.
The issue of cumulative meta-analysis is important. We report the findings of these results without showing the forest plots because
of limitations of the software. For newer non-penicillins versus penicillins, there was no effect over time for clinical cure (P = 0.17) or
for clinical cure or improvement (P = 0.60). It is difficult to draw robust conclusions from this analysis because clinically important
changes (other than bacterial resistance) may affect the results.
The reviewer asks for an analysis addressing the duration of treatment. We agree that treatment duration is a clinically important issue.
In fact we completed a study showing therapeutic equivalency for three versus 10 days of TMP/SMX2 . This study was excluded from
the current literature synthesis because it was a within-class antibiotic comparison (not eligible). Four other studies compared two
antibiotics with differing duration of treatment. Three of these compared two different antibiotics for differing duration making it
difficult to isolate treatment duration as the key variable. Only one study compared two durations for the same antibiotic (cefixime
four versus 10 days) and found similar efficacy. Because of differing pharmacokinetics and tissue penetration, we do not think it is
wise to generalise results about TMP/SMX and cefixime to antibiotics in general. Readers should incorporate these findings cautiously.
Because study duration was not one of our study questions, we have not done a systematic search to identify relevant literature. We
will consider adding this question to future reviews.
We strongly endorse the reviewer’s call for more clinical trials in this area, particularly with placebo control and look forward to other
readers’ comments.
Reference list
1 de Ferranti SD, Ioannidis JPA, Lau j, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics
for acute sinusitis? A meta-analysis. BMJ 1998;317:632-637
2 Williams JW, Jr., Holleman DR, Jr., Samsa GP, Simel DL. Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole
for acute maxillary sinusitis. JAMA 1995; 273:1015-1021.

of my criticisms.
John W. Williams Jr
Contributors
Erdem Cantekin
This response was originally added to the Cochrane Review in 2000.

Amoxicillin results for cure
Summary
The heterogeneity in this outcome may be explained by the choice of cure as your outcome measure. You are pooling relative benefit
instead of relative risk. If the outcome is entered as failure to cure the heterogeneity disappears and the pooled RR is significant even
with a random model. RR = 0.68 (95% CI 0.55 to 0.83).
In my view it is therefore wrong to conclude that Amoxicillin does not have significant benefit in maxillary sinusitis.
of my criticisms.
Reply
The current author group has analysed the data differently to the earlier authors group. Unlike the previous version, in the meta-
analyses the data of all placebo-controlled studies were combined across antibiotic classes. In the new analyses pooled risk ratios using
the clinical failure rate as an outcome measure were calculated.
The new meta-analyses results do not have any statistically significant heterogeneity between the individual study results.
The data of all placebo-controlled studies were combined despite which antibiotic was used because it was anticipated that there would
be only a few placebo-controlled studies available in the analyses. Further, it was presumed that researchers in different countries had
had local reasons for selecting particular antibiotics for their trials, taking into account for example, local resistance rates to antibiotics
among community-acquired pathogens.
This reply was added 9 October 2007.
Contributors
Christopher Cates
This feedback comment was posted 1999.
Antibiotics for acute maxillary sinusitis, 27 September 2010
Summary
Dear Authors,
The Cochrane Report on “acute maxillary rhinosinusitis” is not very helpful for GPs because it is misleading in some points:
A) Most of the relevant studies are ruled out by not fulfilling the inclusion criterion “Duration of symptoms > 1 week”. But “Acute
maxillary sinusitis as defined by: a history of URTI lasting 7 to 30 days...”. But there are important issues besides diagnostic via duration
of sickness and CT findings.
B) For 5 of the remaining 6 placebo-controlled RCTs used for the meta-analyses, the external validity is weak. For practical applicability
it is not so important to know if there might be any subgroups in acute rhinosinusitis that profit from antibiotics. Rather, we need
results from trials with completely realistic practice conditions. Mixed inclusion criteria for meta-analyses are therefore questionable.
* X-ray or CT is not routinely accessible in general practice nor indicated for diagnosis of acute rhinosinusitis. As stated in the report
“In the referral guidelines for imaging of the European Commission, radiograph is not indicated as a routine diagnostic method (ECRP
2007)”. The results of the following studies are therefore not applicable: Axelsson 1970, Lindbaek 1996a+b, Lindbaek 1998a+b, van
Buchem 1997.
* The Haye-trial used x-ray to exclude those with positive findings. As there has been yet no general-practice-based-trial to prove that
these findings would be a good reason for antibiotics anyway, this filter criterion seems not only artificial but also deletes the practical
use.
C) Most of the Cochrane-report is concerned with the comparative trials. But very few of these studies applied any of the successful
diagnostic criteria (see below) - so unequivocal results were likely to result.
In fact, my main point is that for us GPs it is very important to keep in mind the special prevalences, supplies and priorities of
primary care.Thus we focused our german DEGAM (German Society of General Practitioners) guideline “akute rhinosinusitis” (http:/
/www.degam-leitlinien.de/) on primary care. We grouped the evidence from diagnostic and therapeutic clinical trials in the categories
“predominantly primary care/secondary care/unknown setting”. (The guideline included literature on sinusitis until April 2007 - the
trials of Haye and Merenstein were not included).
Evaluating literature on acute rhinosinusitis in adults, this focus leads to interesting discoveries:
1. In primary care, antibiotics proved only helpful when a technical diagnostic test was added to clinical evaluation: CT (Lindbaek
1996) / nasal swabs + culture (Kaiser 2001) / CRP (Hansen 2000); trials with clinical evaluation only (Stalman 1997, Bucher 2003,
Merenstein 2005) or added plain-x-ray (van Buchem 1997, Rantanen 1973, Norrelund 1978, Kristo 2005) or added ultrasound (Laine
1998, Varonen 2000, Varonen 2003) were negative.
2. Strikingly, in secondary care (ENT) studies with CE plus plain x-ray were significantly positive (Axelsson 1970, Wald 1976)
3. Comparative studies showed no significant difference between various types of antibiotics (Stalman 1997, de Ferranti 1998, de Bock
1997, Williams 2000, Piccirillo 2001)
4. Nearly all trials with positive effect of corticoid nasal spray for acute rhinosinusitis were done by allergologists (Sinusitis Study Group)
- thus making confounding by allergies likely.
The above findings might be explained by combining the following observations:
1. In cases of acute maxillary sinusitis the prevalence of pathogenic bacteria in sinus puncture differs by setting: 34% in primary care
(Hansen 1995, van Buchem 1995) / ENT 45% (Axelsson 1973) / soldiers 72-78% (Savolainen 1997, Penttil? 1997) - the latter probably
due to endemic spreads of hemophilus influenzae.
2. Diagnostic tests can moderately “raise” the prevalence of bacterial vs viral infections. Positive Likelihood-ratios for diagnostic test
are approximately 4 for CT (Hansen 1995) / plain X-ray 3,4 (Vaaronen 2000) / ultrasound 2,8 (Vaaronen 2000) / clinical test 1-2
(Hansen 1995) and 2.1-3.3 for CRP (Lindbaek 1996)
3. Calculating post-test prevalence by applying LR to pre-test prevalence suggests that antibiotic trials were only significantly positive
when post-test bacterial prevalence was > 60% (probably due to relatively small trials)
Comment: In a health system with immediate direct accessibility to specialists (like in Germany), the study results suggest that primary
care guidelines should be applied for example by ENT-specialists when involved directly. Referred patients would probably merit from
secondary care guideline.
Because of interpretation of mixed data, we discarded the use of the results of the preceding Cochrane-report of Williams “Antibiotics
for acute maxillary sinusitis”.
Conclusion: after reading your interesting report, I would summarize the primary-care-related evidence on antibiotics for acute rhinos-
inusitis as follows
* Antibiotics + referral if complications are suspected
* Antibiotics with small proven effect if symptoms >7days (Merenstein 2005, ?Haye?)
* Antibiotics with small proven effect if symptoms <7days + severe pain + CRP and/or ESR is markedly raised (Hansen 2000)
I would like to suggest that future Cochrane reports reflect the difference of primary and secondary (+maybe tertiary) care.
With best greetings from Germany and thanks for your work.
Uwe Popert
Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback.
Reply
Thank you for these comments. We understand the need to have guidance in primary care; however, the review only can use the
available studies. Cochrane Reviews typically do not provide a strong recommendation on how to apply the results in clinical practice
but leave these conclusions to be done locally, as practice also depends on many other factors than evidence of effectiveness.
The purpose of this review was to quantify the effectiveness of antibiotic therapy for adult patients diagnosed with acute sinusitis and
treated in ambulatory settings (primary or secondary care). In this review only randomised controlled studies with adults were included
and thus studies with children, e.g. Kristo 2005 and Wald 1976, were excluded.
We aimed to find trials which focused on patients who most probably had bacterial sinusitis. In primary care, diagnosis of adult acute
sinusitis is often symptom-based alone, without e.g. any imaging (e.g. Meltzer 2004; Fokkens 2007). Many clinical guidelines in US
and Europe state that patients with URTI and sinus symptoms should not be treated with antibiotics during the first seven to 10 days
in case the signs and symptoms are not severe. Bacterial sinusitis is more probable if the signs and symptoms have lasted at least seven
days (Meltzer 2004). Therefore we defined that if study inclusion criteria were clinical only, symptoms had to have lasted at least seven
days. Although CT or endoscopy or culture are not investigations of primary care, studies which used these diagnostic methods were
not excluded, however, from the analyses of studies conducted with primary care patients, although it may be that the proportion of
the patients with bacterial infection is higher.
Five of the six placebo-controlled studies (which fulfilled our definition of acute maxillary sinusitis) enrolled study participants from
unselected primary care patients, even though the study procedures were conducted in secondary care. The study by Axelsson 1970 did
not define the setting where the patients were enrolled. None of the included studies reported patients to be enrolled from secondary
care.
Results and conclusions
The main outcome in this review was clinical failure defined as a lack of cure or improvement at seven to 15 days of follow-up. On
average 80% of participants in placebo group were found to be cured or improved at seven to 15 days after the start of treatment,
in antibiotic group the figure was 90% (difference of 10% in the number of failures). One study (Lindbaek 1996+Lindbaek 1996b)
accepted solely participants with opacity or fluid-level by using CT scan. In this study pathogenic bacteria connected with acute sinusitis
were documented in 58% of participants. It is obvious that the participants selected for this study represented patients with a more
severe form of disease. Another study (Haye 1998) included patients with clinical symptoms and signs of acute maxillary sinusitis
but excluded those with radiological evidence of empyema thereby selecting probably the mildest end of the diseased. Even in these
two studies representing extreme ends of the severity spectrum of the disease, the differences between antibiotic and placebo groups
regarding the numbers of failures were similar (10% and 4%, respectively).
The patients in the placebo-controlled studies were enrolled from unselected primary care populations (except perhaps Axelsson 1970).
The individual studies represented clinical conditions ranging from mild to more severe, depending on the inclusion criteria, like in
real GP practice setting. All these studies favoured antibiotics to some extent or were inconclusive. After pooling the results of the
individual studies we have made several sensitivity analyses for the main outcome and have discussed the uncertainty issues related to
the results.
In conclusion, we see that the overall result of the meta-analysis of this outcome corresponds to the mixture of patients in GP practice.
However, compared to the situation where no imaging is used, the benefit of antibiotics may be somewhat overestimated. Even when
special effort is put to select those patients from primary care who most probable have bacterial sinusitis, the benefit of antibiotics seems
to be modest. It is obvious that there are patients who benefit from antibiotics but we do not have proper means to identify them so far.
This reply was added 20 December 2010.
Contributors
Uwe Popert
WHAT’S NEW
Last assessed as up-to-date: 20 March 2013.
Date Event Description
20 March 2013 New citation required but conclusions have not changed We amended the secondary outcome ’Ability to work’
to include activity impairment in general.
Our conclusions remain unchanged.
20 March 2013 New search has been performed Searches conducted. We included three new studies com-
paring antibiotic against placebo (Garbutt 2012; Hadley
2010; Meltzer 2005) and one new study comparing an-
tibiotic against antibiotic (Lari 2010) in this updated re-
view. We excluded one new study comparing antibiotic
against placebo (Gananca 1977).

HISTORY
Protocol first published: Issue 1, 1997
Review first published: Issue 3, 1999
Date Event Description
2 November 2010 Feedback has been incorporated Feedback comment added.
19 March 2010 New search has been performed Searches conducted. We included two new studies
comparing antibiotic against antibiotic (Desrosiers
2008; Marple 2010) in this updated review. We ex-
cluded six new studies (Miyamoto 2005; Sabater
1995; Schering-Plough 2003; Serra 2007; Stalman
1997a; Williamson 2007). The conclusions remain
unchanged.
20 December 2007 Amended Converted to new review format.
9 October 2007 Feedback has been incorporated Response to Feedback added.
5 October 2007 New citation required and conclusions have changed Substantive amendment.
29 May 2007 New search has been performed Searches conducted.
5 October 2005 Feedback has been incorporated Feedback added.
1 December 2001 New search has been performed Searches conducted.
6 October 1998 New search has been performed Searches conducted. Review first published Issue 3,
1999.
CONTRIBUTIONS OF AUTHORS
Anneli Ahovuo-Saloranta (AAS) was responsible for study selection, data extraction, analysis and writing the review.
Ulla-Maija Rautakorpi (UMR) was responsible for study selection, data extraction and writing the review.
Oleg Borisenko (OB) was responsible for writing the review (and study selection and data extraction in the previous version).
Marjukka Mäkelä (MM), Helena Liira (HL) and John Williams (JW) were responsible for writing the review.

DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• Finnish Office for Health Technology Assessment/FinOHTA, National Institute for Health and Welfare/THL, Finland.
External sources
• No sources of support supplied
NOTES
The 2008 update contained substantial changes to the previous version published in 2003 (Williams 2003). There was a near total
change in the authors from the previous version. Only two of the previous authors (John W. Williams, Jr. and Marjukka Mäkelä)
participated in the 2008 revision.
1. We updated the objectives and added two new objectives:
a) to compare the effect of short versus long courses of antibiotics for acute maxillary sinusitis; and
b) to compare the side effects of different treatments.
We discarded the previous objective of studying the effects of microbial resistance on the efficacy of antibiotics, as it was not feasible
to find reliable resistance data on population levels.
2. Several changes were made to the inclusion criteria. This version now also includes participants with a clinical diagnosis of acute
maxillary sinusitis without imaging or culture. This is because many of these patients are seen in primary care settings where imaging
is not always available and the culture does not provide help to the clinician at the point of decision on whether to prescribe antibiotics
or not. Studies with adolescents (at least 12 years old) were also included provided that less than 20% of participants were under 18
years of age. Trials including patients with acute exacerbations of chronic sinusitis were included only if they reported separately the
data on the subgroup with acute sinusitis or if at least 80% of participants had acute sinusitis (the acute exacerbation was considered as
part of the chronic form of the disease, which is a separate and more complicated entity often related to background factors that have
an effect on recovery).
3. The search strategy was amended.
4. Unlike the previous version, in meta-analyses the data from all placebo-controlled studies were combined across antibiotic classes.
In the new analyses the clinical failure rate was used as an outcome measure.
5. Risk of bias was assessed for each included study as an additional quality assessment tool.
Compared to the 2003 version of the review the overall clinical conclusions were unchanged.

INDEX TERMS
Medical Subject Headings (MeSH)

Acute Disease; Anti-Bacterial Agents [∗ therapeutic use]; Clinical Trials as Topic; Maxillary Sinusitis [∗ drug therapy]; Randomized
Controlled Trials as Topic
MeSH check words

Adult; Humans


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Antibiotics for acute maxillary sinusitis in adults (Review)

Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M

Antibiotics for acute maxillary sinusitis in adults (Review)

Antibiotics for acute maxillary sinusitis in adults (Review) ii

Antibiotics for acute maxillary sinusitis in adults

Editorial group: Cochrane Acute Respiratory Infections Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Antibiotics for acute maxillary sinusitis

Antibiotics compared to placebo for uncomplicated acute maxillary sinusitis

Patient or population: patients with uncomplicated acute maxillary sinusitis

Assumed risk Corresponding risk

122 per 1000 104 per 1000

Quality of life and activ- Impact Number of participants ⊕

GRADE Working Group grades of evidence

that a new large study could change this estimate.

outcome data and baseline comparability.

Description of the condition

Antibiotics for acute maxillary sinusitis in adults (Review) 6

METHODS We reviewed the following drug therapies:

We included trials with adults or trials that separately reported

Antibiotics for acute maxillary sinusitis in adults (Review) 7

Antibiotics for acute maxillary sinusitis in adults (Review) 8

Antibiotics for acute maxillary sinusitis in adults (Review) 9

Antibiotics for acute maxillary sinusitis in adults (Review) 10

Antibiotics for acute maxillary sinusitis in adults (Review) 11

Measures of treatment effect Assessment of heterogeneity

Antibiotics for acute maxillary sinusitis in adults (Review) 12

Subgroup analysis and investigation of heterogeneity

Antibiotics for acute maxillary sinusitis in adults (Review) 13

Antibiotics for acute maxillary sinusitis in adults (Review) 14

Antibiotics for acute maxillary sinusitis in adults (Review) 15

Antibiotics versus placebo Antibiotics versus placebo

Antibiotics for acute maxillary sinusitis in adults (Review) 16

Antibiotics for acute maxillary sinusitis in adults (Review) 17

Antibiotics for acute maxillary sinusitis in adults (Review) 18

7. Quality of life Cephalosporins and macrolides versus amoxicillin with

Antibiotics for acute maxillary sinusitis in adults (Review) 19

Antibiotics for acute maxillary sinusitis in adults (Review) 20

Antibiotics compared to other antibiotics for uncomplicated acute maxillary sinusitis

Patient or population: patients with uncomplicated acute maxillary sinusitis

Outcomes Impact No of participants Quality of the evidence Comments

ment or a lack of full re-

GRADE Working Group grades of evidence

Antibiotics for acute maxillary sinusitis in adults (Review) 22

Antibiotics for acute maxillary sinusitis in adults (Review) 23

Antibiotics for acute maxillary sinusitis in adults (Review) 24

Antibiotics for acute maxillary sinusitis in adults (Review) 25

Implications for practice

Antibiotics for acute maxillary sinusitis in adults (Review) 26

Lexchin 2003 RevMan 2012

Linder 2003 Rosenfeld 2007

Antibiotics for acute maxillary sinusitis in adults (Review) 37

Antibiotics for acute maxillary sinusitis in adults (Review) 38

Characteristics of included studies [ordered by study ID]

Methods Randomised, single-blind study (investigator). Diagnosis of acute sinusitis confirmed

Interventions 2 treatment arms:

Notes Study supported by a pharmaceutical company. 5 of the authors were affiliated to a

Bias Authors’ judgement Support for judgement

Antibiotics for acute maxillary sinusitis in adults (Review) 39

this was an outcome. However, the results

Blinding? (Participant and investigator) High risk Quote: “Single-blinded (investigator)”

Free of other bias? Co-interventions Low risk Comment: no co-interventions included in