Fluoroquinolones For Treating Typhoid and Paratyph

Cochrane Database of Systematic Reviews
Fluoroquinolones for treating typhoid and paratyphoid fever

(enteric fever) (Review)
Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA
Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA.
Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever).
Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD004530.
DOI: 10.1002/14651858.CD004530.pub4.
www.cochranelibrary.com
Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 1 Clinical failure. . . . . . .
Analysis 1.2. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 2 Microbiological failure. . . .
Analysis 1.3. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 3 Relapse. . . . . . . . .
Analysis 1.4. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 4 Convalescent faecal carriage. .
Analysis 1.5. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 5 Fever clearance time. . . . .
Analysis 1.6. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 6 Duration of hospitalization. .
Analysis 1.7. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 7 Serious adverse events. . . .
Analysis 1.8. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 8 Non-serious adverse events. .
Analysis 2.1. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 1 Clinical Failure. . . . . . .
Analysis 2.2. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 2 Microbiological failure. . . . .
Analysis 2.3. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 3 Relapse. . . . . . . . . .
Analysis 2.4. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 4 Convalescent faecal carriage. . .
Analysis 2.5. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 5 Fever clearance time. . . . .
Analysis 2.6. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 6 Non serious adverse events. . .
Analysis 3.1. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 1 Clinical failure. . . . .
Analysis 3.2. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 2 Microbiological failure. . .
Analysis 3.3. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 3 Non-serious adverse events.
Analysis 4.1. Comparison 4 Fluoroquinolone versus cefixime, Outcome 1 Clinical failure. . . . . . . . . .
Analysis 4.2. Comparison 4 Fluoroquinolone versus cefixime, Outcome 2 Microbiological failure. . . . . . .
Analysis 4.3. Comparison 4 Fluoroquinolone versus cefixime, Outcome 3 Relapse. . . . . . . . . . . .
Analysis 4.4. Comparison 4 Fluoroquinolone versus cefixime, Outcome 4 Convalescent faecal carriage. . . . .
Analysis 4.5. Comparison 4 Fluoroquinolone versus cefixime, Outcome 5 Fever clearance time. . . . . . . .
Analysis 4.6. Comparison 4 Fluoroquinolone versus cefixime, Outcome 6 Duration of hospitalization. . . . .
Analysis 4.7. Comparison 4 Fluoroquinolone versus cefixime, Outcome 7 Serious adverse Events. . . . . . .
Analysis 4.8. Comparison 4 Fluoroquinolone versus cefixime, Outcome 8 Non-serious adverse events. . . . .
Analysis 5.1. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 1 Clinical failure. . . . . . . . .
Analysis 5.2. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 2 Microbiological failure. . . . . .
Analysis 5.3. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 3 Relapse. . . . . . . . . . .
Analysis 5.4. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 4 Convalescent faecal carriage. . . .
Analysis 5.5. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 5 Fever clearance time. . . . . . .
Analysis 5.6. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 6 Non-serious adverse events. . . .
Analysis 6.1. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 1 Clinical failure. . . . . . . .
Analysis 6.2. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 2 Microbiological failure. . . . .
Analysis 6.3. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 3 Relapse. . . . . . . . . .
Analysis 6.4. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 4 Convalescent faecal carriage. . .
Analysis 6.5. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 5 Fever clearance time. . . . . .
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Analysis 6.6. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization. . . .

Analysis 6.7. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 7 Serious adverse events. . . . . .
Analysis 6.8. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 8 Non-serious adverse events. . . . .
Analysis 7.1. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 1 Clinical failure. . . . . . . . . .
Analysis 7.2. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 2 Microbiological failure.
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Analysis 7.3. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 3 Relapse. . . . . . . . . . . . .
Analysis 7.4. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 4 Convalecsent faecal carriage. . . . . .
Analysis 7.5. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 5 Fever clearance time. . . . . . . .
Analysis 7.6. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 6 Duration of hospitalization. . . . . .
Analysis 7.7. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 7 Serious adverse events. . . . . . . .
Analysis 7.8. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 8 Non-serious adverse events. . . . . .
Analysis 8.2. Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 2 Fever Clearance time. . . . . . . .
Analysis 9.1. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 1 Microbiological Failure. . . . . . .
Analysis 9.3. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 3 Fever clearance time. . . . . . . .
Analysis 10.1. Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 1 Microbiological failure. . . . . .
Analysis 10.2. Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 2 Relapse. . . . . . . . . . .
Analysis 11.1. Comparison 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days), Outcome 1 All
outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 12.1. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 1 Relapse. . . . . . . . . . .
Analysis 12.2. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 2 Fever clearance time. . . . . . .
Analysis 12.3. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 3 Non-serious adverse events. . . .
Analysis 13.1. Comparison 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days), Outcome 1 All outcomes. .
Analysis 14.1. Comparison 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days), Outcome 1 All outcomes.
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Fluoroquinolones for treating typhoid and paratyphoid fever

(enteric fever)
Emmanuel E Effa1 , Zohra S Lassi2 , Julia A Critchley3 , Paul Garner4 , David Sinclair4 , Piero L Olliaro5 , Zulfiqar A Bhutta2
1 Internal
Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria. 2 Division of Women and Child Health, Aga Khan
University Hospital, Karachi, Pakistan. 3 Institute of Health and Society, Newcastle University, Newcastle, UK. 4 International Health
Group, Liverpool School of Tropical Medicine, Liverpool, UK. 5 UNICEF/UNDP/World Bank/WHO Special Programme for Research
and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland
Contact address: Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box
3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.
Editorial group: Cochrane Infectious Diseases Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2012.
Review content assessed as up-to-date: 1 February 2011.
Citation: Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD004530. DOI:
10.1002/14651858.CD004530.pub4.
ABSTRACT
Background
Typhoid and paratyphoid are febrile illnesses, due to a bacterial infection, which remain common in many low- and middle-income
countries. The World Health Organization (WHO) currently recommends the fluoroquinolone antibiotics in areas with known
resistance to the older first-line antibiotics.
Objectives
To evaluate fluoroquinolone antibiotics for treating children and adults with enteric fever.
Search methods
We searched The Cochrane Infectious Disease Group Specialized Register (February 2011); Cochrane Central Register of Controlled
Trials (CENTRAL), published in The Cochrane Library (2011, Issue 2); MEDLINE (1966 to February 2011); EMBASE (1974 to
February 2011); and LILACS (1982 to February 2011). We also searched the metaRegister of Controlled Trials (mRCT) in February
2011.
Selection criteria
Randomized controlled trials examining fluoroquinolone antibiotics, in people with blood, stool or bone marrow culture-confirmed
enteric fever.
Data collection and analysis
Two authors independently assessed the trials methodological quality and extracted data. We calculated risk ratios (RR) for dichotomous
data and mean difference for continuous data with 95% confidence intervals (CI).
Comparative effectiveness has been interpreted in the context of; length of treatment, dose, year of study, known levels of antibiotic
resistance, or proxy measures of resistance such as the failure rate in the comparator arm.
Main results
Twenty-six studies, involving 3033 patients, are included in this review.
Fluoroquinolones versus older antibiotics (chloramphenicol, co-trimoxazole, amoxicillin and ampicillin)
In one study from Pakistan in 2003-04, high clinical failure rates were seen with both chloramphenicol and co-trimoxazole, although
resistance was not confirmed microbiologically. A seven-day course of either ciprofloxacin or ofloxacin were found to be superior. Older
studies of these comparisons failed to show a difference (six trials, 361 participants).
In small studies conducted almost two decades ago, the fluoroquinolones were demonstrated to have fewer clinical failures than
ampicillin and amoxicillin (two trials, 90 participants, RR 0.11, 95% CI 0.02 to 0.57).
Fluoroquinolones versus current second-line options (ceftriaxone, cefalexin, and azithromycin)
The two studies comparing a seven day course of oral fluoroquinolones with three days of intravenous ceftriaxone were too small to
detect important differences between antibiotics should they exist (two trials, 89 participants).
In Pakistan in 2003-04, no clinical or microbiological failures were seen with seven days of either ciprofloxacin, ofloxacin or cefixime
(one trial, 139 participants). In Nepal in 2005, gatifloxacin reduced clinical failure and relapse compared to cefixime, despite a high
prevalence of NaR in the study population (one trial, 158 participants, RR 0.04, 95% CI 0.01 to 0.31).
Compared to a seven day course of azithromycin, a seven day course of ofloxacin had a higher rate of clinical failures in populations
with both multi-drug resistance (MDR) and nalidixic acid resistance (NaR) enteric fever in Vietnam in 1998-2002 (two trials, 213
participants, RR 2.20, 95% CI 1.23 to 3.94). However, a more recent study from Vietnam in 2004-05, detected no difference between
gatifloxacin and azithromycin with both drugs performing well (one trial, 287 participants).
Authors conclusions
Generally, fluoroquinolones performed well in treating typhoid, and maybe superior to alternatives in some settings. However, we were
unable to draw firm general conclusions on comparative contemporary effectiveness given that resistance changes over time, and many
studies were small. Policy makers and clinicians need to consider local resistance patterns in choosing a fluoroquinolone or alternative.
There is some evidence that the newest fluoroquinolone, gatifloxacin, remains effective in some regions where resistance to older
fluoroquinolones has developed. However, the different fluoroquinolones have not been compared directly in trials in these settings.
PLAIN LANGUAGE SUMMARY

Fluoroquinolones for treating enteric fever
Researchers in The Cochrane Collaboration conducted a review of the effect of fluoroquinolone antibiotics in people enteric fever.
After searching for relevant studies, they identified 26 studies involving 3033 patients. Their findings are summarized below.
What is enteric fever and how might fluoroquinolones work?
Enteric fever is a common term for two similar clinical illnesses known individually as typhoid fever and paratyphoid fever. These are
most common in low- and middle-income countries where water and sanitation may be inadequate.
Enteric fever typically causes fever and headache with diarrhoea, constipation, abdominal pain, nausea and vomiting, or loss of appetite.
In left untreated some people can develop serious complications and can be fatal.
The fluoroquinolones are a large family of antibiotic drugs, which are commonly used for a variety of infectious diseases. In the past,
enteric fever responded extremely well to fluoroquinolones, but drug resistance has become a major public health problem in many
areas especially Asia.
What the research says
Effect of using fluoroquinolones:
Generally, fluoroquinolones are effective in typhoid.
Policy makers and clinicians will need to consider local antibiotic resistance when considering treatment options for enteric fever.
One relatively new fluoroquinolone, gatifloxacin, seems to remain effective in some regions where resistance to older fluoroquinolones
has developed.
BACKGROUND
Description of the condition

Enteric fever is a common term to encompass two similar clinical
illnesses, caused by different serotypes of the bacterium Salmonella
enterica. Typhoid fever (due to Salmonella typhi) is generally more
common, and more severe, but recent reports suggest that the relative frequency of paratyphoid fever (due to Salmonella paratyphi) may be increasing (Chandel 2000; Ahmad 2002; Butt 2005;
Ochiai 2005; Jesudason 2005; Woods 2006; Maskey 2008). In the
year 2000, there were an estimated 21.6 million cases of typhoid
fever, with 210,000 deaths, and 5.4 million cases of paratyphoid
fever (Ochiai 2008; Crump 2004).
The symptoms of enteric fever are generally non-specific and can
vary among different populations (Parry 2002). Common symptoms include fever, headache, and gastrointestinal complaints;
such as diarrhoea, constipation, abdominal pain, nausea and vomiting, or loss of appetite (Lee 2000; Richens 2000). Severe disease
occurs in 10 to15% of people, and complications such as; intestinal perforation, intestinal bleeding, shock, pancreatitis (inflammation of the pancreas), pneumonia, myocarditis (inflammation
of the heart muscles), meningitis (inflammation of the covering of
the brain), or psychosis (altered mental state) can occur, typically
after the illness has lasted more than two weeks (Parry 2002).
The bacteria may be shed in the faeces during the acute illness, during convalescence, and occasionally for prolonged periods when
the person is labelled a chronic carrier (defined as excretion of
the bacterium in the stool or urine for more than one year (Bhan
2005)). Infection occurs when food or water contaminated with
faeces harbouring the bacteria are ingested. The organisms then
penetrate the intestinal lining, multiply in lymphoid tissues, and
are released into the blood stream from where they spread throughout the body to various organs; most commonly the liver, spleen,
bone marrow, and gall bladder (Lesser 2001).
The enteric fevers remain a major health problem in low- and middle-income countries where water and sanitation services may be
inadequate. They are endemic throughout Asia (with the highest
incidence in South and Southeast Asia), the Middle East, Africa,
and South and Central America (Ivanoff 1995; Crump 2004). In
high-income countries, most cases occur in travellers returning
from these endemic areas (McNabb 2008). The highest incidence
has been reported in children between five and 10 years of age (Lin
2000; Siddiqui 2006; Sur 2006), and in those under five years of
age (Sinha 1999; Saha 2001; Saha 2003; Brooks 2005).
Diagnosis and treatment
The diagnosis of enteric fever can be difficult due to the non

specific nature of the symptoms. A definitive diagnosis is possible
when the organisms are isolated from blood, bone marrow or other
body fluids. Blood cultures are typically positive in 60 to 80%
of cases, while bone marrow cultures are more sensitive with 80
to 95% positive, even after prior antibiotic therapy (Parry 2002).
Serological tests, such as the Widal reaction, have been widely used
but these are non-specific, giving false positive results, and can be
difficult to interpret. More recently, there has been interest in the
use of DNA probes and polymerase chain reaction (PCR) testing
, but these are not widely available in enteric fever endemic areas
(Parry 2002).
Untreated the disease last 3 to 4 weeks with fever, septicaemia,
and a 10-30% mortality. Treatment is with antibiotics and most
patients are managed as outpatients.
Antibiotic resistance
Resistance of S. typhi and S. paratyphi to commonly used antibiotics has become problematic. Resistance to the highly effective
chloramphenicol in the 1970s was associated with simultaneous
resistance to sulfonamides, tetracycline, and streptomycin; this led
to the use of alternative agents such as co-trimoxazole and amoxicillin (Parry 2002). Subsequently, multi-drug resistant (MDR)
strains (resistant to chloramphenicol, ampicillin, co-trimoxazole
and streptomycin) emerged and are now prevalent in many parts
of the world.
In the Indian subcontinent and China, the frequency of MDR
strains ranges from 50% to 80% of all S. typhi isolates and
has reached 100% during outbreaks (Lee 2000). In sub-Saharan
Africa, MDR S. typhi has been found in 61% and 82.4% of isolates in Nigeria and Kenya, respectively (Akinyemi 2005;Kariuki
2004). Surveillance studies can show considerable geographic differences in the proportion of MDR isolates within the same region;
MDR S. typhi is far more common in India, Pakistan and Vietnam
than in areas of China and Indonesia (Ochiai 2008). Longitudinal
studies have also shown that the proportion of MDR strains can
decrease over time following changes in antibiotic use (Lakshmi
2006; Maskey 2008). Indeed several areas have reported a re-emergence of strains susceptible to first-line antibiotics such as chloramphenicol (Takkar 1995; Sood 1999; Wasfy 2002; Rodrigues
2003; Butt 2005; Walia 2005; Mohanty 2006; Gupta 2009).
Infection with resistant strains can lead to higher treatment failure
rates, an increased risk of complications, and an increased potential
for transmission due to prolonged faecal carriage (Coovadia 1992;
Bhutta 1996; Mermin 1999; Rupali 2004; Walia 2005; Crump
2008).
The isolates that respond less well clinically to fluoroquinolones
are usually nalidixic acid resistant (NaR) by disc susceptibility testing and have high minimum inhibitory concentrations (MICs) although their breakpoints remain within the range set by the Clinical and Laboratory Standard Institute (CLSI). Using current CLSI
disk breakpoints (CLSI 2007) means that fluoroquinolones may
continue to be used inappropriately thereby increasing the risks of
treatment failure. A key consideration now is the suggested need
to redefine breakpoints for isolates with reduced susceptibility to
fluoroquinolones in order to identify these strains, offer appropriate therapy and stem the emergence of more resistant organisms
(Crump 2003, Parry 2010, BSAC 2011).
Description of the intervention

The fluoroquinolones are a large family of anti-infective drugs,
synthesized around a quinolone core, that possess a broad spectrum
of antibacterial activity (Congeni 2002).
Nalidixic acid, the prototype quinolone, was first introduced into
clinical use in 1962. Four generations of fluoroquinolones have
subsequently been developed, classified according to their spectrum of antibacterial activity, and used to treat a range of urinary
tract, respiratory, gastrointestinal, and sexually transmitted infections (Oliphant 2002):
second generation; eg ciprofloxacin, ofloxacin, pefloxacin,
norfloxacin; broad gram-negative cover but limited activity
against gram-positive bacteria;
third generation; eg levofloxacin, sparfloxacin, gatifloxacin,
moxifloxacin; improved activity against gram-positive bacteria;
fourth generation; eg trovafloxacin, gemifloxacin; improved
activity against anaerobic bacteria.
Subsequently, several of these products have been withdrawn from
clinical use (Committee 2006), and norfloxacin is not generally
recommended for the treatment of enteric fever due to its poor
bioavailability (Miller 2000; Hooper 2000).
Adverse events
Fluoroquinolones generally have few adverse effects. The most
common are mild and self-limiting symptoms affecting either the
gastrointestinal system (nausea, vomiting or diarrhoea), or the
central nervous systems (headaches and dizziness) (Bertino 2000;
Oliphant 2002). Rare and serious adverse effects have been linked
to specific fluoroquinolone compounds and several have subse-
quently been withdrawn from clinical use: prolongation of the corrected QT (QTc) interval with grepafloxacin, liver toxicity with
trovafloxacin, and anaphylaxis, haemolytic anaemia and renal failure with temafloxacin.(Bertino 2000; Fish 2001)
How the intervention might work

In the past, enteric fevers responded extremely well to the fluoroquinolones, but quinolone resistant strains of S. typhi, especially in
Asia, have become a major public health problem (Chuang 2009;
Parry 2010; Smith 2010; Parry 2010).The susceptibility of S. typhi
to the fluoroquinolones can be divided into three categories:
fully susceptible; susceptible to both nalidixic acid and
ciprofloxacin;
reduced susceptibility: NaR, but susceptible to
ciprofloxacin (Threlfall 1999; Ackers 2000; Crump 2003); or
resistant: both NaR and ciprofloxacin resistant (Rupali
2004; Parry 2006; Kownhar 2007).
However, not all strains with reduced susceptibility to fluoroquinolones are NaR suggesting the likelihood of a new mechanism of resistance unrelated to the principal mechanisms of resistance already known (Threlfall 2003; Cooke 2006). There are
emerging reports of isolates with absolute fluoroquinolone resistance (Harish 2004; Adachi 2005; Renuka 2005; Ahmed 2006;
Mohanty 2006; Walia 2006; Joshi 2007). To date, fluoroquinolone
resistance has been reported in several countries including India
(Renuka 2005,Gaind 2006, Kownhar 2007), Vietnam (Ahmed
2006), Kuwait (Dimitrov 2009), South Africa (Keddy 2010), UK
(Cooke 2007) and the USA (Medalla 2011). Most of those reported in the UK and the USA have been imported from India,
Vietnam and Bangladesh.
There is current interest in gatifloxacin, which has been found
to be active against NaR strains. The alteration in its structure is
such that it may hypothetically make the drug less susceptible to
the mutations that caused resistance to the older fluoroquinolones
(Fukuda 2001). Studies of gatifloxacin suggest that there may be
fewer cardiac adverse effects than seen with older generation fluoroquinolones, but with a higher incidence of dysglycaemia (high
or low blood sugar) (Frothingham 2005; Park-Wyllie 2006), although some authorities state this may be confined to the elderly,
and those with non-insulin dependent diabetes (Ambrose 2003).
Why it is important to do this review

This review aims to summarise trials comparing fluoroquinolones
and other antibiotics in treating enteric fever. Interpreting trial
data needs to take into account other factors, in particular the year
and location of the study, as antibiotic resistance (and therefore
efficacy), is dynamic and changes with time.
In the earlier version of this review, different generations of fluoroquinolones were combined in the analysis with sub groups accord-
ing to the prevalence of NaR strains (Thaver 2008). It was clear that
there were important differences between the fluoroquinolones,
and this update therefore seeks to group studies by each fluoroquinolone individually. As norfloxacin has poor bioavailability and
is no longer a credible treatment option, studies evaluating this
drug were excluded.
OBJECTIVES
To evaluate the fluoroquinolone antibiotics in the treatment of
enteric fever in children and adults.
Relapse; defined as the recurrence of symptoms with a

positive culture from blood or bone marrow or any sterile
anatomic site, beyond a time period defined by trial authors.
Secondary outcomes
Fever clearance time; defined as the time in hours/days

taken to clear fever from the start of the intervention or control
drug with the definition of fever clearance as specified by trial
authors.
Length of hospital stay; defined as the time in days from
entry into trial until discharge.
Convalescent faecal carriage; defined as a positive faecal
culture detected at any time after the end of treatment up to one
year of follow up.
METHODS
Adverse events (as defined by trial authors)
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
People diagnosed with typhoid or paratyphoid fever based on microbiological confirmation from blood, stool or bone marrow.
Types of interventions
Intervention
Different fluoroquinolone antibiotics, excluding norfloxacin or
other fluoroquinolones not currently in use
Control
Any non-fluoroquinolone antibiotic used to treat enteric fever;
chloramphenicol, ampicillin, amoxicillin, cotrimoxazole, azithromycin or cephalosporins.
An alternative fluoroquinolone, or a different treatment duration
of the same fluoroquinolone.
Types of outcome measures
Primary outcomes
Clinical failure; defined as development of complications,

requiring a change of antibiotic therapy, or remaining
symptomatic beyond a time period specified by trial authors.
Microbiological failure; defined as a positive culture from
blood, bone marrow, or any sterile anatomic site, beyond a time
period specified by trial authors.
Serious adverse events; defined as adverse events leading to

death, inpatient hospitalization, prolonged hospitalization, or
life threatening, resulting in persistent or significant disability or
incapacity, such as joint disease, tendonitis and tendon rupture,
prolongation of QTc interval, seizures, nephrotoxicity,
haematological reactions, or severe dermatologic reactions.
Other adverse events, such as nausea, diarrhoea, headache,
dizziness, mild photosensitivity, hepatic enzyme elevations, and
hypersensitivity reactions.
Search methods for identification of studies

Emmanuel Effa worked with Vittoria Lutje (Information Retrieval
Specialist, Cochrane Infectious Diseases Group) to identify all relevant trials regardless of language or publication status.
Electronic searches
We searched the following databases using the search terms and
strategy described in Appendix 1: Cochrane Infectious Diseases
Group Specialized Register (February 2011); Cochrane Central
Register of Controlled Trials (CENTRAL), published in The
Cochrane Library (2011, Issue 2); MEDLINE (1966 to February
2011); EMBASE (1974 to Febrary 2011); and LILACS (1982 to
February 2011). We also searched the metaRegister of Controlled
Trials (mRCT) in February 2011 using the search term (typhoid
fever) NOT vaccine.
Searching other resources
Researchers
We contacted Christiane Dolecek (in October, 2010) who provided information on unpublished and ongoing trials.
We also checked the reference lists of all retrieved trials and

searched the review authors personal literature collections for relevant trials.
outcomes, such as clinical failure, we extracted the total number

of participants and number of participants that experienced the
event. For continuous outcomes, such as fever clearance time, we
extracted the total number of participants, arithmetic means, and
standard deviations. If the standard deviation was not reported,
we attempted to use the confidence interval or P value to derive
it. The extracted data were entered data into Review Manager 5.1.
and cross-checked by a second author for accuracy.
Data collection and analysis
Assessment of risk of bias in included studies
Reference lists and review authors personal collections
Selection of studies
Two review authors, Emmanuel E Effa (EEE) and Zohra S Lassi
(ZSL), independently assessed all the potential studies identified
by the search strategy and applied the inclusion criteria. Any
disagreements were resolved through discussion. The excluded
studies, and the reason for their exclusion are included in the
Characteristics of excluded studies.
Data extraction and management
For eligible studies, two review authors (EEE and ZSL) extracted
the data using a pre-tested data extraction form. For dichotomous
Two review authors (EEE and ZSL) independently assessed the

risk of bias for each included trial using the Cochrane collaborations Risk of bias tool as described in the Cochrane Handbook of
Systematic Reviews of Intervention (Higgins 2011).
We followed the guidance to assess whether adequate steps were
taken to reduce the risk of bias across six domains: sequence generation, allocation concealment, blinding (of participants, personnel and outcome assessors), incomplete outcome data, selective
outcome reporting and other sources of bias. We have categorized
our judgements as yes (low risk of bias), no (high risk of bias)
or unclear. We compared our entries and resolved disagreements
by discussion.
The risk of bias judgements are displayed in a table and summarised in Figure 1 and Figure 2.
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.
Measures of treatment effect

Dichotomous data are presented and compared using risk ratios
(RR), and continuous data using a mean difference (MD). All results are presented with the corresponding 95% confidence interval (CI).
Where there is no statistical heterogeneity we have used the fixedeffect model. Where statistical heterogeneity was detected, and
we still considered it appropriate to pool the data, we used the
random-effects model.
Subgroup analysis and investigation of heterogeneity

Unit of analysis issues
Trials including more than two comparison groups have been split
and analysed as individual pair-wise comparisons. When conducting meta-analysis we have ensured that participants and cases in
the placebo group are not counted more than once, by dividing
the placebo cases and participants evenly between the intervention
groups.
We planned to investigate heterogeneity by conducting subgroup

analyses according to; drug dose; severe or complicated enteric
fever (as defined by trialists) versus uncomplicated enteric fever;
and different time points for outcome measurements. This was not
possible due to the limited number of trials in each comparison.
We have instead commented on these factors within the text where
appropriate.
Dealing with missing data
Sensitivity analysis
We were unable to conduct an intention-to-treat analysis on culture-positive cases since no further information was available for
culture-positive participants who were lost to follow up.
We planned to assess the robustness of the data by performing a

sensitivity analysis for each of the risk of bias assessment factors,
but were again unable to do this due to the low number of trials.
Assessment of heterogeneity
We assessed for heterogeneity by visually inspecting the forest plots
and by using the Chi2 test for homogeneity, using a 10% level of
statistical significance to indicate statistical heterogeneity.
Assessment of reporting biases

We planned to assess for the presence of publication bias by looking
for funnel plot asymmetry but this was not possible due to the low
number of trials.
Data synthesis
We analysed data using Review Manager 5.1.
We analysed data using pair-wise comparisons. we compared the
fluoroquinolones with each alternative antibiotic and subgrouped
by the specific fluoroquinolone. The data are organised into four
sections:
fluoroquinolones versus first-line antibiotics (chloramphenicol,
co-trimoxazole, and ampicillin or amoxicillin);
fluoroquinolones versus second-line antibiotics (cefixime,
ceftriaxone, azithromycin);
comparison of different fluoroquinolones and different
durations of fluoroquinolones;
a summary of the evidence for gatifloxacin
RESULTS
Description of studies
Results of the search

We assessed 72 trials for eligibility. Twenty-six were included and
36 excluded. Seven studies are awaiting classification and one trial
is ongoing.
Among the seven trials awaiting classification; we were unable to
retrieve full text copies for two (Flores 1991; Soewandojo 1992),
and four did not provide adequate information on the methodology for inclusion (Quintero 1988; Weng 1996, Xiao 1991, Yu
1998). (See the Characteristics of studies awaiting classification
table).
Included studies
The 26 trials included 3033 participants. Most trials were small
and lacked statistical power to detect differences between the treatment regimens. The smallest trial had 23 participants and the
largest had 352 participants.
Trial setting
Nine trials were conducted in Vietnam, two trials in each of Italy,

Nepal and Pakistan, and one trial in each of Albania, Bahrain,
Bangladesh, Egypt, Guatemala, Indonesia, Laos, Morocco and
Turkey. We could not determine the location of one trial (Gottuzzo
1992 N/A).
Twenty-two of the 26 trials were conducted on inpatients. Alam
1995 BGD was conducted on both inpatients and outpatients.
Tran 1995 VNM was a community-based outpatient trial, while
Pandit 2007 NPL and Arjyal 2011 recruited outpatients presenting to the outpatient or emergency department of the study hospital.
Twenty-two trial reports included data on the prevalence of MDR
strains among trial participants, and 13 trial reports included data
on the prevalence of NaR strains.
Of the 13 trials comparing fluoroquinolones with first-line antibiotics, MDR strains were only present in two trials (Phongmany
2005 LAO; Arjyal 2011), they were absent in seven trials, and four
trials did not report it (Gottuzzo 1992 N/A; Yousaf 1992 PAK;
Flores 1994 MEX; Rizvi 2007 PAK).
See Appendix 2 for further details on microbiological results and
sensitivity.
Trials that included patients diagnosed clinically tended to report

outcomes only for culture-confirmed cases of enteric fever and
excluded culture-negative cases from their analysis, even if initially
enrolled in the study. Only Arjyal 2011 detailed analyses were
done both reporting culture positive cases only and intention to
treat which included patients randomized but who were culture
negative..
Interventions
Nineteen trials compared fluoroquinolones with alternative antibiotics: chloramphenicol (eight trials), amoxicillin or ampicillin
(two trials), co-trimoxazole (three trials), azithromycin (four trials), ceftriaxone (two trials), and cefixime (three trials). Seven trials compared different fluoroquinolone treatment durations: two
days versus three days (three trials); three days versus five days (one
trial), five days versus seven days (one trial); seven days versus 10
days (one trial); and 10 days versus 14 days (one trial).
Most trials comparing fluoroquinolones with a non-fluoroquinolone antibiotic treated the participants with the fluoroquinolone for seven (eight trials) or 10 days (six trials) (range: three
to 15 days).
Outcomes
Participants
Three trials were exclusively in children (Vinh 1996 VNM;

Phuong 1999 VNM; Vinh 2005 VNM). Seven trials included
both children and adults (Alam 1995 BGD; Tran 1995 VNM;
Pandit 2007 NPL; Parry 2007 VNM;Rizvi 2007 PAK; Dolecek
2008 VNM; Arjyal 2011), 15 trials were exclusively in adults (Hajji
1988 MAR; Limson 1989 PHL; Gottuzzo 1992 N/A; Morelli
1992 ITA; Yousaf 1992 PAK; Wallace 1993 BHR; Smith 1994
VNM; Cristiano 1995 ITA; Unal 1996 TUR; Chinh 1997 VNM;
Kalo 1997 ALB; Girgis 1999 EGY; Chinh 2000 VNM; Gasem
2003 IDN; Phongmany 2005 LAO), and five trial reports did
not mention the participants age of which one used the keyword
adult (Flores 1994 MEX).
Eighteen trials were conducted specifically on participants with
uncomplicated enteric fever or participants without major complications of enteric fever (Limson 1989 PHL; Gottuzzo 1992
N/A; Wallace 1993 BHR; Flores 1994 MEX; Tran 1995 VNM;
Unal 1996 TUR; Vinh 1996 VNM; Vinh 2005 VNM; Phuong
1999 VNM; Chinh 1997 VNM; Girgis 1999 EGY; Chinh 2000
VNM; Gasem 2003 IDN; Phongmany 2005 LAO; Pandit 2007
NPL; Parry 2007 VNM; Dolecek 2008 VNM; Arjyal 2011 ), and
one included only participants with severe enteric fever (Cristiano
1995 ITA). The remaining trials did not provide this information.
Most trials used blood cultures, bone marrow cultures, or both,
to confirm cases of enteric fever. In Rizvi 2007 PAK, a rapid diagnostic test - Dot Enzyme immunosorbent Assay - was also used
although all but one participant was culture positive.
There were considerable variations regarding the time points at

which outcomes were measured, particularly microbiological failure (such as day two, the end of treatment, and some days after treatment) and relapse (such as during therapy or up to two
months after treatment completion). The precise descriptions also
varied considerably; for example, some trialists defined relapse
as the recurrence of similar signs and symptoms with confirmation by blood and/or bone marrow culture (sterile site, as defined
in protocol), and others as confirmed by positive stool cultures
(non-sterile site) only. Some trialists did not explicitly state how
they confirmed relapse in their trial (see Appendix 3 Definitions
of outcomes). A full summary of adverse events as stated in the
papers is summarized in Appendix 4 and Appendix 5.
Further details are presented in the Characteristics of included
studies tables.
Excluded studies
Of the excluded studies, five were excluded as they used norfloxacin
(Nalin 1987; Sarma 1991; Huai 2000; Bai 1995; ZhongYang
1997), and three involved fluoroquinolones no longer in clinical
use (Abejar 1993; Arnold 1993; Tran 1994). (For further details
see the Characteristics of excluded studies table).
Risk of bias in included studies

See summary of risk of bias assessment in Figure 2
Allocation
The method used to generate the allocation sequence was at low
risk of bias in sixteen trials, and unclear in ten.
Fourteen trials used an adequate method (sealed envelopes) to
conceal allocation. The method used in the remaining 12 trials
was unclear.
Blinding
Three trials were described as double blinded and 22 trials were
open; one trial did not mention use of placebo, but we assumed it
was open (Flores 1994 MEX). In one trial, blinding was unclear
(Rizvi 2007 PAK).
Incomplete outcome data

There were incomplete long term outcome data reported for four
trials (Smith 1994 VNM; Vinh 1996 VNM; Gasem 2003 IDN;
Phongmany 2005 LAO). The reason for this was unclear.
Selective reporting
Most trials reported both efficacy and safety data. In one trial
(Wallace 1993 BHR), there were no reports of adverse events while
in another, the report was incomplete as only mortality and associated data for one participant were reported (Phuong 1999 VNM).
Other potential sources of bias

Two trials were stopped early. One because of a significant difference in the primary outcome (Phongmany 2005 LAO), and
one due to apparent lower efficacy in the control group, the cost
of control drug and inconvenience of intravenous administration
(Wallace 1993 BHR). Two trials were funded by pharmaceutical
companies (Alam 1995 BGD; Girgis 1999 EGY)
Effects of interventions
Fluoroquinolones versus first-line antibiotics

(chloramphenicol, co-trimoxazole, and ampicillin or
amoxicillin)
Comparison 1. Fluoroquinolones versus chloramphenicol
Overall, a seven-day course of any fluoroquinolone appears at

least as effective as a 14-day course of chloramphenicol at reducing clinical and microbiological treatment failures (eight trials, 916 participants). In the most recent study, from Pakistan
in 2003-04, high failure rates were seen with chloramphenicol,
and the fluoroquinolones used (ciprofloxacin and ofloxacin)

were superior.
Eight trials have compared four different fluoroquinolones with
chloramphenicol: Four trials used ciprofloxacin as the comparator
drug (Gottuzzo 1992 N/A; Morelli 1992 ITA; Gasem 2003 IDN;
Rizvi 2007 PAK), four trials used ofloxacin (Morelli 1992 ITA;
Yousaf 1992 PAK; Phongmany 2005 LAO; Rizvi 2007 PAK), two
used pefloxacin (Morelli 1992 ITA; Cristiano 1995 ITA), and one
trial assessed gatifloxacin (Arjyal 2011).
Two studies did not clarify the proportion of participants with
MDR strains (Gottuzzo 1992 N/A; Yousaf 1992 PAK), and seven
did not report NaR data. The dosing of fluoroquinolones varied
from trial to trial and is included in the forest plots as footnotes
to aid interpretation.
Clinical and microbiological response
Only one three-arm study, from Pakistan in 2003-04, demonstrated a statistically significant benefit with fluoroquinolones
compared to chloramphenicol (Rizvi 2007 PAK). The incidence
of clinical and microbiological failure with chloramphenicol was
high in this trial (9/44) suggesting significant resistance, although
this was not confirmed microbiologically. Clinical failures were
lower with both ciprofloxacin (RR 0.05, 95% CI 0.00 to 0.81, 92
participants, one trial, Analysis 1.1; Analysis 1.2), and ofloxacin
(RR 0.05, 95% CI 0.00 to 0.86, 89 participants, one trial, Analysis
1.1; Analysis 1.2).
Conversely, the largest trial to date found no significant difference
between gatifloxacin and chloramphenicol in Nepal in 2006-08
(352 participants, one trial, Analysis 1.1; Analysis 1.2). The remaining older trials were too small to detect clinically important
differences between the treatment regimens should they exist.
Relapse and convalescent faecal carriage
The current trials have not shown a statistically significant difference in post-treatment relapses or fecal carriage with any fluoroquinolone compared to chloramphenicol ( participants, six trials,
Analysis 1.5; Analysis 1.6). The follow-up in the included trials
varied from two weeks to six months.
Fever clearance time
Fever clearance time was significantly longer with chloramphenicol
compared with ciprofloxacin (MD -62.46, 95% CI -75.52 to 49.39, 147 participants, two trials, Analysis 1.5) and ofloxacin
(MD -75.85, 95% CI -88.52 to -63.17, 140 participants, two
trials, Analysis 1.5).
Duration of hospitalisation
Participants who had chloramphenicol in Phongmany 2005 LAO,
stayed a significantly longer number of days in hospital compared
10
with ofloxacin (MD -9.90, 95% CI -11.42 to -8.38, 60 participants, one trial, Analysis 1.6). However, we note that ofloxacin
was given only for three days compared to the 14 days of chloramphenicol, so this is perhaps unsurprising.

Only Rizvi 2007 PAK assessed for relapses, and only Hajji 1988
MAR assessed for convalescent faecal carriage, but there were no
events in either trial.
Adverse events
No difference has been shown between ciprofloxacin and chloramphenicol (173 participants, two trials, Analysis 1.7), or
ofloxacin and chloramphenicol where no serious adverse events
were recorded (50 participants, one trial, Analysis 1.7).
Non-serious adverse events were significantly lower following
treatment with gatifloxacin than with chloramphenicol (RR 0.58,
95% CI 0.44 to 0.78, 844 participants, one trial, Analysis 1.8).
This data included all randomized participants including those
who were culture negative. The events were mainly gastrointestinal in nature and the common ones included abdominal pains,
diarrhoea, nausea and vomiting. Elevated blood sugar was more
common in the gatifloxacin group between the second and seventh days of the study. There was no difference in the number of
participants with low blood sugar for both groups.
The differences between the other fluoroquinolones and chloramphenicol did not reach statistical significance (Analysis 1.8).
Comparison 2. Fluoroquinolones versus cotrimoxazole
In one study, from an area of Pakistan in 2003-04, the fluoroquinolones used (ciprofloxacin and ofloxacin) were superior
to co-trimoxazole. Two small trials done in the 1980s, in the
absence of MDR strains, failed to show a difference with both
drugs performing well.
Three trials have compared three different fluoroquinolones with
cotrimoxazole: two trials used ciprofloxacin; Limson 1989 PHL;
Rizvi 2007 PAK, and one trial each assessed ofloxacin; Rizvi 2007
PAK, and pefloxacin; Hajji 1988 MAR.
Hajji 1988 MAR and Limson 1989 PHL both report the absence
of MDR strains and Hajji 1988 MAR also records that there were
no participants with NaR strains. Limson 1989 PHL and Rizvi
2007 PAK do not report the presence or absence of NaR strains.
Of the three trials, only Rizvi 2007 PAK reports any clinical failures at all. In this trial, from Pakistan in 2003-04, there was a
high incidence of clinical and microbiological failure following
treatment with co-trimoxazole (13/44) suggesting significant resistance, compared with no clinical failures following ciprofloxacin (RR 0.03, 95% CI 0.00 to 0.56, 92 participants, one trial,
Analysis 2.1) or ofloxacin (RR 0.04, 95% CI 0.00 to 0.59, 89
participants, one trial, Analysis 2.1).
The high failure rate with co-trimoxazole is the likely cause of the
longer fever clearance time observed by Rizvi 2007 PAK (Analysis
2.5)
Fever clearance and duration of hospitalisation

Not reported
Adverse events
Serious adverse events were not reported.
No statistically significant difference in non-serious events has
been shown between any individual fluoroquinolone and co-trimoxazole (219 participants, three trials, Analysis 2.6). The events
were mainly gastrointestinal in nature and were self limiting.
Comparison 3. Fluoroquinolones versus amoxicillin or

ampicillin
Two small studies conducted in the 1990s, found that ofloxacin

given for 10 to 14 days reduced clinical and microbiological
failures compared to a 10 to 14 day course of amoxicillin or
ampicillin. The prevalence of antibiotic resistance was not reported.
One small trial has compared ofloxacin with ampicillin (Flores
1994 MEX), and another compared ofloxacin with amoxicillin
(Yousaf 1992 PAK)
There was no indication as to the presence or not of MDR or NaR
strains.

The risk of clinical or microbiological failure was significantly
lower in the ofloxacin group compared to ampicillin or amoxicillin (RR 0.11, 95% CI 0.02 to 0.57, 90 participants, two trials,
Analysis 3.1; RR 0.13; 95% CI 0.03 to 0.68, 90 participants, two
trials, Analysis 3.2 respectively). It should be noted that these two
trials are almost 20 years old and may not be relevant today.

Not reported
Fever clearance and duration of hospitalization

Not reported
11
Adverse events
No serious adverse events occurred in either of the studies. Nonserious events were significantly more following treatment with
ofloxacin compared to amoxicillin (RR 0.27; 95% CI 0.09 to 0.86,
50 participants, one trial, Analysis 3.3). The reported events were
mostly diarrhoea and skin rashes.
time to fever clearance for gatifloxacin (92 hours vs 138 hours, P

<0.0001) and ofloxacin (105 hours vs 201 hours, P <0.0001). This
reductions for ofloxacin were also reflected in the shorter length
of hospital stay in that group (MD -3.00, 95% CI -4.53 to -1.47,
80 participants, one trial, Analysis 4.6).
Adverse events
Fluoroquinolones versus second-line antibiotics
(cefixime, ceftriaxone, azithromycin)
Comparison 4. Fluoroquinolones versus cefixime
In one study from Pakistan in 2003-04 no clinical or microbiological failures were seen with either ciprofloxacin, ofloxacin or
cefixime. In Nepal in 2005, gatifloxacin reduced clinical failure
and relapse compared to cefixime, despite a high prevalence of
NaR in the study population.
Three trials have compared a fluoroquinolone with cefixime. One
trial used ciprofloxacin as the comparator drug (Rizvi 2007 PAK),
two trials used ofloxacin (Phuong 1999 VNM; Rizvi 2007 PAK)
and one gatifloxacin (Pandit 2007 NPL).
In one trial, participants were mostly adults (Pandit 2007 NPL)
while one trial had only child participants (Phuong 1999 VNM).
The third trial included both adult and child participants (Rizvi
2007 PAK). One trial (Pandit 2007 NPL) had a high proportion
of NaR strains, but the other two trials did not report the presence
of these strains ( Phuong 1999 VNM; Rizvi 2007 PAK). In Pandit
2007 NPL, because of its wholly out patient status, community
medical auxiliaries conducted twice daily home-based assessments
and provided directly observed treatment with study drugs. All
participants were then compulsorily seen at the hospital on Day
10.
Serious adverse events were low in two trials comparing ofloxacin

and gatifloxacin with cefixime but there was no significant difference between the comparisons (251 participants, two trials,
Analysis 4.7).
Non-serious adverse events appear to be higher with gatifloxacin
than with cefixime (RR 20.92, 95% CI 2.9 to 150.90, 169 participants, one trial, Analysis 4.8). However it is not clear whether
adverse events were completely reported in this trial. No difference
has been shown between ciprofloxacin or ofloxacin and cefixime.
Comparison 5. Fluoroquinolones versus ceftriaxone
Two studies, conducted almost 20 years ago, compared five to

seven days of an oral fluoroquinolone with three days of intravenous ceftriaxone, and were too small to demonstrate important differences if they exist. The prevalence of NaR strains was
either absent or unreported.
One trial has compared ciprofloxacin with ceftriaxone (Wallace
1993 BHR), and one trial compared ofloxacin (Smith 1994
VNM).
In both trials, over half of participants had MDR strains. There
were no participants with NaR strains in Smith 1994 VNM
whereas the proportion was not stated in Wallace 1993 BHR.
Sample sizes for these studies were quite small resulting in very
wide confidence intervals.
Of the three tested fluoroquinolones, only gatifloxacin has demonstrated a statistically significant reduction in clinical failure compared to cefixime (RR 0.04, 95% CI 0.01 to 0.31, 158 participants, one trial, Analysis 4.1). Microbiological failures were too
low across all three trials to demonstrate any significant differences
for any of the comparisons (379 participants, three trials, Analysis
4.2).
Only gatifloxacin has demonstrated a statistically significant reduction in relapse (RR 0.20, 95% CI 0.04 to 0.93, 138 participants, one trial, Analysis 4.3). There were no reported incidents
of faecal carriage.
Fever Clearance and duration of hospital stay
Fever clearance time was significantly shorter for ofloxacin (MD 24.00, 95% CI -41.46 to -6.54, one trial, 91 participants, Analysis
4.5). There was a statistically significant difference in the median
The proportion of clinical failures was lower with fluoroquinolones

but the result was not statistically significant (89 participants, two
trials, Analysis 5.1). Only one microbiological failure is reported
in either group (Analysis 5.2).
The incidence of relapse and faecal carriage following treatment
was very low with no differences between both groups (42 participants, one trial, Analysis 5.3; Analysis 5.4).
Fever clearance and duration of hospitalization
Only Smith 1994 VNM reported adequate data for the fever clearance time which was significantly shorter with ofloxacin (MD 115.0; 95% CI -150.67 to -79.33, 47 participants, 1 trial, Analysis
5.5). In Wallace 1993 BHR, mean fever clearance times for the
ciprofloxacin and ceftriaxone groups were 4 and 5.2 days respectively. No standard deviation was reported but the P value was
given as 0.04.
12
Similarly, only Smith 1994 VNM reported the duration of hospitalization which averaged nine days (range: 6 to 13 days) in the
ofloxacin group and 12 days (range: 7 to 23 days) in the ceftriaxone group. No values for standard deviation were reported but a
P value was given as 0.01.
Fever clearance time

No consistent statistically significant difference in fever clearance
has been shown between any of the fluoroquinolones and azithromycin (564 participants, four trials, Analysis 6.5).
Duration of hospitalization
Adverse events
No serious adverse events were reported. Non-serious events were
few, mild and self limiting in both groups in the only trial that
recorded them (47 participants, 1 trial, Analysis 5.6).
There was a statistically significant reduction in the duration of

hospital stay in the ofloxacin group (RR 1.01, 95% CI 0.19 to
1.83, 213 participants, two trials, Analysis 6.6)
Adverse events
Comparison 6. Fluoroquinolones versus azithromycin
Azithromycin was superior to ofloxacin in reducing clinical

failures and convalescent faecal carriage in populations with
both MDR and NaR enteric fever in Vietnam. The most recent
study, also from Vietnam, found no difference between gatifloxacin and azithromycin with both drugs performing well.
Four trials involving 564 participants made this comparison.
One trial each compared ciprofloxacin with azithromycin (Girgis
1999 EGY, 64 participants) and gatifloxacin with azithromycin
(Dolecek 2008 VNM, 287 participants). Two trials compared
ofloxacin with azithromycin (Chinh 2000 VNM, 88 participants
and Parry 2007 VNM, 125 participants).
In Girgis 1999 EGY, a third of participants were infected with
MDR strains. The proportion of NaR strains was not reported.
The other trials had varying proportions of participants with MDR
and NaR strains.

Treatment with azithromycin resulted in a statistically significant
decrease in clinical failures compared to ofloxacin (RR 2.20, 95%
CI 1.23 to 3.94, 213 participants, two trials, Analysis 6.1), but no
difference has been shown between ciprofloxacin (64 participants,
one trial, Analysis 6.1), or gatifloxacin (287 participants, one trial,
Analysis 6.1)
No statistically significant difference in microbiological failure has
been seen in any of the trials comparing fluoroquinolones with
azithromycin (564 participants, four trials, Analysis 6.2).

No statistically significant difference in relapse rate has been seen
in any of the trials comparing fluoroquinolones with azithromycin
(479 participants, 4 trials, Analysis 6.3).
Convalescent faecal carriage was lower in the azithromycin group
compared with ofloxacin (RR 13.52, 95% CI 2.64 to 69.36, 193
participants, 2 trials, Analysis 6.4), but no difference has been
shown between ciprofloxacin (64 participants, 1 trial, Analysis
6.4), or gatifloxacin (268 participants, 1 trial, Analysis 6.4)
No significant difference in serious events has been seen between

the ofloxacin with azithromycin groups (88 participants, 1 trial,
Analysis 6.7). Overall, non-serious adverse events were similar
across all the trials (564 participants, four trials, Analysis 6.8).
Head to head comparisons of different
fluoroquinolones or different durations of treatment
Differences in efficacy between the different fluoroquinolones
has not been demonstrated in head to head clinical trials.
The different fluoroquinolones have only been compared as part
of multiple arm studies (Morelli 1992 ITA; Rizvi 2007 PAK).
In these studies no clinical or microbiological failures, or relapses
were seen in the fluoroquinolone treatment arms (see Analysis 1.1;
Analysis 1.2; Analysis 1.3).
None of the comparisons demonstrated one duration was superior to another for failure or relapse, even in the presence
of MDR and NaR strains. Studies were generally too small to
detect what might be important differences.
Comparison 7. Fluoroquinolones for two days versus three
days
Three trials made this comparison: one in adults (Chinh 1997

VNM) and two in children (Vinh 1996 VNM; Vinh 2005 VNM).
They were all ofloxacin trials. All three trials reported the percentage of participants with NaR and MDR strains. These were 2.5.%
and 90% (Vinh 2005 VNM), 5% and 79% (Chinh 1997 VNM),
and 13% and 84% (Vinh 1996 VNM), respectively.
There were no statistically significant differences for all the outcomes in either groups of the trials. There were no serious adverse
events.
Comparison 8. Fluoroquinolones three days versus five days
Only one trial (Tran 1995 VNM) with over 70% children compared three days with five days of ofloxacin. The majority of S. typhi isolates (91%) were MDR. Some participants had NaR strains,
although the precise number of these participants was not available.
13
Fever clearance time was significantly shorter in the three day

group compared with the five day group (MD -12.0; 95% CI 18.07 to -5.93,195 participants, one trial, Analysis 8.2). There
were no differences in the risk of relapse and adverse events in
either groups.
Comparison 9. Fluoroquinolone five days versus seven days
One trial made this comparison (Unal 1996 TUR) with pefloxacin. Thirteen percent of the strains were MDR. There was no
report of the proportion with NaR strains.
There were no clinical failures in either arm, and we did not detect a
statistically significant difference in microbiological failure, relapse
and fever clearance time. Adverse events were not serious and they
were similar in both groups.
Comparison 10. Fluoroquinolone seven days versus 10 or 14

days
One trial compared pefloxacin for seven days with 10 days (Kalo
1997 ALB) in a population wholly infected with ampicillin resistant S. typhi some of whom were MDR. The proportion of participants with NaR strains was not reported.
There was no statistically significant difference in microbiological
failure. There were no clinical failures or convalescent faecal carriers. Adverse events were mild and self limiting.
Comparison 11. Fluoroquinolone 10 days versus 14 days
One trial, with 7% of the participants infected with NaR strains,

made this comparison (Alam 1995 BGD). There was no statistically significant difference in relapse or fever clearance time. There
were no clinical or microbiological failures, or convalescent faecal
carriers. Adverse events (gastrointestinal symptoms, headache and
rashes in both arms, and one case of joint pain in the 14-day arm)
were mild and self limiting.
Comparison 13. Gatifloxacin versus chloramphenicol
No statistically significant difference has been shown in the risk

of clinical or microbiological failure, or relapse, between a 7-day
course of gatifloxacin and 14 days of chloramphenicol in Nepal
(352 participants, one trial, Analysis 11.1). Treatment with gatifloxacin may however be associated with fewer adverse events (RR
0.58, 95% CI 0.44 to 0.78, 844 participants, one trial, Analysis
11.1).
Comparison 14. Gatifloxacin versus cefixime
Compared to 7-days of cefixime, a 7-day course of gatifloxacin was

shown to produce a statistically significant reduction in clinical
failure (RR 0.04; 95% CI 0.01 to 0.31, 158 participants, one trial,
Analysis 13.1), and relapse (RR 0.2; 95% CI 0.04 to 0.93, 138
participants, one trial, Analysis 13.1) in Nepal. There was however
no difference in microbiological failure assessed at day 10 (158
participants, one trial, Analysis 13.1). Gatifloxacin was associated
with a statistically significant increase in adverse events (RR 19.25,
95% CI 2.66 to 139.30, 169 participants, one trial, Analysis 13.1).
The events were mainly vomiting and in two cases, this was severe
enough to require intravenous fluids.
Comparison 15. Gatifloxacin versus azithromycin
No statistically significant difference has been shown in the risk

of clinical or microbiological failure, or relapse, between a 7-day
course of gatifloxacin and 7 days of azithromycin in Vietnam (287
participants, one trial, Analysis 14.1). There is also no evidence of
a difference in the incidence of adverse events (285 participants,
one trial, Analysis 14.1).
DISCUSSION
Summary of main results

Summary of gatifloxacin comparisons
In the light of the emerging interest in gatifloxacin, we have summarised the results in this section for this one drug.
One trial each compared gatifloxacin with chloramphenicol
(Arjyal 2011), cefixime (Pandit 2007 NPL) and azithromycin
(Dolecek 2008 VNM). All the trials had a majority of participants
infected with NaR strains equally distributed between groups. In
Pandit 2007 NPL and Arjyal 2011, MDR strains were negligible
(0.58% and 0% respectively). All the trials were conducted in areas previously known to have a high prevalence of MDR and NaR
salmonella isolates.
Fluoroquinolones versus older antibiotics

In one study from Pakistan in 2003-04, high clinical failure rates
were seen with both chloramphenicol and co-trimoxazole, although resistance was not confirmed microbiologically. A seven
day course of either ciprofloxacin or ofloxacin was found to be
superior. Older studies of these comparisons failed to show a difference.
In two small studies conducted almost two decades ago the fluoroquinolones were demonstrated to be more effective than ampicillin and amoxicillin.
14
Fluoroquinolones versus current second-line options
Potential biases in the review process
The two studies comparing a seven day course of oral fluoroquinolones with three days of intravenous ceftriaxone were too
small to detect important differences between antibiotics should
they exist.
In Pakistan in 2003-04 no clinical or microbiological failures were
seen with seven days of either ciprofloxacin, ofloxacin or cefixime.
In Nepal in 2005, gatifloxacin reduced clinical failure and relapse
compared to cefixime, despite a high prevalence of NaR in the
study population.
Compared to a seven day course of azithromycin, a seven day
course of ofloxacin had a higher rate of clinical failures in populations with both MDR and NaR enteric fever in Vietnam in
1998-2002. However, the most recent study, also from Vietnam
in 2004-05, found no difference between gatifloxacin and azithromycin, with both drugs performing well.
Although we found several trials from China, and published in

the Chinese language, we were unable to extract adequate details
on the trial methodology to allow inclusion. These studies are
listed in the Studies awaiting assessment table. A recent study of
over 30,000 apparent RCTs in China showed that only 6.8% were
authentic RCTs (Wu 2009).
Agreements and disagreements with other

studies or reviews
In our previous update (Thaver 2008), different types of fluoroquinolone were combined in the meta analyses in spite of their
dissimilarity. In this revision, we have analysed them separately
with the intention of highlighting the effectiveness of different
fluoroquinolones. We also considered the changing pattern of resistance across various regions over different times.
Fluoroquinolones versus alternative fluoroquinolones

Differences in efficacy between the available fluoroquinolones, or
between different durations of treatment with an individual fluoroquinolone, have not been demonstrated in head to head clinical
trials.
AUTHORS CONCLUSIONS
Implications for practice
Adverse events
Overall, the adverse event profiles were similar for the fluoroquinolone and non-fluoroquinolone antibiotics. They were
mostly mild and self limiting.The risk of dysglycaemia with gatifloxacin has been reported in several studies (Frothingham 2005,
Park-Wyllie 2006). However, in the three studies included in this
review which report on dysglycaemia ( Pandit 2007 NPL; Dolecek
2008 VNM; Arjyal 2011), no difference was detected in the risk
of hypoglycaemia or hyperglycaemia among those studied
Overall completeness and applicability of

evidence
Most of the included trials were conducted on inpatients and may
not be representative of the majority of settings where most enteric
fever is managed as outpatients. The data are likely to represent a
subset of patients with more severe illness who may respond less
favourably to conventional therapy.
The changing epidemiology of resistance patterns across various
regions precludes any generalization of the results of the included
studies. Indeed, some included studies are nearly two decades old
and thus may not be useful in informing practice.
In addition, overall, there are too few studies in each comparison, and the studies themselves are too small, to make any firm
conclusions on the prescience or absence of important differences
between the different treatment options.
Generally, fluoroquinolones performed well in the treating typhoid. Generally, fluoroquinolones performed well in the treating
typhoid, and maybe superior to alternatives in some settings. However, we were unable to draw firm general conclusions on comparative contemporary effectiveness given that resistance changes
over time, and many studies were small. In choosing any fluoroquinolone, clinicians need to take into account current, local resistance patterns.
There is some evidence that the newest fluoroquinolone, gatifloxacin, remains effective in some regions where resistance to older
fluoroquinolones has developed. However, the different fluoroquinolones have not been compared directly in head to head trials.
Implications for research

The re-emergence of chloramphenicol sensitive strains in some
regions may suggest a similar trend for other first line drugs which
had been abandoned following prevalent MDR. Trials may therefore focus on re-examining these relatively inexpensive alternatives
in robust comparisons with fluoroquinolones in appropriate endemic populations.
Most of the studies were small . Given the importance of the study
question, we would recommend multi-centred, adequately powered trials, with robust methods and analytical design. Given the
nature of the disease and the importance of accurate diagnoses,
we would recommend the development of robust diagnostic tests
and gold standards for defining disease and resistance patterns,
15
based on molecular methods if possible. Rapid diagnostic tests for

diagnosing enteric fever should be made more widely available in
endemic areas; this will ensure more efficient participant recruitment in trials and avoid the problem of syndromic treatment. In
addition, it will reduce the widespread abuse of antibiotics, especially the use of fluoroquinolones for suspected typhoid fever.
Emmanuel Effas fellowship to Liverpool School of Tropical

Medicine, and the update of this review was supported by a grant
from the World Health Organization. The Cochrane Infectious
Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of low- and middlecountries.
Definitions of outcomes and their measurement should also be

standardized to make more effective comparisons and adaptability
across regions.
We acknowledge Vittoria Lutje, Trials Search Co-ordinator for the

CIDG for assistance with the searches as well as staff of the CIDG
for assistance during the process of updating the review.
The Contact Editor for this review was Dr Mical Paul.
Thanks to Durrane Thaver, who wrote the original and first update
of this review. She is fondly remembered by all of us that knew
her.
ACKNOWLEDGEMENTS
REFERENCES
References to studies included in this review

Alam 1995 BGD {published data only}
Alam MN, Haq SA, Das KK, Baral PK, Mazid MN,
Siddique RU, et al. Efficacy of ciprofloxacin in enteric
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Arjyal 2011 {published data only}
Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S,
Agrawaal KK, Shakya N, Shrestha K, Sharma M, Lama S,
Shrestha K, Khatri NS, Shrestha U, Campbell JI, Baker
S, Farrar J, Wolbers M, Dolecek C. Gatifloxacin versus
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Chinh 1997 VNM {published data only}
Chinh NT, Solomon T, Mai XT, Nguyen TL, Nguyen TT,
Wain J, et al. Short courses of ofloxacin for the treatment
of enteric fever. Transactions of the Royal Society of Tropical
Chinh 2000 VNM {published data only}
Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX,
Diep TS, et al. A randomized controlled comparison of
azithromycin and ofloxacin for treatment of multidrugresistant or nalidixic acid-resistant enteric fever.
Antimicrobial agents and chemotherapy 2000;44(7):18559.
Cristiano 1995 ITA {published data only}
Cirstiano P, Imparato L, Carpinelli C, Lauria F, Iovene MR,
Corrado MF, et al. Pefloxacin versus chloramphenicol in the
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Dolecek 2008 VNM {published data only}
Dolecek C, La TTP, Rang NN, Phuong LT, Tuan PQ,
DU DC, et al. A multi-center randomised controlled trial
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and adults in Vietnam. PLoS ONE 2008;3(5):e2188.
Flores 1994 MEX {published data only}
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ofloxacin vs oral ampicillin in the management of typhoid.
Investigacion Medica Internacional 1994;21(2):8892.
Gasem 2003 IDN {published data only}
Gasem MH, Keuter M, Dolmans WM, Van Der VenJongekrijg J, Djokomoeljanto R, Van Der Meer JW.
Persistence of Salmonellae in blood and bone marrow:
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Antimicrobial Agents and Chemotherapy 2003;47(5):
172731.
Girgis 1999 EGY {published data only}
Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM,
Tribble D, et al. Azithromycin versus ciprofloxacin for
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Gottuzzo 1992 N/A {published data only}
Gottuzzo E, Carillo C. Typhoid fever. Evaluation of
the efficacy and safety of ciprofloxacin in comparison
with chloramphenicol. In: HL Dupont editor(s). Use
of quinolones in travel medicine. Second Conference on
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Germany: Springer-Verlag, 1992:1622.
Hajji 1988 MAR {published data only}
Hajji M, el Mdaghri N, Benbachir M, el Filali KM,
Himmich H. Prospective randomized comparative trial of
pefloxacin versus cotrimoxazole in the treatment of typhoid
fever in adults. European Journal of Clinical Microbiology
and Infectious Diseases 1988;7(3):3613.
16
Kalo 1997 ALB {published data only}

Kalo T, Davachi F, Nushi A, Dedja S, Karapici L, Como N,
et al. Therapeutic efficacy of perfloxacin in treatment of
ampicillin-resistant typhoid fever in 7 days versus 10 days.
International Journal of Infectious Diseases 1997;2(1):124.
Limson 1989 PHL {published data only}
Limson BM, Littaua RT. Comparative study of ciprofloxacin
versus co-trimoxazole in the treatment of Salmonella enteric
fever. Infection 1989;17(2):1056.
Morelli 1992 ITA {published data only}
Morelli G, Mazzoli S, Tortoli E, Simonetti MT, Perruna F,
Postiglione A. Fluoroquinolones versus chloramphenicol in
the therapy of typhoid fever: a clinical and microbiological
study. Current Therapeutic Research 1992;52(4):53242.
Pandit 2007 NPL {published data only}
Pandit, A, Arjyal, A, Day JN, Paudyal B, et al. An open
randomized comparison of gatifloxacin versus cefixime for
the treatment of uncomplicated enteric fever. PLoS ONE
2007;2(6):e542.
Parry 2007 VNM {published data only}
Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung
le T, et al. Randomized controlled comparison of ofloxacin,
azithromycin, and an ofloxacin-azithromycin combination
for treatment of multidrug-resistant and nalidixic acidresistant typhoid fever. Antimicrobial Agents Chemotherapy
2007;51(3):81925.
Phongmany 2005 LAO {published data only}
Phongmany S, Phetsouvanh R, Sisouphone S, Darasavath
C, Vongphachane P, Rattanavong O, et al. A randomized
comparison of oral chloramphenicol versus ofloxacin in
the treatment of uncomplicated typhoid fever in Laos.
Transactions of the Royal Society of Tropical Medicine and
Hygiene 2005;99(6):4518.
Phuong 1999 VNM {published data only}
Phuong CXT, Kneen R, Nguyen TA, Truong DL, White
NJ, Parry CM. A comparative study of ofloxacin and
cefixime for treatment of typhoid fever in children. The
Dong Nai Pediatric Center Typhoid Study Group. Pediatric
Infectious Disease Journal 1999;18(3):2458.
Rizvi 2007 PAK {published data only}
Rizvi Q. Effeciveness of anti-typhoid drugs currently used
in Pakistan. Pakistan Journal of Surgery 2007;23(1):5764.
Smith 1994 VNM {published data only}
Smith MD, Duong NM, Hoa NT, Wain J, Ha HD, Diep
TS, et al. Comparison of ofloxacin and ceftriaxone for
short-course treatment of enteric fever. Antimicrobial Agents
and Chemotherapy 1994;38(8):171620.
Tran 1995 VNM {published data only}
Tran TH, Bethell DB, Nguyen TT, Wain J, To SD, Le TP,
et al. Short course of ofloxacin for treatment of multidrugresistant typhoid. Clinical Infectious Diseases 1995;20(4):
91723.
Unal 1996 TUR {published data only}
Unal S, Hayran M, Tuncer S, Gur D, Uzun O, Akova M,
et al. Treatment of enteric fever with pefloxacin for 7 days
versus 5 days: a randomized clinical trial. Antimicrobial

Agents and Chemotherapy 1996;40(12):2898900.
Vinh 1996 VNM {published data only}
Vinh H, Wain J, Vo TN, Cao NN, Mai TC, Bethell D, et al.
Two or three days of ofloxacin treatment for uncomplicated
multidrug-resistant typhoid fever in children. Antimicrobial
Agents and Chemotherapy 1996;40(4):95861.
Vinh 2005 VNM {published data only}
Vinh H, Duong NM, Phuong lT, Truong NT, Bay PV,
Wain J, et al. Comparative trial of short-course ofloxacin
for uncomplicated typhoid fever in Vietnamese children.
Annals of Tropical Paediatrics 2005;25(1):1722.
Wallace 1993 BHR {published data only}
Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall
EJ, Rowe B, et al. Ciprofloxacin versus ceftriaxone in the
treatment of multiresistant typhoid fever. European Journal
of Clinical Microbiology and Infectious Diseases 1993;12(12):
90710.
Yousaf 1992 PAK {published data only}
Yousaf MH, Hasnain SS, Mohsin A, Ara N. A comparative
study of efficacy and safety of three antimicrobials
in the treatment of enteric fever. Pakistan Journal of
Gastroenterology 1992;6(2):468.
References to studies excluded from this review

Abejar 1993 {published data only}
Abejar NH, Dimaano EM, Cabanban AB. Fleroxacin versus
chloramphenicol in enteric fever. An open, randomized,
parallel study. Philippine Journal of Internal Medicine 1993;
31(6):32730.
Agalar 1997 {published data only}
Agalar C, Usubutun S, Tutuncu E, Turkyilmaz R.
Comparison of two regimens for ciprofloxacin treatment of
enteric infections. European Journal of Clinical Microbiology
and Infectious Diseases 1997;16(11):8036.
Akhtar 1989 {published data only}
Akhtar MA, Karamat KA, Malik AZ, Hashmi A, Khan
QM, Rasheed P. Efficacy of ofloxacin in typhoid fever,
particularly in drug resistant cases. Reviews of Infectious
Diseases 1989;2 Suppl 5:1193.
Akhtar 1992 {published data only}
Akhtar MA, Hussain A, Karamat KA, Naqi N, Zubdi N.
Role of ciprofloxacin in typhoid fever. Journal of Pakistan
Medical Association 1992;42(1):910.
Arnold 1993 {published data only}
Arnold K, Hong C, Nelwan R, Trujillo Z, Kadio A, Barros
M, et al. Randomized comparative study of fleroxacin and
chloramphenicol in typhoid fever. American Journal of
Medicine 1993;94(3A):195S200S.
Bai 1995 {published data only}
Bai YM, Lin JB, Duan MT, Zhang Y, Liang B. Comparison
of therapeutic effect of enoxacin and norfloxacin in the
treatment of typhoid fever. Zhonghua Chuan Ran Bing
Za Zhi [Chinese Journal of Infectious Diseases] 1995;13(2):
1178.
17
Bavdekar 1991 {published data only}

Bavdekar A, Chaudhari M, Bhave S, Pandit A. Ciprofloxacin
in typhoid fever. Indian Journal Pediatrics 1991;58(3):
3359.
Bethell 1996 {published data only}
Bethell DB, Day NP, Dung NM, McMullin C, Loan HT,
Tam DT, et al. Pharmacokinetics of oral and intravenous
ofloxacin in children with multidrug-resistant typhoid
fever. Antimicrobial Agents and Chemotherapy 1996;40(9):
216772.
Chakravorty 1991 {published data only}
Chakravorty B, Jain N, Gupta B, Rajvanshi P, Sen MK,
Krishna A. Chloramphenicol resistant enteric fever. Journal
of Indian Medical Association 1993;91(1):1013.
Chukwani 1998 {published data only}
Chukwani CM, Onyemelukwe GC, Okonkwo PO,
Coker HAB, Ifudu ND. Fleroxacin vs ciprofloxacin in the
management of typhoid fever. Clinical Drugs Investigation
1998;16(4):27988.
Daga 1994 {published data only}
Daga MK, Sarin K, Sarkar R. A study of culture positive
multidrug resistant enteric fever - changing pattern
and emerging resistance to ciprofloxacin. Journal of the
Association of Physicians of India 1994;42(8):599600.
Duong 1995 {published data only}
Duong NM, Chau NVV, Anh DCV, Hoa NTT, Tam DTH,
Hai DT, et al. Short course fleroxacin in the treatment of
typhoid fever. JAMA Southeast Asia 1995;11 Suppl:215.
Hou 1993 {published data only}
Hou SR. Clinical study of Chinese ofloxacin. Zhonghua Yi
Xue Za Zhi 1993;73(4):2556.
Huai 2000 {published data only}
Huai Y, Zhu Q, Wang X. Ceftriaxone vs. norfloxacin in
the treatment of resistant typhoid fever in 60 children.
Zhonghua Er Ke Za Zhi [Chinese Journal of Pediatrics] 2000;
38(6):3868.
Jia 1994 {published data only}
Jia FZ, Zhu JQ, Huang SY, Chen HK, Bai JY, Li ZC, et al.
Clinical study on therapy of typhoid fever with pefloxacin.
Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of
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Jinlong 1998 {published data only}
Jinlong Z, Wennan H, Guosheng M, Zhigang H, Jianping
Z. Evaluation of effectiveness of ofloxacin and S-(-)
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Liberti 2000 {published data only}
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Lu 1995 {published data only}

Lu Y, Zhang H, Mu G, Qiu D, Hu P. Clinical study
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Nalin 1987 {published data only}
Nalin DR, Hoagland VL, Acuna G, Bran JL, Carrilo
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July 19-24; Istanbul. Copenhagen, Munksgaard, 1987:
11745.
Nelwan 1995 {published data only}
Nelwan RH, Hendarwanto, Zulkarnain I, Gunawan J,
Supandiman I, Yusuf H, et al. A comparative study of short
course ciprofloxacin treatment in typhoid and paratyphoid
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Peyramond 1986 {published data only}
Peyramond D, Tiguad S, Lucht F, Vedrinne JM, Salord
F, Bertrand JL. Clinical evaluation of ofloxacin in the
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Sarma 1991 {published data only}
Sarma PS, Durairaj P. Randomized treatment of patients
with typhoid and paratyphoid fevers using norfloxacin or
chloramphenicol. Transactions of the Royal Society of Tropical
Secmeer 1997 {published data only}
Secmeer G, Kanra G, Figen G, Akan O, Ceyhan M, Ecevit
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Singh 1993 {published data only}
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ciprofloxacin and norfloxacin in multidrug resistant enteric
fever in adults. Journal of the Indian Medical Association
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Suhendro 2007 {published data only}
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tolerability of ciprofloxacin XR compared with ciprofloxacin
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Takkar 1994 {published data only}
Takkar VP, Kumar R, Khurana S, Takkar R. Comparison
of ciprofloxacin versus cephelexin and gentamicin in the
treatment of multi-drug resistant typhoid fever. Indian
Pediatrics 1994;31(2):2001.
Tanphaichitra 1986 {published data only}
Tanphaichitra D, Sahaphong S, Srimuang S. Ofloxacin,
a new quinolone in the treatment of genitourinary and
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Tran 1994 {published data only}
Tran TH, Nguyen MD, Huynh DH, Nguyen TT, To SD,
Le TP, et al. A randomized comparative study of fleroxacin
18
and ceftriaxone in enteric fever. Transactions of the Royal

Society of Tropical Medicine and Hygiene 1994;88(4):4645.
Uwaydah 1992 {published data only}
Uwaydah AK, al Soub H, Matar I. Randomized prospective
study comparing two dosage regimens of ciprofloxacin for
the treatment of typhoid fever. Journal of Antimicrobial
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Wain 1997 {published data only}
Wain J, Hoa NTT, Chinh NT, Vinh H, Everett J, Diep
TS, et al. Quinolone-resistant Salmonella typhi in Viet
Nam: molecular basis of resistance and clinical response to
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Weng 1996a {published data only}
Weng YL, Jia FZ. Clinical efficacy evaluation of
fluoroquinolones in typhoid fever (clinical analysis of 391
cases). Chinese Journal of Clinical Pharmacology 1996;12(3):
1427.
Yang 1991 {published data only}
Yang JG, Wa XL, Shen XJ, Wang KL, Zhu XB, Chen ZY.
Short course of ofloxacin in the treatment of 28 patients
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Zavala 1989 {published data only}
Zavala-Trujillo I, Nava-Zavala A, Marcano MG, Renteria
M. Fleroxacin in the treatment of enteric fever and
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Suppl 5:11889.
Zhang 1991 {published data only}
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ZhongYang 1997 {published data only}
ZhongYang H, Zheng L, Xinchung L, Hanjun H, Yi L X.
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References to studies awaiting assessment

Bran 1991 {published data only}
Bran JL, Garcia JF, Mendez O. Comparative, double
blind study of chloramphenicol and ciprofloxacin in the
treatment of typhoid fever (abstract 751). Proceedings of
the 31st Interscience Conference on Antimicrobial Agents
and Chemotherapy; 1991 Sept 29-Oct 2; Chicago, Illinois.
Washington, DC: American Society of Microbiology, 1991:
224.
Flores 1991 {published data only}
Flores GR. Pharmacological treatment of typhoid fever: A
comparative study of ciprofloxacin versus trimethoprimsulfamethoxazole [Tratamiento farmacolgico del paciente
con fiebre tifoidea: estudio comparativo entre ciprofloxacina
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Quintero 1988 {published data only}

Quintero-Perez NP, Andrea-Villanueva J, Leon-Garnica M,
Bertin-Montano M, Chagollan-Rodriguez E, RodiguezNoriega E. Comparative double blind efficacy and safety
study of ciprofloxacin with chloramphenicol in the
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and abstracts of the 28th Interscience Conference on
Antimicrobial Agents and Chemotherapy; 1988 Oct 2326; Los Angeles, California. Washington, DC: American
Society for Microbiology, 1988:177.
Soewandojo 1992 {published data only}
Soewandojo E, Suharto JR. Comparative study of
ciprofloxacin vs chloramphenicol in patients with typhoid
fever. Typhoid fever, profile, diagnosis and treatment
in 1990. Proceedings of the 1st ISAC International
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11925.
Weng 1996 {published data only}
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Indicates the major publication for the study
23
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Alam 1995 BGD
Methods
Generation of allocation sequence: unclear

Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture-positive participants in the final analysis: 64/72 (88.
9%)
Participants
69 analysed : 35 in 10-day group: 34 in 14-day group

Adults (18 to 65 years) and 11 children (< 18 years)
Both outpatients and inpatients (ciprofloxacin 10-day group had 20 outpatients and 14
inpatients, ciprofloxacin 14-day group had 21 outpatients and 14 inpatients)
Inclusion criteria: blood or bone marrow culture positive for S. typhi or S. paratyphi
Exclusion criteria: hypersensitivity to quinolones; severe renal disease; pregnant or lactating; patients < 18 years were randomized only if had MDR strain
Interventions
1. Ciprofloxacin (500 mg oral twice daily for 10 days)

Outcomes
1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Convalescent faecal carriage
6. Serious adverse events
7. Other adverse events
Notes
Location: Bangladesh
Date: 1992-3
Severity of illness at entry: not reported
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Unclear risk

bias)
Patients randomly assigned to two regimens
Allocation concealment (selection bias)
Unclear risk
Not stated
Blinding (performance bias and detection Unclear risk

bias)
All outcomes
Not stated
Incomplete outcome data (attrition bias)

All outcomes(short term)
Data was reported for all the patients in

short term follow-up
Low risk
24
Alam 1995 BGD
(Continued)

All outcomes(long term)
Low risk
Data was missed for 3, 22 and 32 patients

on 2, 6 and 12 months respectively for patients in 10 days treatment
Whereas data was missing for 2, 20 and 31
patients on 2, 6, and 12 months respectively for those on 14 days treatment. missing outcome data balanced between groups
Selective reporting (reporting bias)
High risk
Efficacy and adverse events reported
Other bias
High risk
Supported by research grant from Beximco

pharmaceuticals ltd
Arjyal 2011
Methods
Generation of allocation sequence: blocks of 50

Allocation concealment: sealed envelops
Blinding: non-blinded
Inclusion of all randomized culture-positive participants in the final analysis: 348/352
(98.9%)
Participants
352 analysed: 175 in chloramphenicol: 177 in gatifloxacin

Adults and children: chloramphenicol 15 yrs (8-22) and in gatifloxacin 16 yrs (9-22)
Outpatients
Inclusion criteria: Patients with fever for more than 3 days who were clinically diagnosed
to have enteric fever patients who received amoxicillin or co-trimoxazole were included
as long as they did not show evidence of clinical response
Exclusion criteria: pregnancy or lactation, age under 2 years and weight less than 10
kg, shock, jaundice, gastrointestinal bleeding or any other signs of severe typhoid fever,
hypersensitivity, known previous treatment with a quinolone antibiotic or 3rd generation
cephalosporin or macrolide within one week of hospital admission
Interventions
1. Gatifloxacin (10 mg/kg/day in a single oral dose for 7 days)

2. Chloramphenicol (75 mg/kg/day in four divided oral doses for 14 days)
Outcomes
1. Clinical failure
3. Relapse
4. enteric fever complications
Notes
Location: Nepal
Date: May 2006 - August 2008
Risk of bias
25
Arjyal 2011
(Continued)
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Patients were randomly allocated to one

of two treatments. Randomization was performed in blocks of 50..
The random allocations were placed in

sealed opaque envelopes
Low risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Open study for participants and investigators but final outcome assessors blinded

Low risk
Missing data balanced across both groups

Low risk
Missing data balanced across groups
Low risk
Efficacy and safety data reported
Other bias
Low risk
Study seems free from other bias
Chinh 1997 VNM

Methods
Generation of allocation sequence: blocks

Allocation concealment: sealed envelopes
Blinding: open
(93.5%)
Participants
100 analysed: 47 in 2-day group: 53 in 3-day group

Mean age in 2-day group was 25.3 (8.9) and 3 days group 24.2 (7.1); adults >15 yrs
Inpatients
Inclusion criteria: clinically suspected uncomplicated enteric fever were included
Exclusion criteria: pregnant, had severe disease required intensive care, had known hypersensitivity to quinolones or had treatment with quinolones in the week before admission, those who had received previous treatment with chloramphenicol, ampicillin,
cephalosporins or trimethoprim-sulphamethoxazole were also excluded
Interventions
1. Ofloxacin (15 mg/kg/day for two days)

2. Ofloxacin (10 mg/kg/day for three days)
Outcomes
1. Clinical failure
3. Relapse
26
Chinh 1997 VNM
(Continued)
Notes
Location: Viet Nam

Date: November 1993 - December 1995
Risk of bias
Bias
Authors judgement

bias)
patients were allocated at random...Randomization was in blocks
Treatment codes were contained in serially

numbered sealed envelopes...
Low risk

bias)
All outcomes
in an open, randomised ?

Low risk
All outcome data addressed

Low risk
50% of outcome data at follow up presented but results unlikely to affect observed effect size
Low risk
Other bias
Low risk
Chinh 2000 VNM

Methods
Generation of allocation sequence: computer-generated

Blinding: open
(42%)
Participants
88 analysed : 44 in ofloxacin group; 44 in azithromycin group

Adult inpatients aged >15 years
Inclusion criteria: clinical with blood culture positive for S. Typhi or S. Paratyphi
Exclusion criteria: severe or complicated disease; significant underlying disease; hypersensitivity to either trial drug; pregnant; history of treatment with fluoroquinolone or
third-generation cephalosporins or macrolides within 1 week of admission
Interventions
1. Ofloxacin (200 mg oral twice daily for 5 days at 8 mg/kg/day)

2. Azithromycin (1 gm oral daily for 5 days at 20 mg/kg/day)
27
Chinh 2000 VNM
(Continued)
Outcomes
1. Clinical failure
3. Relapse
4. Fever clearance time (mean and 95% confidence intervals; SD calculated by review
author)
5. Complications
6. Length of hospitalization (mean and 95% confidence interval; SD calculated by review
author)
9. Other adverse events (number of events stated)
Notes
Location: Vietnam
Date: not available
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias
Authors judgement

bias)
Patients were allocated to one of two treatment groups in an open randomised comparison Computer generated randomization list. Information from trial authors
The treatment allocations were kept in serially numbered sealed envelopes
Low risk

bias)
All outcomes
Open comparison

Low risk
outcomes were presented for all randomised

Low risk
9/44 from ofloxacin group and 10/44 from

azithromycin group were missing from the
long term treatment but unlikely to affect
estimate of effect
Low risk
Efficacy and adverse event data reported
Other bias
Low risk
28
Cristiano 1995 ITA

Methods

Blinding: open
Inclusion of all randomized culture-positive participants in the final analysis: 100%
Participants
60 analysed: 30 in pefloxacin group; 30 in chloramphenicol group

Adult inpatients aged 17 to 64 years
Inclusion criteria: Severe culture-positive typhoid sepsis
Exclusion criteria: Received any known or presumed antibiotic active against S. Typhi,
allergy to pyridoxine-carboxylic acid derivatives or to chloramphenicol
Interventions
1. Pefloxacin (1200 mg intravenous in 3 divided doses every 8 hours for 5 days, and
orally for the next 10 days)
2. Chloramphenicol (2 g in 4 divided doses every 6 hours for 15 days)
Outcomes
1. Clinical failure
3. Relapse
4. Fever clearance time (no SD)
6. Length of hospitalisation (no SD)
Notes
Location: Italy
Date: 1991-3
Severity of illness at entry: all severe
Risk of bias
Bias
Authors judgement

bias)
The enrolled patients were randomly assigned (by means of a computerized list..
No information provided
Unclear risk

bias)
All outcomes
..an open, randomised clinical study

Low risk
No pre specified outcomes but all relevant

outcome data accounted for

Low risk
No pre specified outcomes but all relevant

outcome data accounted for
Low risk
29
Cristiano 1995 ITA
Other bias
(Continued)
Unclear risk
Pefloxacin was supplied by Rhone-poulenc

Pharma Italy S.P.A. Milan, Italy
Dolecek 2008 VNM

Methods
Generation of allocation sequence: computer-generated, block randomization

Blinding: open
(93%)
Participants
285 analysed: 145 in gatifloxacin group; 140 in azithromycin group

Adult and children inpatients aged 1 to 41 years (210/287 (73%) participants below the
age of 15 years)
Inclusion criteria: clinical or culture-positive enteric fever
Exclusion criteria: no consent; pregnancy; age < 6 months; history of hypersensitivity
to either of the trial drugs; any signs of severe typhoid fever or previous reported treatment with a fluoroquinolone antibiotics; a third-generation cephalosporin or macrolide
antibiotic within 1 week before to hospital admission
Interventions
1. Gatifloxacin (10 mg/kg/day oral once daily for 7 days)

2. Azithromycin (20 mg/kg/day oral once daily for 7 days)
Outcomes
1. Clinical failure
3. Relapse
5. Complications
6. Length of hospitalization
Notes
Location: Vietnam (multi-centre, 3 hospitals)

Date: 2004-5
Received as an unpublished trial (with additional data), but reference updated to current
citation upon publication
Risk of bias
Bias
Authors judgement

bias)

An independent administrator from the
study generated the random number sequence in excel using RAND function
30
Dolecek 2008 VNM
(Continued)
Low risk
..assignments were folded and kept in

opaque, sealed, sequentially numbered envelopes at all three study sites?

bias)
All outcomes
Open label study

Low risk
No loss to follow up and data was analysed

for all the participants randomized

Low risk
In Gatifloxocin group 7, 8, and 80 participants were lost to follow-up and in Azithromycin group 5, 11 and 79participants were
lost to follow-up. Unlikely to affect observed effect size as loss is similar
Low risk
Report includes all pre specified outcomes

including efficacy and safety data
Other bias
Low risk
Flores 1994 MEX

Methods

Blinding: open
Participants
40 analysed: 20 in ofloxacin group; 20 in ampicillin group

Adult male or females; most probably inpatients.
Inclusion criteria: Age over 16 with clinical features of typhoid fever as well as positive
blood cultures for S. typhi
Exclusion criteria: Previous adverse reactions, complicated disease, severe renal insufficiency, severe neutropenia, requirement of concomitant systemic antimicrobial, convulsions, grave psychiatric disorders, pregnancy or lactation
Interventions
1. Ampicillin (1 g every 6 hours for 10 days)

2. Ofloxacin (400 mg every 12 hours for 10 days)
Outcomes
1. Clinical failure
Notes
Location: Mexico
Date: not reported
31
Flores 1994 MEX
(Continued)
Risk of bias
Bias
Authors judgement

bias)
A comparative open study with groups assigned randomly...
Not stated
Unclear risk

bias)
All outcomes
Open study

High risk
Relapse and fever clearance times not reported

High risk
Convalescent faecal carriage not reported
Low risk
Other bias
Unclear risk
Language
Gasem 2003 IDN

Methods
Generation of allocation sequence: random-number table

Blinding: open
Participants
55 analysed: 28 in ciprofloxacin group; 27 in chloramphenicol group

Adult inpatients
Inclusion criteria: clinical and 14 years
Exclusion criteria: severe complications; treatment with chloramphenicol, ciprofloxacin, other fluoroquinolones before admission; history of allergy to chloramphenicol/
quinolone; malaria or other infection; white blood cell count < 2000/mL; pregnant or
lactating
Interventions

2. Chloramphenicol (500 mg oral 4 times a day for 14 days)
Outcomes
1. Clinical failure
2. Microbiological response to treatment at day 3 or day 5
3. Relapse
5. Complications
32
Gasem 2003 IDN
(Continued)

Notes
Location: Indonesia
Date: not reported
Severity of illness at entry: none had severe complications on enrolment
Risk of bias
Bias
Authors judgement

bias)
..patients were randomly assigned to either.. ....The distribution of the envelopes was derived from a randomly permuted table..
..treatment group by means of sealed envelopes containing the names of the study
drugs.?
Low risk

bias)
All outcomes
..randomised, open-label, parallel controlled trial

Low risk
Outcome data addressed, no information

on loss to follow-up

High risk
No data provided
Low risk
Other bias
Low risk
Girgis 1999 EGY

Methods
Generation of allocation sequence: random-number list, block randomization

Blinding: open
Participants
64 analysed: 28 in ciprofloxacin group; 36 in azithromycin group

Adult inpatients aged > 18 years
Inclusion criteria: clinical
Exclusion criteria: pregnant or lactating; allergy to ciprofloxacin or erythromycin/other
macrolides; those with complications of typhoid fever; inability to swallow medications;
significant underlying illness; treatment within past 4 days with an antibiotic with potential efficacy against S. Typhi
33
Girgis 1999 EGY
(Continued)
Interventions

2. Azithromycin (1 g oral once daily for the first day followed by oral 500 mg once daily
for total duration of 7 days)
Outcomes
1. Clinical failure
3. Relapse
5. Complications
7. Cost of treatment
Notes
Location: Egypt
Date: 1997-8
Risk of bias
Bias
Authors judgement

bias)
..each subject was randomly assigned.. assignments, determined by block randomisation based on a random number list
Treatment assignments..were sealed in envelopes
Low risk

bias)
All outcomes
Open study

Low risk

Low risk
Low risk
Other bias
High risk
Supported by an unrestricted grant from

Pfizer
34
Gottuzzo 1992 N/A

Methods

Blinding: double
(97%)
Participants
98 analysed: 49 in ciprofloxacin group; 49 in chloramphenicol group

Adult inpatients
Inclusion criteria: clinical with culture positive for S. typhi or S. paratyphi
Interventions
1. Ciprofloxacin (500 mg oral every 12 hours for 10 days)

2. Chloramphenicol (750 mg oral every 6 hours for 14 days)
Outcomes
1. Clinical failure
2. Relapse
Notes
Location: not available

Date: not available
Risk of bias
Bias
Authors judgement

bias)
Randomized study but mode of generation

of sequence not stated
Not stated
Unclear risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Double blind. Placebos given during remaining days of therapy in the longer arm

High risk
Fever clearance time not reported for comparison arm

Low risk
Relevant data reported
Low risk
Other bias
Low risk
35
Hajji 1988 MAR

Methods

Blinding: open
Participants
42 analysed: 24 in pefloxacin group; 18 in co-trimoxazole group

Exclusion criteria: not reported
Interventions
1. Pefloxacin (400 mg oral twice daily for 14 days)

2. Co-trimoxazole (160/800 mg oral twice daily for 14 days)
5 participants were given intravenous pefloxacin for mean 4.8 days; 4 were given intramuscular co-trimoxazole for mean 6 days
Outcomes
1. Cure
2. Relapse
3. Fever clearance time (no SD, non-exact P value)
4. Chronic carrier state
5. Serious Adverse events
Notes
Location: Morocco
Date: 1984-5
Severity of illness at entry: comatose or neurological disorders in 3 participants in pefloxacin group and 2 participants in co-trimoxazole group
Risk of bias
Bias
Authors judgement

bias)
A comparative open and randomised trial.

.
Not stated
Unclear risk

bias)
All outcomes
Open study

Low risk

Low risk
Low risk
36
Hajji 1988 MAR
(Continued)
Other bias
Unclear risk
Insufficient information to assess whether

an important risk of bias exists
Kalo 1997 ALB

Methods

Blinding: open
Participants
30 analysed: 15 in 7-day group; 15 in 10-day group

Inclusion criteria: blood-culture positive; ampicillin-resistant S. typhi
Exclusion criteria: received quinolones within 2 weeks before hospitalization
Interventions
1. Perfloxacin (400 mg oral twice daily for 7 days)

2. Perfloxacin (400 mg oral twice daily for 10 days)
Outcomes
1. Clinical failure
3. Relapse
Notes
Location: Albania
Date: 1992-4
Risk of bias
Bias
Authors judgement

bias)
The patients were divided into two groups
No information available
Unclear risk

bias)
All outcomes
Open study

Low risk

Low risk
37
Kalo 1997 ALB
(Continued)
Low risk
Other bias
Unclear risk

Limson 1989 PHL

Methods

Blinding: open
Participants
40 analysed: 20 in ciprofloxacin group; 20 in co-trimoxazole group

Exclusion criteria: complications; drug allergy; renal impairment
Interventions

2. Co-trimoxazole (160/800 mg oral twice daily for 14 days)
Outcomes
1. Clinical failure
Notes
Location: Philippines
Date: not reported
Risk of bias
Bias
Authors judgement

bias)
Patients were randomly assigned.. using a

table of random numbers
Not stated
Unclear risk

bias)
All outcomes
Open study

Low risk
All outcome data reported

Low risk
All outcome data reported
38
Limson 1989 PHL
(Continued)
Low risk
Safety and efficacy reported
Other bias
Unclear risk

Morelli 1992 ITA

Methods

Blinding: open
Participants
156 analysed: 30 each in ofloxacin and chloramphenicol groups; 36 in pefloxacin group;

20 each in ciprofloxacin,
enoxacin, and norfloxacin groups
Inclusion criteria: blood culture positive for S. typhi; high fever for not more than 5 days;
toxic symptomatology
Exclusion criteria: hypersensitivity or allergy to fluoroquinolone or antibiotic treatment
Interventions
1. Ofloxacin (300 mg oral every 8 hours for 15 days)

2. Pefloxacin (400 mg oral every 8 hours for 15 days)
3. Ciprofloxacin (500 mg oral every 8 hours for 15 days)
4. Enoxacin (300 mg oral every 8 hours for 15 days)
5. Norfloxacin (400 mg oral every 8 hours for 15 days)
Outcomes
1. Clinical failure
2. Relapse
Notes
Location: Italy
Date: 1985-90
We prepared different comparisons with these data: a combination of all 5 fluoroquinolone groups vs the chloramphenicol
group; and norfloxacin vs ofloxacin, pefloxacin, and enoxacin
Risk of bias
Bias
Authors judgement

bias)

..patients in this open study were randomly assigned, by means of a computerized list
39
Morelli 1992 ITA
(Continued)
Unclear risk
Not stated

bias)
All outcomes
Open study

Low risk

Low risk
Low risk
Other bias
Unclear risk

Pandit 2007 NPL

Methods
Generation of allocation sequence: computer-generated, block randomization

Blinding: open
(87%)
Participants
158 analysed: 88 in gatifloxacin group; 70 in cefixime group

Adults and children outpatients aged 2.75 to 50 years (60/169 (35.5%) were children
aged < 14 years)
Exclusion criteria: not residing 2.5 km radius from hospital; age not between 2 to 65
years; not willing to give informed consent; not able to take oral medications; pregnant
or lactating; history of seizures; not able to stay in city for treatment duration; known
contraindication to cephalosporins or fluoroquinolones; complicated typhoid fever or
received third-generation cephalosporins, fluoroquinolones, or macrolide in week before
presentation to clinic
Interventions
1. Gatifloxacin (10 mg/kg/day in single dose oral for 7 days)

2. Cefixime (20 mg/kg/day in 2 divided doses oral for 7 days)
Outcomes
1. Clinical failure
3. Relapse
6. Complications
8 Other adverse events
40
Pandit 2007 NPL
(Continued)
Notes
Location: Nepal
Date: 2005
Risk of bias
Bias
Authors judgement

bias)
Patients were randomised in blocks from

a computer generated randomisation list
Treatment allocations were kept in sealed

opaque envelopes..
Low risk

bias)
All outcomes
Open label study

Low risk
Relevant outcome data addressed

Low risk
Missing outcome data at 1, 3 and 6 months

(22/169, 28/169 and 39/169 respectively)
unlikely to affect effect estimate
Low risk
Report includes all pre specified outcomes
Other bias
Low risk
Study seems free of other bias
Parry 2007 VNM

Methods

Blinding: open
(88%)
Participants
125 analysed: 63 in ofloxacin group; 62 in azithromycin group

Adults and children inpatients 3 to 42 years (87% (163/187) were children < 15 years
for all three arms)
Exclusion criteria: severe or complicated disease; inability to swallow oral medications;
history of significant underlying disease or hypersensitivity to either of trial drugs; pregnant or lactating; history of treatment
41
Parry 2007 VNM
(Continued)
Interventions
1. Ofloxacin (20 mg/kg/day in 2 divided doses oral for 7 days)

2. Azithromycin (10 mg/kg/day once a day oral for 7 days)
Comparison not included in this review:
3. Ofloxacin-azithromycin (15 mg/kg/day in 2 divided doses oral ofloxacin for 7 days
and 10 mg/kg/day once a day
oral azithromycin for first 3 days)
Outcomes
1. Clinical failure
3. Relapse
author)
5. Complications
6. Length of hospitalization (mean and 95% confidence intervals; SD calculated by
review author)
9. Other adverse events (numbers not stated)
Notes
Location: Vietnam
Date: 1998-2002
Risk of bias
Bias
Authors judgement

bias)
Computer generated randomization list
Treatment allocations were kept in serially

numbered sealed envelopes
Low risk

bias)
All outcomes
an open randomised comparison.

Low risk

Low risk
Incomplete outcome data unlikely to affect

observed effect size
Low risk
Other bias
Low risk
Study seems free of other bias
42
Phongmany 2005 LAO

Methods
Generation of allocation sequence: random-number table, block randomization

Blinding: open
(96%)
Participants
50 analysed: 27 in ofloxacin group; 23 in chloramphenicol group

Inclusion criteria: clinical or blood culture positive typhoid fever
Exclusion criteria: age <15 years; pregnant; lactating; not able to take oral medication;
not willing to give informed consent; not able to stay in hospital for the duration of
treatment; known to have contraindications to chloramphenicol or ofloxacin; severe
typhoid fever; or intractable vomiting
Interventions
1. Ofloxacin (15 mg/kg/day in 2 divided doses oral for 3 days)

2. Chloramphenicol (50 mg/kg/day oral in 4 divided doses for 14 days)
Outcomes
1. Clinical failure
3. Complications
Notes
Location: Laos
Date: 2001-3
Risk of bias
Bias
Authors judgement

bias)
..randomised in blocks of 10 from a random number table
Treatment allocations kept in sealed

opaque envelopes
Low risk

bias)
All outcomes
..prospective randomised open-label controlled trial

Low risk

High risk
Patients not followed up after discharge.

No data for long term outcomes like relapse
and convalescent faecal carriage
43
Phongmany 2005 LAO
(Continued)
Low risk
Other bias
High risk
Trial stopped early because of apparently

significant difference in primary outcome
Phuong 1999 VNM

Methods

Blinding: open
(49%)
Participants
82 analysed: 38 in ofloxacin group; 44 in cefixime group

Children inpatients aged < 15 years
Inclusion criteria: fever and no obvious source of infection for > 7 days or < 7 days if
family history of typhoid fever
Exclusion criteria: severe disease; hypersensitivity to quinolones or third-generation
cephalosporins; received either drug during this illness; or responded to ampicillin, chloramphenicol, or co-trimoxazole
Interventions
1. Ofloxacin (10 mg/kg/day oral in 2 divided doses for 5 days)

2. Cefixime (20 mg/kg/day oral in 2 divided doses for 7 days)
Outcomes
1. Clinical failure
3. Relapse
5. Complications
Notes
Location: Vietnam
Date: 1995-6
Risk of bias
Bias
Authors judgement

bias)

..Patients were randomised to receive
ofloxacin.or cefixime... Computer generated list
44
Phuong 1999 VNM
(Continued)
Low risk
treatment codes were contained in serially

numbered sealed envelops ..

bias)
All outcomes
Open study

Low risk
All pre specified outcome data addressed

Low risk
All data reported
High risk
Incomplete report of adverse events. Only

mortality and associated data for one patient reported
Other bias
Unclear risk
No information on ethical clearance
Rizvi 2007 PAK

Methods

Blinding: Unclear
(70%) on Typhi Dot and 87/227 (38.3%) on Widal test
Participants
227 analysed: 48 in ciprofloxacin, 45 in ofloxacin, 46 in cefixime, 44 in chloramphenicol

and 44 in co-trimoxazole
>12 yrs of age
Both outpatients and inpatients: hospitalised for 24 hours and then attended clinics for
assessments
Inclusion criteria: above 12 yrs of age with clinically and bacteriologically proven diagnosis of typhoid fever, either on positive blood or stool culture or by positive Typhi-Dot
test
Exclusion criteria: patients with signs and symptoms similar to those of typhoid fever
but proved bacteriologically to be caused by other organism were excluded. Patients with
salmonellosis caused by organisms other than S. typhi and S. paratyphi were not included.
Pregnant women and patients with previously known hypersensitivity to any of the trial
drugs were also not included
Interventions

2. Ofloxacin (200 mg oral twice daily for 7 days)
3. Cefixime (200 mg oral twice daily for 7 days)
4. Chloramphenicol (750 mg oral 6 hourly for 14 days)
5. Cotrimoxazole (960 mg oral twice daily for 14 days)
45
Rizvi 2007 PAK
(Continued)
Outcomes
1. Clinical cure
3. Relapse
4. Clinical Failure
5. Fever Clearance
6. Adverse events
Notes
Location: Pakistan
Date: Jan 2003 to Jan 2004
Risk of bias
Bias
Authors judgement

bias)
The patients were randomly assigned to

one of the following
Unclear risk
Not stated

bias)
All outcomes
Not stated

Low risk
Relevant outcomes addressed

Low risk
outcomes data presented
Low risk
No selective reporting
Other bias
Unclear risk

Smith 1994 VNM

Methods

Blinding: open
Participants
47 analysed: 22 in ofloxacin group; 25 in ceftriaxone group

Inclusion criteria: clinical or culture positive for enteric fever
Exclusion criteria: hypersensitivity to beta-lactam antibiotics or quinolones; previous
treatment with broad-spectrum cephalosporins or quinolone within 1 week of hospital
admission; those who responded to ampicillin, chloramphenicol, or co-trimoxazole
46
Smith 1994 VNM
(Continued)
Interventions
1. Ofloxacin (200 mg oral every 12 hours for 5 days)

2. Ceftriaxone (3 g intravenous once a day for 3 days)
Outcomes
1. Clinical failure
3. Relapse
5. Complications
6. Length of hospitalization (mean and range)
Notes
Location: Vietnam
Date: 1992-3
Risk of bias
Bias
Authors judgement

bias)
Patients were randomised to receive?.
Treatment codes were contained in individual sealed envelopes?..
Low risk

bias)
All outcomes
...open, randomised comparison...

Low risk
All primary outcome data reported.

Unclear risk
Specific numbers for post discharge follow

up not reported
Low risk
Other bias
Unclear risk
No information given on ethical clearance

for undertaking this study
47
Tran 1995 VNM

Methods

Blinding: open
Inclusion of all randomized culture-positive participants in the final analysis: 50% (114/
228)
Participants

Adults and children outpatients (180 culture positive were aged < 17 years)
Exclusion criteria: unable to take oral medications due to vomiting; severe disease; shock;
impaired consciousness; bleeding; peritonitis; pregnant; neonates; received a fluoroquinolone
Interventions
1. Ofloxacin (15 mg/kg/day oral for 3 days)

2. Ofloxacin (10 mg/kg/day oral for 5 days)
Outcomes
1. Clinical failure
3. Relapse
Notes
Location: Vietnam
Date: 1993-3
Risk of bias
Bias
Authors judgement

bias)
Patients were randomised to receive..

Computer generated
Treatment allocation were kept in sealed

envelopes ...
Low risk

bias)
All outcomes
open label

Low risk

Low risk
291/425 overall but 81, 78 and 132 for D3,

D5
and blood culture negative arms respec-
48
Tran 1995 VNM
(Continued)
tively but unlikely to affect measured effect

size
Low risk
Other bias
High risk
Ofloxacin was provided by Professor A

Bryskier of Roussel-UCLAF Pharmaceuticals, Paris
Unal 1996 TUR

Methods

Blinding: open
(100%)
Participants
46 analysed: 22 in 5-day group: 24 in 7-day group

Mean age was 24 years (18-40 years ) in 5 days and 26 years (18-68) in 7 days group
inpatients
Inclusion criteria: All patients with febrile disease and at least one positive blood and/or
bone marrow culture for salmonella
Exclusion criteria: Patients under 16 years of age, pregnant and lactating women, those
with jaundice and hepatic failure, and the patients who had received any antibiotic within
the last 2 weeks
Interventions

2. Pefloxacin (400 mg oral twice daily for 7 days
Outcomes
1. Clinical failure
3. Relapse
4. Clinical cure
Notes
Location: Turkey
Date: June 1992 to October 1994
Risk of bias
Bias
Authors judgement

bias)
..were randomised to receive pefloxacin

for 5 days..
..were randomised to receive pefloxacin

for 5 days..
Unclear risk
49
Unal 1996 TUR
(Continued)

bias)
All outcomes
Open study

Unclear risk

Unclear risk
Unclear risk
Other bias
Unclear risk

Vinh 1996 VNM

Methods

Blinding: open
(26%)
Participants

Children inpatients aged 1 to 15 years
Inclusion criteria: clinical or blood culture positive for S. typhi
Exclusion criteria: severe disease; complications, such as reduced level of consciousness,
jaundice, shock, gastrointestinal bleed, clinical signs of intestinal perforation, prostate,
and vomiting; unable to take oral medication; allergic to fluoroquinolones; received
antibiotics that had efficacy against this organism
Interventions

Outcomes
1. Clinical failure
3. Relapse
5. Complications
Notes
Location: Vietnam
Date: not reported
50
Vinh 1996 VNM
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Patients were randomised to receive either

ofloxacin? Computer generated
After enrolment in the study, a sealed envelope containing the treatment regimen to
be given was opened
Low risk

bias)
All outcomes
open study

Low risk

Unclear risk
No data for 34 and 74 subjects at the 1 and

3 month follow up respectively. No indication how these were handled
Low risk
Other bias
Unclear risk

Vinh 2005 VNM

Methods

Blinding: open
(97%)
Participants
196 analysed: 89 in ofloxacin 2-day group; 107 in ofloxacin 3-day group

Children inpatients aged < 15 years
Exclusion criteria: no informed consent from parent or guardian; previous treatment
active against S. Typhi or S. Paratyphi (but those with no response to chloramphenicol,
ampicillin, or co-trimoxazole were included); severe or complicated disease
Interventions

Outcomes
1. Clinical failure
3. Relapse
51
Vinh 2005 VNM
(Continued)
author)
5. Complications
6. Length of hospitalization (mean and 95% confidence intervals; SD calculated by
review author)
Notes
Location: Vietnam
Date: 1994-6
Risk of bias
Bias
Authors judgement

bias)
A computer-generated, randomised
treatment allocation was..
Randomized treatment allocation was

contained in serially numbered sealed envelopes..
Low risk

bias)
All outcomes
open study

Low risk
All outcomes addressed

High risk
Data for 6 culture positive children randomized to 2-day treatment excluded from
analysis
Low risk
Other bias
Unclear risk

52
Wallace 1993 BHR

Methods

Blinding: open
6%)
Participants
42 analysed: 20 in ciprofloxacin group; 22 in ceftriaxone group

Adult inpatients
Inclusion criteria: blood culture positive for S. Typhi
Exclusion criteria: only positive Widal and/or a positive stool culture; age < 16 years;
unable to take oral medications; possible proven pregnancy; and lack of fever at admission
Interventions

2. Ceftriaxone (3 g/day intravenous for 7 days)
Outcomes
1. Clinical failure
3. Relapse
4. Fever clearance time (SD not reported)
6. Complication
Notes
Location: Bahrain
Date: not reported
Risk of bias
Bias
Authors judgement

bias)
..patients were randomised to receive No

indication as to how sequence was generated
Not stated
Unclear risk

bias)
All outcomes
Open study

Low risk

Low risk
High risk
No report of adverse events
53
Wallace 1993 BHR
(Continued)
Other bias
High risk
Trial stopped early because of apparent

lower efficacy in the control group, cost of
control drug and inconvenience of intravenous administration
Yousaf 1992 PAK

Methods

Blinding: open
4%)
Participants
75 analysed a : 25 in ofloxacin group; 25 in chloramphenicol group; 25 in amoxicillin

group
Adult inpatients
Inclusion criteria: culture positive
Exclusion criteria: if received previous antibiotic therapy known to be effective against
S. Typhi
Interventions

2. Chloramphenicol (50 mg/kg/day, then 30 mg/kg/day when afebrile for 14 days)
3. Amoxicillin (4 to 6 g/day oral for 14 days)
Outcomes
1. Clinical failure
Notes
Location: Pakistan
Date: 1989-92
Risk of bias
Bias
Authors judgement

bias)
The patients were randomly divided into

three groups...
unclear
Unclear risk

bias)
All outcomes
open study

Relevant short term outcomes reported
Low risk
54
Yousaf 1992 PAK
(Continued)

High risk
Long term outcomes not reported
Low risk
Other bias
Unclear risk

Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Abejar 1993
One arm allocated to fleroxacin which is no longer in clinical use
Agalar 1997
Not a randomized controlled trial because 1 group consisted of participants admitted in 1994 and the other
group of participants admitted in 1995
Akhtar 1989
No mention of randomization
Akhtar 1992
Quasi-randomized controlled trial: participants were allocated alternatively to either ciprofloxacin group or
chloramphenicol group, and resistance strains assigned to a third ciprofloxacin group; author provided this
additional information
Arnold 1993
Bai 1995
One arm allocated to norfloxacin which is no longer recommended for use by the WHO and the other arm
enoxacin which is no longer in clinical use
Bavdekar 1991
Interventions not randomly assigned
Bethell 1996
Children from the Vinh 1996 VNM trial (which is included in this review) were entered into this pharmacokinetic study of oral vs intravenous ofloxacin
Chakravorty 1991
All treated with chloramphenicol; some switched over to another drug based on culture results
Chukwani 1998
2 different fluoroquinolone drugs were given for different durations (one for 7 days and one for 14 days) in
this randomized controlled trial
Daga 1994
Treatment assigned depending on treatment already taken, clinical course, and complications
Duong 1995
Hou 1993
Randomized controlled trial comparing Chinese ofloxacin with Japanese ofloxacin
55
(Continued)
Huai 2000
Jia 1994
One arm allocated to norfloxacin which is no longer recommended for use by the WHO
Jinlong 1998
Quasi-randomized controlled trial
Kumar 2007
Described as a randomized controlled parallel study of ofloxacin vs ceftriaxone in 93 children with multidrug resistant typhoid fever proven by blood culture. The main outcome reported for both arms is mean fever
clearance time; however the number of children in each arm is not available. We have contacted the author for
additional information (December 2007) and will include this study if further information becomes available
Liberti 2000
Lu 1995
A total of 130 participants with any infectious disease were randomized into 2 groups (enoxacin and cefotaxime)
; there were only 2 participants with enteric fever in enoxacin group and 1 participant with enteric fever in
cefotaxime group
Nalin 1987
Nelwan 1995
Randomized controlled trial comparing 3 days with 6 days of ciprofloxacin that included 20 participants with
serologically confirmed enteric fever (of a total of 59 participants randomized). We contacted the author (17
December 2003) to obtain additional data for blood culture confirmed cases and will include this in future
updates should it become available
Peyramond 1986
Not a randomized controlled trial
Sarma 1991
Secmeer 1997
No randomization; allocation based on co-trimoxazole susceptibility
Singh 1993
Suhendro 2007
Compares 2 different formulations of ciprofloxacin; described as a prospective, open labelled, clinical trial,
comparing safety and efficacy of extended-release ciprofloxacin 1000 mg once daily (Ciprofloxacin XR) and
ciprofloxacin intermediate release 500 mg 2 times daily (Ciprofloxacin bid) in adults with typhoid fever
Takkar 1994
Not randomized
Tanphaichitra 1986
Randomized controlled trial of gonorrhoea; part of the report, but not part of the trial, were 8 participants
with enteric fever that treated with ofloxacin
Tran 1994
Uwaydah 1992
Compares 2 ciprofloxacin doses, not durations
Wain 1997
Study on S. Typhi isolates from blood cultures of participants included in 3 trials included in this review:
Smith 1994 VNM; Vinh 1996 VNM; and Nguyen 1997
56
(Continued)
Weng 1996a
A description of likely several trials involving fluoroquinolones
Yang 1991
One group given fleroxacin which is no longer in clinical use
Zavala 1989
Zhang 1991
Randomized controlled trial including several infections; randomization not applied to the 63 typhoid participants treated with enoxacin
ZhongYang 1997
Randomized controlled trial comparing ofloxacin with norfloxacin for 14 days
Characteristics of studies awaiting assessment [ordered by study ID]

Bran 1991
Methods

Blinding: double
Participants
102 analysed a : 51 in ciprofloxacin group; 51 in chloramphenicol group; only the total number of participants (102)
was provided, but we assumed 51 in each group
Age not mentioned (adult dosages used); most probably inpatients
Inclusion criteria: blood and/or bone marrow culture positive for S. Typhi
Interventions

Outcomes
Notes
Location: Guatemala
Date: not reported
Conference abstract
57
Flores 1991
Methods
NA
Participants
NA
Interventions
NA
Outcomes
NA
Notes
Unable to retrieve this study
Quintero 1988
Methods
Reported as a double blind study but exact methods are unclear
Participants
26 participants: 13 in each group

Age not mentioned (adult dosages used); most probably inpatients
Inclusion criteria: not reported
Interventions
1. Ciprofloxacin (750 mg oral 3 times a day for unknown duration)

2. Chloramphenicol (750 mg oral 4 times a day for unknown duration)
Outcomes
1. Clinical failure
Notes
Location: Mexico
Date: not reported
Conference abstract
Soewandojo 1992
Methods
NA
Participants
NA
Interventions
NA
Outcomes
NA
Notes
Unable to retrieve this study
58
Weng 1996
Methods
Unclear
Participants
Children and adults aged 14 to years
Interventions
Several different fluoroquinolones given orally and parenterally
Outcomes
Cure and efficiency rate

Fever clearance
Bacterial clearance rate
Notes
Chinese language, unclear if randomized trials
Xiao 1991
Methods
Unclear
Participants
Adult and children inpatients aged 11 to 62 years

Inclusion criteria: clinical with blood or bone marrow culture positive for S. Typhi
Exclusion criteria: not mentioned
Interventions
We evaluated 3 of the available 5 groups:

1. Norfloxacin (300 to 400 mg oral thrice a day for 14 days)
Outcomes
1. Clinical failure
Notes
Location: China (Chinese language)

Date: not reported
Yu 1998
Methods

Blinding: open
Participants
80 analysed: 40 in levofloxacin group; 40 in cefixime group

Adult aged 18 to 65 years; most probably inpatients
Inclusion criteria: clinical with blood or bone marrow culture positive for S. Typhi or S. Paratyphi
Exclusion criteria: not mentioned
Interventions
1. Levofloxacin (200 mg oral twice a day for 10 days)

2. Cefixime (200 mg oral twice a day for 10 days)
Outcomes
1. Clinical failure
59
Yu 1998
(Continued)
3. Relapse
5. Complications
Notes
Location: China (Chinese language)

Date: not reported
Severity of illness at entry: included mild, common, and severe types (1 severe type illness in levofloxacin group
and 2 in cefixime group)
Characteristics of ongoing studies [ordered by study ID]

ISRCTN66534807
Trial name or title
A randomised clinical trial of Azithromycin versus Ofloxacin in the treatment of adults with uncomplicated
typhoid fever at Mahosot Hospital, Vientiane, Lao Peoples Democratic Republic (PDR)
Methods
randomised clinical trial
Participants
Inclusion criteria: adult (15 years) non-pregnant patients with suspected or blood-culture proven typhoid;
fever > 37.5 C; informed written consent to the study; able to stay in hospital for 7 days; able to take oral
medication; bodyweight > 40 kg; likely to be able to complete 6 months follow up; none of the exclusion
criteria
Exclusion criteria: known hypersensitivity to ofloxacin or azithromycin; administration of chloramphenicol,
co-trimoxazole, ampicillin, azithromycin, or a fluoroquinolone during previous week; pregnancy or breastfeeding; contraindications to ofloxacin or azithromycin; evidence for severe typhoid
Interventions
1. Ofloxacin 7.5 mg/kg every 12 hours for 3 days

2. Azithromycin 20 mg/kg every 24 hours for 3 days
Outcomes

2. Cure
3. Relapse
4. Faecal carriage
Starting date
1 May 2004
Anticipated end date: 31 December 2007
Contact information
Dr Paul Newton (paul@tropmedres.ac), Microbiology laboratory, Ministry of Health, Mahosot Hospital,

Vientiane, Laos
Notes
Location: Laos
Registration number: ISRCTN66534807
Source of funding: The Wellcome Trust (UK)
Percentage of children in trial: none
E-mail update by Dr Newton on 5 December 2007: on hold because of considerable decline in incidence of
60
ISRCTN66534807
(Continued)
typhoid in Vientiane
61
DATA AND ANALYSES
Comparison 1. Fluoroquinolone versus chloramphenicol
Outcome or subgroup title

1 Clinical failure
1.1 Ciprofloxacin versus
chloramphenicol
1.2 Ofloxacin versus
chloramphenicol
1.3 Pefloxacin versus
chloramphenicol
1.4 Gatifloxacin versus
chloramphenicol
2 Microbiological failure
chloramphenicol
chloramphenicol
chloramphenicol
chloramphenicol
3 Relapse
chloramphenicol
chloramphenicol
chloramphenicol
chloramphenicol
4 Convalescent faecal carriage
chloramphenicol
chloramphenicol
chloramphenicol
chloramphenicol
5 Fever clearance time
chloramphenicol
chloramphenicol
6 Duration of hospitalization
No. of
studies
No. of
participants
8
4
293
Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only
0.24 [0.07, 0.82]
249
0.15 [0.03, 0.64]
126
0.0 [0.0, 0.0]
352
0.79 [0.32, 1.96]
5
2
142
Risk Ratio (M-H, Random, 95% CI)

Subtotals only
0.05 [0.00, 0.81]
199
0.16 [0.02, 1.07]
126
0.0 [0.0, 0.0]
352
4.94 [0.24, 102.24]
6
4
292

Subtotals only
0.15 [0.02, 1.15]
149
0.14 [0.01, 2.65]
126
0.15 [0.02, 1.21]
352
0.56 [0.17, 1.90]
3
1
50

Subtotals only
0.16 [0.01, 2.89]
60
0.11 [0.01, 1.98]
126
0.13 [0.02, 1.01]
273
0.32 [0.01, 7.82]
3
2
147
Mean Difference (IV, Fixed, 95% CI)

140
Subtotals only
-62.46 [-75.52, -49.
39]
-75.85 [-88.52, -63.
17]
Subtotals only
Statistical method
Effect size
62

chloramphenicol
chloramphenicol
7 Serious adverse events
chloramphenicol
chloramphenicol
8 Non-serious adverse events
chloramphenicol
chloramphenicol
chloramphenicol
chloramphenicol
55
-0.40 [-1.63, 0.83]
50
-9.9 [-11.42, -8.38]
3
2
203
153

0.99 [0.18, 5.52]

0.99 [0.18, 5.52]
50
0.0 [0.0, 0.0]
8
4
1410
253

0.76 [0.61, 0.94]

1.00 [0.61, 1.64]
207
1.06 [0.60, 1.87]
106
1.32 [0.69, 2.52]
844
0.58 [0.44, 0.78]
Comparison 2. Fluoroquinolone versus co-trimoxazole

1 Clinical Failure
co-trimoxazole
co-trimoxazole
co-trimoxazole
co-trimoxazole
co-trimoxazole
co-trimoxazole
3 Relapse
co-trimoxazole
co-trimoxazole
5.1 ciprofloxacin versus
co-trimoxazole
co-trimoxazole
No. of
studies
No. of
participants
3
2
132

Subtotals only
0.06 [0.01, 0.43]
89
0.04 [0.00, 0.59]
42
0.0 [0.0, 0.0]
3
2
132

Subtotals only
0.06 [0.01, 0.43]
89
0.04 [0.00, 0.59]
42
0.0 [0.0, 0.0]
1
1
181
92

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
89
0.0 [0.0, 0.0]
1
1
1
42
92

92
0.0 [0.0, 0.0]

Subtotals only
-84.0 [-99.72, -68.
28]
-96.0 [-115.64, -76.
36]
Statistical method
Effect size
63
6 Non serious adverse events

co-trimoxazole
co-trimoxazole
co-trimoxazole
3
2
219
110

0.70 [0.46, 1.08]

0.62 [0.34, 1.12]
67
0.92 [0.46, 1.83]
42
0.56 [0.14, 2.21]
Comparison 3. Fluroqunolone versus ampicillin/amoxicillin

1 Clinical failure
ampicillin
amoxicillin
ampicillin/amoxicillin
amoxicillin
amoxicillin
No. of
studies
No. of
participants
2
1
90
40

0.11 [0.02, 0.57]

0.09 [0.01, 1.54]
50
0.13 [0.02, 0.93]
2
1
90
40

0.13 [0.03, 0.68]

0.14 [0.01, 2.60]
50
0.13 [0.02, 0.93]
2
2
90
90

0.33 [0.12, 0.93]

0.33 [0.12, 0.93]
Statistical method
Effect size
Comparison 4. Fluoroquinolone versus cefixime

1 Clinical failure
cefixime
1.2 Ofloxacin versus cefixime
cefixime
cefixime
cefixime
3 Relapse
No. of
studies
No. of
participants
3
1
94

Subtotals only
0.0 [0.0, 0.0]
2
1
173
158

0.14 [0.02, 1.11]

0.04 [0.01, 0.31]
3
1
94

Subtotals only
0.0 [0.0, 0.0]
2
1
173
158

0.23 [0.01, 4.66]

0.27 [0.01, 6.43]
Subtotals only
Statistical method
Effect size
64

cefixime
cefixime
cefixime
cefixime
7 Serious adverse Events
cefixime
cefixime
cefixime
94
0.0 [0.0, 0.0]
2
1
131
138

0.33 [0.01, 7.72]

0.20 [0.04, 0.93]
1
1
147

Subtotals only
0.27 [0.01, 6.40]
1
1
94

Subtotals only
-12.00 [-24.42, 0.
42]
-24.0 [-41.46, -6.54]
-3.0 [-4.53, -1.47]
-3.0 [-4.53, -1.47]
Subtotals only
3.46 [0.15, 82.56]
1.67 [0.15, 18.11]
1
1
1
2
1
1
91
81
81
82
169

2
1
94

Subtotals only
1.57 [0.83, 2.95]
1
1
91
169

1.70 [0.83, 3.49]

20.92 [2.90, 150.90]
Comparison 5. Fluoroquinolone versus ceftriaxone

1 Clinical failure
ceftriaxone
ceftriaxone
ceftriaxone
ceftriaxone
3 Relapse
ceftriaxone
ceftriaxone
ceftriaxone
No. of
studies
No. of
participants
2
1
42

Subtotals only
0.08 [0.01, 1.41]
47
0.09 [0.01, 1.46]
2
1
42

Subtotals only
0.0 [0.0, 0.0]
47
0.38 [0.02, 8.80]
2
1
42

Subtotals only
0.37 [0.02, 8.48]
23
0.36 [0.02, 8.04]
1
1
42

Subtotals only
0.37 [0.02, 8.48]
Statistical method
Effect size
65
47

ceftriaxone
ceftriaxone
47
1
1
47
47

-113.00 [-150.67, 79.33]

-113.00 [-150.67, 79.33]
0.57 [0.06, 5.85]
0.57 [0.06, 5.85]
Comparison 6. Fluoroquinolone versus azithromycin

1 Clinical failure
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
3 Relapse
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
azithromycin
6 Duration of Hospitalization
azithromycin
No. of
studies
No. of
participants
4
1
64

Subtotals only
0.0 [0.0, 0.0]
213
2.20 [1.23, 3.94]
287
0.98 [0.32, 2.96]
4
1
64

Subtotals only
0.0 [0.0, 0.0]
213
1.32 [0.30, 5.76]
285
0.64 [0.11, 3.79]
4
1
64

Subtotals only
0.0 [0.0, 0.0]
163
6.11 [0.31, 119.33]
264
0.12 [0.01, 2.20]
4
1
64

Subtotals only
0.0 [0.0, 0.0]
193
13.52 [2.64, 69.36]
268
2.87 [0.12, 69.82]
3
1
64
Mean Difference (IV, Random, 95% CI)

Subtotals only
-12.0 [-24.39, 0.39]
213
2
2
213

30.41 [-22.12, 82.

93]
Subtotals only
1.01 [0.19, 1.83]
Statistical method
Effect size
66

azithromycin
azithromycin
azithromycin
8.3 Gatifloxain versus
azithromycin
1
1
88
88

1.0 [0.06, 15.49]

1.0 [0.06, 15.49]
4
1
64

Subtotals only
1.21 [0.73, 1.99]
213
0.56 [0.27, 1.16]
287
1.96 [0.18, 21.36]
Comparison 7. Fluoroquinolone 2 days vs 3 days
No. of
studies
No. of
participants
1 Clinical failure
3 Relapse
4 Convalecsent faecal carriage
3
2
3
2
3
3
3
2
396
296
312
262
396
396
396
296
Statistical method
Effect size
1.16 [0.54, 2.53]
1.94 [0.44, 8.47]
0.65 [0.14, 2.97]
0.31 [0.01, 7.45]
-5.41 [-14.59, 3.78]
-0.33 [-0.73, 0.06]
2.40 [0.22, 26.08]
0.18 [0.01, 3.61]
No. of
studies
No. of
participants
1 Relapse
2 Fever Clearance time
1
1
1
154
195
425
Statistical method
Effect size
0.32 [0.01, 7.65]
-12.0 [-18.07, -5.93]
1.73 [0.74, 4.03]
No. of
studies
No. of
participants
1 Microbiological Failure
2 Relapse
1
1
1
1
46
46
46
46
Statistical method
Effect size
3.26 [0.14, 76.10]
3.26 [0.14, 76.10]
-7.20 [-7.78, -6.62]
0.82 [0.21, 3.25]
67

2 Relapse
No. of
studies
No. of
participants
1
1
30
30
Statistical method
Effect size
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Comparison 11. Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days)

1 All outcomes
1.1 Clinical failure (need
for rescue medication or
persistence of fever until day
10)
1.2 Microbiological failure
(blood culture +ve on day 8)
1.3 Relapse (reappearance of
culture confirmed or syndromic
enteric fever on days 11 to 31)
1.4 Convalescent faecal
carriage
1.5 Serious adverse events
1.6 Other adverse events
(selected gastrointestinal
adverse events)
No. of
studies
No. of
participants
Statistical method
Effect size
1
1

Totals not selected

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
No. of
studies
No. of
participants
1 Relapse
1
1
69
69

69
Statistical method
Effect size
0.19 [0.01, 3.91]
-16.80 [-42.65, 9.
05]
0.43 [0.15, 1.27]
68
Comparison 13. Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days)

1 All outcomes
for rescue medication or
persistence of fever until day 7)
1.2 Relapse (fever plus +ve
blood culture within 1 month
of successful treatment)
(blood culture +ve on day 10)
1.5 Other adverse events (may
be incompletely reported)
No. of
studies
No. of
participants
Statistical method
Effect size
1
1

Totals not selected

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
1
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
Comparison 14. Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days)

1 All outcomes
for rescue medication of
persistence of fever until day
10)
1.2 Relapse (symptoms and
signs of typhoid fever within 1
month of successful treatment)
(blood culture +ve on day 7 to
9)
1.4 Convalescent faecal
carriage
1.6 Other adverse events (may
be incompletely reported)
No. of
studies
No. of
participants
Statistical method
Effect size
1
1

Totals not selected

0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0
1

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
69
Analysis 1.1. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 1 Clinical failure.

Review:
Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)
Comparison: 1 Fluoroquinolone versus chloramphenicol

Outcome: 1 Clinical failure
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
Risk Ratio
Weight
Gottuzzo 1992 N/A (1)
1/48
0/48
Morelli 1992 ITA (2)
0/20
0/30
Gasem 2003 IDN (3)
1/28
2/27
16.4 %
0.48 [ 0.05, 5.01 ]
Rizvi 2007 PAK (4)
0/48
9/44
79.6 %
0.05 [ 0.00, 0.81 ]
Subtotal (95% CI)
144
149
100.0 %
0.24 [ 0.07, 0.82 ]
1/25
2/25
15.1 %
0.50 [ 0.05, 5.17 ]
0/30
0/30
Phongmany 2005 LAO (7)
0/27
1/23
12.2 %
0.29 [ 0.01, 6.69 ]
Rizvi 2007 PAK (8)
0/45
9/44
72.7 %
0.05 [ 0.00, 0.86 ]
Subtotal (95% CI)
127
122
100.0 %
0.15 [ 0.03, 0.64 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Ciprofloxacin versus chloramphenicol

4.0 %
3.00 [ 0.13, 71.85 ]

Not estimable
Total events: 2 (Fluoroquinolone), 11 (Chloramphenicol)

Heterogeneity: Chi2 = 4.03, df = 2 (P = 0.13); I2 =50%
Test for overall effect: Z = 2.28 (P = 0.023)
2 Ofloxacin versus chloramphenicol
Yousaf 1992
PAK (5)
Not estimable

Heterogeneity: Chi2 = 1.75, df = 2 (P = 0.42); I2 =0.0%
3 Pefloxacin versus chloramphenicol
0/36
0/30
Not estimable
Cristiano 1995 ITA (10)
0/30
0/30
Not estimable
66
60
Not estimable
Subtotal (95% CI)

Heterogeneity: not applicable
Test for overall effect: not applicable
4 Gatifloxacin versus chloramphenicol
Arjyal 2011 (11)
Subtotal (95% CI)
8/177
10/175
100.0 %
0.79 [ 0.32, 1.96 ]
177
175
100.0 %
0.79 [ 0.32, 1.96 ]

0.001 0.01 0.1

Favours fluoroquinolone
10 100 1000
Favours chloramphenicol
70
(1) Ciprofloxacin 500mg BD for 10 days vs Chloramphenicol 750mg QDS for 14 days
(2) Ciprofloxacin 500mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
(5) Ofloxacin 200mg BD for 14 days vs Chloramphenicol 50mg/kg/day for 14 days
(6) Ofloxacin 300mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
(7) Ofloxacin 15mg/kg in 2 divided doses for 3 days vs Cloramphenicol 50mg/kg in 4 divided doses for 14 days
(8) Ofloxacin 200mg BD for 7 days vs Chloramphenicol 750mg QDS for 14 days
(9) Pefloxacin 400mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
(10) Pefloxacin 400mg (IV) TDS for 5 days vs Chloramphenicol 500mg (PO) QDS for 15 days
(11) Gatifloxacin 10mg/kg OD for 7 days vs Chloramphenicol 75mg/kg in 4 divided doses for 14 days
Analysis 1.2. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 2 Microbiological failure.

Review:

Outcome: 2 Microbiological failure
Study or subgroup
Fluoroquinolone
Chloramphenicol
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
0/20
0/30
Rizvi 2007 PAK
0/48
9/44
100.0 %
0.05 [ 0.00, 0.81 ]
68
74
100.0 %
0.05 [ 0.00, 0.81 ]
1/25
3/25
60.2 %
0.33 [ 0.04, 2.99 ]
0/30
0/30
Rizvi 2007 PAK
0/45
9/44
Subtotal (95% CI)
Not estimable

Yousaf 1992
PAK
Not estimable
39.8 %
0.001 0.01 0.1
0.05 [ 0.00, 0.86 ]
10 100 1000
(Continued . . . )
71
(. . .
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
100
99
Subtotal (95% CI)
Risk Ratio
MH,Random,95%
CI
Weight
100.0 %
Continued)
Risk Ratio
MH,Random,95%
CI
0.16 [ 0.02, 1.07 ]

Heterogeneity: Tau2 = 0.31; Chi2 = 1.19, df = 1 (P = 0.28); I2 =16%
0/36
0/30
Not estimable
Cristiano 1995 ITA
0/30
0/30
Not estimable
Subtotal (95% CI)
66
60
Not estimable

Arjyal 2011
Subtotal (95% CI)
2/177
0/175
100.0 %
4.94 [ 0.24, 102.24 ]
177
175
100.0 %
4.94 [ 0.24, 102.24 ]

0.001 0.01 0.1

10 100 1000
(1) Ciprofloxacin 500mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
(2) Ofloxacin 300mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
(3) Pefloxacin 400mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days
72
Analysis 1.3. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
Risk Ratio
Weight
Morelli 1992 ITA
0/20
3/30
38.8 %
0.21 [ 0.01, 3.87 ]
Gottuzzo 1992 N/A
0/47
4/48
61.2 %
0.11 [ 0.01, 2.05 ]
Gasem 2003 IDN (1)
0/28
0/27
Not estimable
Rizvi 2007 PAK
0/48
0/44
Not estimable
143
149
100.0 %
0.15 [ 0.02, 1.15 ]
100.0 %
0.14 [ 0.01, 2.65 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)

Morelli 1992 ITA
0/30
3/30
Rizvi 2007 PAK
0/45
0/44
75
74
100.0 %
0.14 [ 0.01, 2.65 ]
Subtotal (95% CI)
Not estimable

Morelli 1992 ITA
0/36
3/30
60.4 %
0.12 [ 0.01, 2.23 ]
Cristiano 1995 ITA
0/30
2/30
39.6 %
0.20 [ 0.01, 4.00 ]
Subtotal (95% CI)
66
60
100.0 %
0.15 [ 0.02, 1.21 ]
4/177
7/175
100.0 %
0.56 [ 0.17, 1.90 ]
177
175
100.0 %
0.56 [ 0.17, 1.90 ]

Arjyal 2011
Subtotal (95% CI)

0.001 0.01 0.1
10 100 1000
(1) Gasem 2003 IDN reports that no relapses were observed but patients were not routinely monitored after day 14.
73
Analysis 1.4. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 4 Convalescent faecal

carriage.
Review:

Outcome: 4 Convalescent faecal carriage
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
Risk Ratio
Weight
0/20
4/30
100.0 %
0.16 [ 0.01, 2.89 ]
20
30
100.0 %
0.16 [ 0.01, 2.89 ]
0/30
4/30
100.0 %
0.11 [ 0.01, 1.98 ]
30
30
100.0 %
0.11 [ 0.01, 1.98 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Morelli 1992 ITA
Subtotal (95% CI)

Morelli 1992 ITA
Subtotal (95% CI)

Morelli 1992 ITA
0/36
4/30
66.2 %
0.09 [ 0.01, 1.66 ]
Cristiano 1995 ITA
0/30
2/30
33.8 %
0.20 [ 0.01, 4.00 ]
Subtotal (95% CI)
66
60
100.0 %
0.13 [ 0.02, 1.01 ]
0/139
1/134
100.0 %
0.32 [ 0.01, 7.82 ]
139
134
100.0 %
0.32 [ 0.01, 7.82 ]

Arjyal 2011
Subtotal (95% CI)

0.001 0.01 0.1
10 100 1000
74
Analysis 1.5. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 5 Fever clearance time.
Review:

Outcome: 5 Fever clearance time
Study or subgroup
Fluoroquinolone
N
Mean
Difference
Chloramphenicol
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Gasem 2003 IDN (1)
28 122.4 (33.6)
27 136.8 (52.8)
31.0 %
-14.40 [ -37.88, 9.08 ]
Rizvi 2007 PAK (2)
48
44
69.0 %
-84.00 [ -99.72, -68.28 ]
Subtotal (95% CI)
76
72 (24)
156 (48)
100.0 % -62.46 [ -75.52, -49.39 ]
71
Heterogeneity: Chi2 = 23.30, df = 1 (P<0.00001); I2 =96%

Test for overall effect: Z = 9.37 (P < 0.00001)
Phongmany 2005 LAO
27
55 (20.1)
21
93.5 (46.8)
35.1 %
-38.50 [ -59.90, -17.10 ]
Rizvi 2007 PAK
48
60 (24)
44
156 (48)
64.9 %
-96.00 [ -111.72, -80.28 ]
Subtotal (95% CI)
75
100.0 % -75.85 [ -88.52, -63.17 ]
65

Test for subgroup differences: Chi2 = 2.08, df = 1 (P = 0.15), I2 =52%
-100
-50
50
100
(1) Days
(2) Days
75
Analysis 1.6. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 6 Duration of

hospitalization.
Review:

Outcome: 6 Duration of hospitalization
Study or subgroup
Fluoroquinolone
Mean
Difference
Chloramphenicol
Mean(SD)
Mean(SD)
Gasem 2003 IDN (1)
28
11.7 (2)
27
12.1 (2.6)
Subtotal (95% CI)
28
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
27
100.0 %
-0.40 [ -1.63, 0.83 ]
100.0 %
-0.40 [ -1.63, 0.83 ]
100.0 %
-9.90 [ -11.42, -8.38 ]

Phongmany 2005 LAO
Subtotal (95% CI)
27
8.9 (2.33)
27
23
18.8 (3.04)
23
100.0 % -9.90 [ -11.42, -8.38 ]

-100
-50
50
100
(1) Days
76
Analysis 1.7. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 7 Serious adverse events.
Review:

Outcome: 7 Serious adverse events
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
Risk Ratio
Weight
Gottuzzo 1992 N/A
2/49
1/49
39.6 %
2.00 [ 0.19, 21.34 ]
Gasem 2003 IDN
0/28
1/27
60.4 %
0.32 [ 0.01, 7.57 ]
Subtotal (95% CI)
77
76
100.0 %
0.99 [ 0.18, 5.52 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Phongmany 2005 LAO
Subtotal (95% CI)
0/27
0/23
Not estimable
27
23
Not estimable

Total (95% CI)
104
99
100.0 %
0.99 [ 0.18, 5.52 ]

Test for subgroup differences: Not applicable
0.01
0.1
Favours fluoroquinolones
10
100
77
Analysis 1.8. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 8 Non-serious adverse

events.
Review:

Outcome: 8 Non-serious adverse events
Study or subgroup
Fluoroquinolone
Chloramphenicol
n/N
n/N
Risk Ratio
Weight
18/20
4/10
3.5 %
2.25 [ 1.04, 4.87 ]
Gottuzzo 1992 N/A
0/49
10/49
6.9 %
0.05 [ 0.00, 0.79 ]
Gasem 2003 IDN
0/28
1/27
1.0 %
0.32 [ 0.01, 7.57 ]
18/48
5/22
4.5 %
1.65 [ 0.70, 3.87 ]
145
108
15.9 %
1.00 [ 0.61, 1.64 ]
10/30
5/10
4.9 %
0.67 [ 0.30, 1.48 ]
3/25
4/25
2.6 %
0.75 [ 0.19, 3.01 ]
0/27
0/23
15/45
4/22
3.5 %
1.83 [ 0.69, 4.88 ]
127
80
11.1 %
1.06 [ 0.60, 1.87 ]
18/36
4/10
4.1 %
1.25 [ 0.55, 2.86 ]
Cristiano 1995 ITA
7/30
5/30
3.3 %
1.40 [ 0.50, 3.92 ]
Subtotal (95% CI)
66
40
7.4 %
1.32 [ 0.69, 2.52 ]
59/426
99/418
65.6 %
0.58 [ 0.44, 0.78 ]
426
418
65.6 %
0.58 [ 0.44, 0.78 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Morelli 1992 ITA
Rizvi 2007 PAK
Subtotal (95% CI)

Morelli 1992 ITA
Yousaf 1992
PAK
Phongmany 2005 LAO

Rizvi 2007 PAK
Subtotal (95% CI)
Not estimable

Morelli 1992 ITA

Arjyal 2011
Subtotal (95% CI)

0.002
0.1
10
500
(Continued . . . )
78
(. . .
Study or subgroup
Fluoroquinolone
Total (95% CI)
Chloramphenicol
n/N
n/N
764
646
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI
100.0 %
0.76 [ 0.61, 0.94 ]

0.002
0.1
10
500
Analysis 2.1. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 1 Clinical Failure.

Review:
Comparison: 2 Fluoroquinolone versus co-trimoxazole

Outcome: 1 Clinical Failure
Study or subgroup
Fluoroquinolone
Cotrimoxazole
n/N
n/N
Risk Ratio
Weight
Limson 1989 PHL (1)
0/20
2/20
15.1 %
0.20 [ 0.01, 3.92 ]
Rizvi 2007 PAK (2)
0/48
13/44
84.9 %
0.03 [ 0.00, 0.56 ]
Subtotal (95% CI)
68
64
100.0 %
0.06 [ 0.01, 0.43 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Ciprofloxacin versus co-trimoxazole
Total events: 0 (Fluoroquinolone), 15 (Cotrimoxazole)

2 Ofloxacin versus co-trimoxazole
Rizvi 2007 PAK (3)
0/45
13/44
100.0 %
0.04 [ 0.00, 0.59 ]
Subtotal (95% CI)
45
44
100.0 %
0.04 [ 0.00, 0.59 ]

3 Pefloxacin versus co-trimoxazole
Hajji 1988 MAR (4)
0/24
0/18
Not estimable
Subtotal (95% CI)
24
18
Not estimable

0.005
0.1
10
200
Favours cotrimoxazole
79
(1) Ciprofloxacin 500 mg BD for 10 days vs Co-trimoxazole 160/800 mg BD for 14 days

(2) Ciprofloxacin 500mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days
(3) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days
(4) Pefloxacin 400 mg BD for 14 days vs Co-trimoxazole 160/800 mg BD for 14 days
Analysis 2.2. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 2 Microbiological failure.

Review:

Study or subgroup
Fluoroquinolone
Cotrimoxazole
n/N
n/N
Risk Ratio
Weight
Limson 1989 PHL (1)
0/20
2/20
15.1 %
0.20 [ 0.01, 3.92 ]
Rizvi 2007 PAK (2)
0/48
13/44
84.9 %
0.03 [ 0.00, 0.56 ]
Subtotal (95% CI)
68
64
100.0 %
0.06 [ 0.01, 0.43 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Rizvi 2007 PAK (3)
0/45
13/44
100.0 %
0.04 [ 0.00, 0.59 ]
Subtotal (95% CI)
45
44
100.0 %
0.04 [ 0.00, 0.59 ]

Hajji 1988 MAR (4)
0/24
0/18
Not estimable
Subtotal (95% CI)
24
18
Not estimable

0.001 0.01 0.1
10 100 1000
80
(1) Ciprofloxacin 500 mg BD for 10 days vs Co-trimoxazole 160/800 mg BD for 14 days

(3) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 ays
(4) Pefloxacin 400 mg BD for 14 days vs Co-trimoxazole 160/800 mg BD for 14 days
Analysis 2.3. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
Fluoroquinolone
Cotrimoxazole
n/N
n/N
Risk Ratio
Weight
Rizvi 2007 PAK (1)
0/48
0/44
Not estimable
Subtotal (95% CI)
48
44
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Rizvi 2007 PAK (2)
0/45
0/44
Not estimable
Subtotal (95% CI)
45
44
Not estimable
88
Not estimable

Total (95% CI)
93

Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%
0.01
0.1
Favours fluoroqunolone
10
100

(2) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days
81
Analysis 2.4. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 4 Convalescent faecal

carriage.
Review:

Study or subgroup
Fluoroquinolone
Cotrimoxazole
n/N
n/N
0/24
0/18
Not estimable
24
18
Not estimable
Hajji 1988 MAR
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours Pefloxacin
10
100
Favours Cotrimoxazole
Analysis 2.5. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 5 Fever clearance time.
Review:

Study or subgroup
Fluoroquinolone
Mean
Difference
Cotrimoxazole
Mean(SD)
Mean(SD)
48
72 (24)
44
156 (48)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
1 ciprofloxacin versus co-trimoxazole

Rizvi 2007 PAK
Subtotal (95% CI)
48
100.0 %
44
-84.00 [ -99.72, -68.28 ]
100.0 % -84.00 [ -99.72, -68.28 ]

Rizvi 2007 PAK
Subtotal (95% CI)
48
48
60 (48)
44
100.0 %
156 (48)
-96.00 [ -115.64, -76.36 ]
100.0 % -96.00 [ -115.64, -76.36 ]
44

Test for subgroup differences: Chi2 = 0.87, df = 1 (P = 0.35), I2 =0.0%
-100
-50
50
100
82
Analysis 2.6. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 6 Non serious adverse events.
Review:

Outcome: 6 Non serious adverse events
Study or subgroup
Fluoroquinolone
Cotrimoxazole
n/N
n/N
Risk Ratio
Weight
5/20
6/20
17.8 %
0.83 [ 0.30, 2.29 ]
10/48
9/22
36.7 %
0.51 [ 0.24, 1.07 ]
68
42
54.5 %
0.62 [ 0.34, 1.12 ]
15/45
8/22
31.9 %
0.92 [ 0.46, 1.83 ]
45
22
31.9 %
0.92 [ 0.46, 1.83 ]
3/24
4/18
13.6 %
0.56 [ 0.14, 2.21 ]
24
18
13.6 %
0.56 [ 0.14, 2.21 ]
82
100.0 %
0.70 [ 0.46, 1.08 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Limson 1989 PHL
Rizvi 2007 PAK
Subtotal (95% CI)

Rizvi 2007 PAK
Subtotal (95% CI)

Hajji 1988 MAR
Subtotal (95% CI)

Total (95% CI)
137

0.05
0.2
20
83
Analysis 3.1. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 1 Clinical failure.

Review:
Comparison: 3 Fluroqunolone versus ampicillin/amoxicillin

Study or subgroup
Fluoroquinolone
Ampicillin/Amoxycillin
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
n/N
n/N
M-H,Fixed,95% CI
Flores 1994 MEX (1)
0/20
5/20
40.7 %
0.09 [ 0.01, 1.54 ]
Subtotal (95% CI)
20
20
40.7 %
0.09 [ 0.01, 1.54 ]
1 Ofloxacin versus ampicillin
Total events: 0 (Fluoroquinolone), 5 (Ampicillin/Amoxycillin)

2 Ofloxacin versus amoxicillin
Yousaf 1992
PAK (2)
1/25
8/25
59.3 %
0.13 [ 0.02, 0.93 ]
Subtotal (95% CI)
25
25
59.3 %
0.13 [ 0.02, 0.93 ]
45
100.0 %
0.11 [ 0.02, 0.57 ]

Total (95% CI)
45

0.005
0.1
10
200
Favours ampicillin
(1) Ofloxacin 400 mg BD 10 days vs Ampicillin 1 g QDS for 10 days

(2) Ofloxacin 200 mg oral BD for 14 days vs Amoxicillin 4 to 6 g/day for 14 days
84
Analysis 3.2. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 2 Microbiological failure.

Review:

Study or subgroup
Fluoroquinolone
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
n/N
n/N
M-H,Fixed,95% CI
Flores 1994 MEX (1)
0/20
3/20
30.4 %
0.14 [ 0.01, 2.60 ]
Subtotal (95% CI)
20
20
30.4 %
0.14 [ 0.01, 2.60 ]
1 Ofloxacin versus ampicillin/amoxicillin

PAK (2)
1/25
8/25
69.6 %
0.13 [ 0.02, 0.93 ]
Subtotal (95% CI)
25
25
69.6 %
0.13 [ 0.02, 0.93 ]
45
100.0 %
0.13 [ 0.03, 0.68 ]
Yousaf 1992

Total (95% CI)
45

0.001 0.01 0.1

10 100 1000
Favours ampicillin
(1) Ofloxacin 400 mg BD 10 days vs Ampicillin 1 g QDS for 10 days

(2) Ofloxacin 200 mg oral BD for 14 days vs Amoxicillin 4 to 6 g/day for 14 days
85
Analysis 3.3. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 3 Non-serious adverse

events.
Review:

Study or subgroup
Fluoroquinolone
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
n/N
n/N
M-H,Fixed,95% CI
Flores 1994 MEX
1/20
1/20
8.3 %
1.00 [ 0.07, 14.90 ]
Yousaf 1992
3/25
11/25
91.7 %
0.27 [ 0.09, 0.86 ]
45
45
100.0 %
0.33 [ 0.12, 0.93 ]
PAK
Total (95% CI)

0.01
0.1
10
100
Favours ampicillin
86
Analysis 4.1. Comparison 4 Fluoroquinolone versus cefixime, Outcome 1 Clinical failure.

Review:
Comparison: 4 Fluoroquinolone versus cefixime

Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
Rizvi 2007 PAK (1)
0/48
0/46
Not estimable
Subtotal (95% CI)
48
46
Not estimable
Phuong 1999 VNM (2)
1/38
8/44
Rizvi 2007 PAK (3)
0/45
0/46
Subtotal (95% CI)
83
90
100.0 %
0.14 [ 0.02, 1.11 ]
1/88
19/70
100.0 %
0.04 [ 0.01, 0.31 ]
88
70
100.0 %
0.04 [ 0.01, 0.31 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Ciprofloxacin versus cefixime
Total events: 0 (Fluoroquinolone), 0 (Cefixime)

2 Ofloxacin versus cefixime
100.0 %
0.14 [ 0.02, 1.11 ]

Not estimable

3 Gatifloxacin versus cefixime
Pandit 2007 NPL (4)
Subtotal (95% CI)

0.005
0.1
10
200
Favours cefixime
(1) Ciprofloxacin 500mg BD for 7 days vs Cefixime 200mg BD for 7 days

(2) Ofloxacin 10mg/kg in 2 divided doses for 5 days vs Cefixime 20mg/kg in 2 divided doses for 7 days
(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days)
(4) Gatifloxacin 10mg/kg/day in single oral dose for 7 days vs Cefixime 20mg/kg in 2 divided doses oral for 7 days
87
Analysis 4.2. Comparison 4 Fluoroquinolone versus cefixime, Outcome 2 Microbiological failure.

Review:

Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
Rizvi 2007 PAK (1)
0/48
0/46
Not estimable
Subtotal (95% CI)
48
46
Not estimable
Phuong 1999 VNM (2)
0/38
2/44
Rizvi 2007 PAK (3)
0/45
0/46
Subtotal (95% CI)
83
90
100.0 %
0.23 [ 0.01, 4.66 ]
0/88
1/70
100.0 %
0.27 [ 0.01, 6.43 ]
88
70
100.0 %
0.27 [ 0.01, 6.43 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

100.0 %
0.23 [ 0.01, 4.66 ]

Not estimable

Pandit 2007 NPL (4)
Subtotal (95% CI)

0.002
0.1
10
500
Favours cefixime

(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days
88
Analysis 4.3. Comparison 4 Fluoroquinolone versus cefixime, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
Rizvi 2007 PAK (1)
0/48
0/46
Not estimable
Subtotal (95% CI)
48
46
Not estimable
Phuong 1999 VNM (2)
0/20
1/20
Rizvi 2007 PAK (3)
0/45
0/46
Subtotal (95% CI)
65
66
100.0 %
0.33 [ 0.01, 7.72 ]
2/87
6/51
100.0 %
0.20 [ 0.04, 0.93 ]
87
51
100.0 %
0.20 [ 0.04, 0.93 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

100.0 %
0.33 [ 0.01, 7.72 ]

Not estimable

Pandit 2007 NPL (4)
Subtotal (95% CI)

0.01
0.1
10
100
Favours cefixime

(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days
89
Analysis 4.4. Comparison 4 Fluoroquinolone versus cefixime, Outcome 4 Convalescent faecal carriage.
Review:

Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
0/82
1/65
100.0 %
0.27 [ 0.01, 6.40 ]
82
65
100.0 %
0.27 [ 0.01, 6.40 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Pandit 2007 NPL
Subtotal (95% CI)

0.001 0.01 0.1

10 100 1000
Favours cefixime
Analysis 4.5. Comparison 4 Fluoroquinolone versus cefixime, Outcome 5 Fever clearance time.
Review:

Study or subgroup
Fluoroquinolone
Mean
Difference
Cefixime
Mean(SD)
Mean(SD)
48
72 (24)
46
84 (36)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Rizvi 2007 PAK
Subtotal (95% CI)
48
46
100.0 %
-12.00 [ -24.42, 0.42 ]
100.0 %
-12.00 [ -24.42, 0.42 ]
100.0 %
-24.00 [ -41.46, -6.54 ]

Rizvi 2007 PAK
Subtotal (95% CI)
45
45
60 (48)
46
84 (36)
100.0 % -24.00 [ -41.46, -6.54 ]
46

-200
-100
Favours Fluoroquinolone
100
200
Favours Cefixime
90
Analysis 4.6. Comparison 4 Fluoroquinolone versus cefixime, Outcome 6 Duration of hospitalization.

Review:

Study or subgroup
Fluoroquinolone
Mean
Difference
Cefixime
Mean(SD)
Mean(SD)
37
11 (3)
44
14 (4)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Phuong 1999 VNM
Total (95% CI)
37
100.0 %
44
-3.00 [ -4.53, -1.47 ]
100.0 % -3.00 [ -4.53, -1.47 ]

-10
-5
10
Favours cefixime
91
Analysis 4.7. Comparison 4 Fluoroquinolone versus cefixime, Outcome 7 Serious adverse Events.
Review:

Outcome: 7 Serious adverse Events
Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
Phuong 1999 VNM
1/38
0/44
100.0 %
3.46 [ 0.15, 82.56 ]
Subtotal (95% CI)
38
44
100.0 %
3.46 [ 0.15, 82.56 ]
2/92
1/77
100.0 %
1.67 [ 0.15, 18.11 ]
92
77
100.0 %
1.67 [ 0.15, 18.11 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Pandit 2007 NPL
Subtotal (95% CI)

0.01
0.1
10
100
Favours cefixime
92
Analysis 4.8. Comparison 4 Fluoroquinolone versus cefixime, Outcome 8 Non-serious adverse events.
Review:

Study or subgroup
Fluoroquinolone
Cefixime
n/N
n/N
Risk Ratio
Weight
18/48
11/46
100.0 %
1.57 [ 0.83, 2.95 ]
48
46
100.0 %
1.57 [ 0.83, 2.95 ]
15/45
9/46
100.0 %
1.70 [ 0.83, 3.49 ]
45
46
100.0 %
1.70 [ 0.83, 3.49 ]
25/92
1/77
100.0 %
20.92 [ 2.90, 150.90 ]
92
77
100.0 %
20.92 [ 2.90, 150.90 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Rizvi 2007 PAK
Subtotal (95% CI)

Rizvi 2007 PAK
Subtotal (95% CI)

Pandit 2007 NPL
Subtotal (95% CI)

0.05
0.2
20
Favours cefixime
93
Analysis 5.1. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 1 Clinical failure.

Review:
Comparison: 5 Fluoroquinolone versus ceftriaxone

Study or subgroup
Fluoroquinolone
Ceftriaxone
n/N
n/N
Risk Ratio
Weight
0/20
6/22
100.0 %
0.08 [ 0.01, 1.41 ]
20
22
100.0 %
0.08 [ 0.01, 1.41 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Ciprofloxacin versus ceftriaxone

Wallace 1993 BHR (1)
Subtotal (95% CI)
Total events: 0 (Fluoroquinolone), 6 (Ceftriaxone)

2 Ofloxacin versus ceftriaxone
Smith 1994 VNM (2)
0/22
6/25
100.0 %
0.09 [ 0.01, 1.46 ]
Subtotal (95% CI)
22
25
100.0 %
0.09 [ 0.01, 1.46 ]

0.002
0.1
10
500
Favours ceftriaxone
(1) Ciprofloxacin 500 mg BD for 7 days vs Ceftriaxone 3 g/day IV for 7 days

(2) Ofloxacin 200 mg BD for 5 days vs Ceftriaxone 3 g IV OD for 3 days
94
Analysis 5.2. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 2 Microbiological failure.

Review:

Study or subgroup
Fluoroquinolone
Ceftriaxone
n/N
n/N
Risk Ratio
Weight
0/20
0/22
Not estimable
20
22
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Subtotal (95% CI)

Smith 1994 VNM (2)
0/22
1/25
100.0 %
0.38 [ 0.02, 8.80 ]
Subtotal (95% CI)
22
25
100.0 %
0.38 [ 0.02, 8.80 ]

0.01
0.1
10
100
Favours ceftriaxone

95
Analysis 5.3. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
Fluoroquinolone
Ceftriaxone
n/N
n/N
Risk Ratio
Weight
0/20
1/22
100.0 %
0.37 [ 0.02, 8.48 ]
20
22
100.0 %
0.37 [ 0.02, 8.48 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Subtotal (95% CI)

Smith 1994 VNM (2)
0/11
1/12
100.0 %
0.36 [ 0.02, 8.04 ]
Subtotal (95% CI)
11
12
100.0 %
0.36 [ 0.02, 8.04 ]

0.01
0.1
10
100
Favours ceftriaxone

96
Analysis 5.4. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 4 Convalescent faecal carriage.
Review:

Study or subgroup
Fluoroquinolone
Ceftriaxone
n/N
n/N
Risk Ratio
Weight
Wallace 1993 BHR
0/20
1/22
100.0 %
0.37 [ 0.02, 8.48 ]
Subtotal (95% CI)
20
22
100.0 %
0.37 [ 0.02, 8.48 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
10
100
Favours ceftriaxone
Analysis 5.5. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 5 Fever clearance time.
Review:

Study or subgroup
Fluoroquinolone
Mean
Difference
Ceftriaxone
Mean(SD)
Mean(SD)
Smith 1994 VNM
22
81 (25)
25
196 (87)
Total (95% CI)
22
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

100.0 %
-115.00 [ -150.67, -79.33 ]
100.0 % -115.00 [ -150.67, -79.33 ]
25

-100
-50
50
100
Favours ceftriaxone
97
Analysis 5.6. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 6 Non-serious adverse events.
Review:

Study or subgroup
Fluoroquinolone
Ceftriaxone
n/N
n/N
Risk Ratio
Weight
Smith 1994 VNM
1/22
2/25
100.0 %
0.57 [ 0.06, 5.85 ]
Total (95% CI)
22
25
100.0 %
0.57 [ 0.06, 5.85 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
10
100
Favours cefixime
98
Analysis 6.1. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 1 Clinical failure.

Review:
Comparison: 6 Fluoroquinolone versus azithromycin

Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
0/28
0/36
Not estimable
28
36
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Ciprofloxacin versus azithromycin

Girgis 1999 EGY (1)
Subtotal (95% CI)
Total events: 0 (Fluoroquinolone), 0 (Azithromycin)

2 Ofloxacin versus azithromycin
Chinh 2000 VNM (2)
6/44
2/44
15.3 %
3.00 [ 0.64, 14.06 ]
Parry 2007 VNM (3)
23/63
11/62
84.7 %
2.06 [ 1.10, 3.85 ]
107
106
100.0 %
2.20 [ 1.23, 3.94 ]
6/145
6/142
100.0 %
0.98 [ 0.32, 2.96 ]
145
142
100.0 %
0.98 [ 0.32, 2.96 ]
Subtotal (95% CI)

3 Gatifloxacin versus azithromycin
Dolecek 2008 VNM (4)
Subtotal (95% CI)

0.01
0.1
10
100
Favours azithromycin
(1) Ciprofloxacin 500 mg BD for 7 days vs Azithromycin 1 g OD followed by 500 mg OD for 6 days
(2) Ofloxacin 200 mg BD for 5 days vs Azithromycin 1 gm OD for 5 days
(3) Ofloxacin 10 mg/kg BD for 7 days vs Azithromycin 10 mg/kg OD for 7 days
(4) Gatifloxacin 10 mg/kg OD for 7 days vs Azithromycin 20 mg/kg OD for 7 days
99
Analysis 6.2. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 2 Microbiological failure.

Review:

Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
0/28
0/36
Not estimable
28
36
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Girgis 1999 EGY (1)
Subtotal (95% CI)

Chinh 2000 VNM (2)
2/44
1/44
33.2 %
2.00 [ 0.19, 21.26 ]
Parry 2007 VNM (3)
2/63
2/62
66.8 %
0.98 [ 0.14, 6.77 ]
107
106
100.0 %
1.32 [ 0.30, 5.76 ]
2/145
3/140
100.0 %
0.64 [ 0.11, 3.79 ]
145
140
100.0 %
0.64 [ 0.11, 3.79 ]
Subtotal (95% CI)

Subtotal (95% CI)

0.01
0.1
10
100
Favours azthithromycin
100
Analysis 6.3. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
0/36
0/28
Not estimable
36
28
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Girgis 1999 EGY (1)
Subtotal (95% CI)

Chinh 2000 VNM (2)
2/17
0/21
Parry 2007 VNM (3)
0/62
0/63
79
84
100.0 %
6.11 [ 0.31, 119.33 ]
0/127
4/137
100.0 %
0.12 [ 0.01, 2.20 ]
127
137
100.0 %
0.12 [ 0.01, 2.20 ]
Subtotal (95% CI)
100.0 %
6.11 [ 0.31, 119.33 ]

Not estimable

Subtotal (95% CI)

0.005
0.1
10
200
101
Analysis 6.4. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 4 Convalescent faecal carriage.
Review:

Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
0/28
0/36
Not estimable
28
36
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Girgis 1999 EGY
Subtotal (95% CI)

Chinh 2000 VNM
8/35
0/34
33.6 %
16.53 [ 0.99, 275.62 ]
Parry 2007 VNM
12/62
1/62
66.4 %
12.00 [ 1.61, 89.51 ]
97
96
100.0 %
13.52 [ 2.64, 69.36 ]
1/137
0/131
100.0 %
2.87 [ 0.12, 69.82 ]
137
131
100.0 %
2.87 [ 0.12, 69.82 ]
Subtotal (95% CI)

Dolecek 2008 VNM
Subtotal (95% CI)

0.001 0.01 0.1

10 100 1000
102
Analysis 6.5. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 5 Fever clearance time.
Review:

Study or subgroup
Fluoroquinolone
Mean
Difference
Azithromycin
Mean(SD)
Mean(SD)
28
79.2 (24)
36
91.2 (26.4)
Weight
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI

Girgis 1999 EGY
Subtotal (95% CI)
28
100.0 %
36
-12.00 [ -24.39, 0.39 ]
100.0 % -12.00 [ -24.39, 0.39 ]

Chinh 2000 VNM
44
Parry 2007 VNM
63 196.8 (97.18)
Subtotal (95% CI)
107
134 (76.14)
130 (46.61)
50.7 %
4.00 [ -22.38, 30.38 ]
62 139.2 (67.49)
49.3 %
57.60 [ 28.31, 86.89 ]
44
106
100.0 % 30.41 [ -22.12, 82.93 ]
Heterogeneity: Tau2 = 1234.23; Chi2 = 7.10, df = 1 (P = 0.01); I2 =86%

-100
-50
50
100
103
Analysis 6.6. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization.

Review:

Outcome: 6 Duration of Hospitalization
Study or subgroup
Fluoroquinolone
Mean
Difference
Azithromycin
Weight
IV,Fixed,95% CI
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
Chinh 2000 VNM
44
10.5 (3.38)
44
9.6 (2.37)
44.8 %
0.90 [ -0.32, 2.12 ]
Parry 2007 VNM
63
13.7 (3.85)
62
12.6 (2.21)
55.2 %
1.10 [ 0.00, 2.20 ]
Subtotal (95% CI)
107
100.0 % 1.01 [ 0.19, 1.83 ]
106

-2
-1
Analysis 6.7. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 7 Serious adverse events.
Review:

Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
Chinh 2000 VNM
1/44
1/44
100.0 %
1.00 [ 0.06, 15.49 ]
Total (95% CI)
44
44
100.0 %
1.00 [ 0.06, 15.49 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
10
100
104
Analysis 6.8. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 8 Non-serious adverse events.
Review:

Study or subgroup
Fluoroquinolone
Azithromycin
n/N
n/N
Risk Ratio
Weight
15/28
16/36
100.0 %
1.21 [ 0.73, 1.99 ]
28
36
100.0 %
1.21 [ 0.73, 1.99 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Girgis 1999 EGY
Subtotal (95% CI)

Chinh 2000 VNM
8/44
15/44
93.7 %
0.53 [ 0.25, 1.13 ]
Parry 2007 VNM
1/63
1/62
6.3 %
0.98 [ 0.06, 15.39 ]
Subtotal (95% CI)
107
106
100.0 %
0.56 [ 0.27, 1.16 ]
2/145
1/142
100.0 %
1.96 [ 0.18, 21.36 ]
145
142
100.0 %
1.96 [ 0.18, 21.36 ]

3 Gatifloxain versus azithromycin
Dolecek 2008 VNM
Subtotal (95% CI)

0.02
0.1
10
50
105
Analysis 7.1. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 1 Clinical failure.

Review:
Comparison: 7 Fluoroquinolone 2 days vs 3 days

Study or subgroup
FQ 2D
FQ 3D
n/N
n/N
Chinh 1997 VNM
1/47
6/53
49.5 %
0.19 [ 0.02, 1.50 ]
Vinh 1996 VNM
6/53
2/47
18.6 %
2.66 [ 0.56, 12.55 ]
Vinh 2005 VNM
6/89
4/107
31.9 %
1.80 [ 0.53, 6.19 ]
189
207
100.0 %
1.16 [ 0.54, 2.53 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 13 (FQ 2D), 12 (FQ 3D)

0.01
0.1
Favours 2D
10
100
Favours 3D

Review:

Study or subgroup
FQ 2D
FQ 3D
n/N
n/N
Vinh 1996 VNM
0/53
1/47
63.6 %
0.30 [ 0.01, 7.10 ]
Vinh 2005 VNM
4/89
1/107
36.4 %
4.81 [ 0.55, 42.25 ]
142
154
100.0 %
1.94 [ 0.44, 8.47 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 2D
10
100
Favours 3D
106
Analysis 7.3. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 3 Relapse.

Review:

Outcome: 3 Relapse
Study or subgroup
FQ 2D
FQ 3D
n/N
n/N
Chinh 1997 VNM
0/24
1/26
Vinh 1996 VNM
0/34
0/32
Vinh 2005 VNM
2/89
3/107
65.4 %
0.80 [ 0.14, 4.69 ]
147
165
100.0 %
0.65 [ 0.14, 2.97 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
34.6 %
0.36 [ 0.02, 8.43 ]

Not estimable

0.01
0.1
Favours 2D
10
100
Favours 3D
107
Analysis 7.4. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 4 Convalecsent faecal carriage.
Review:

Outcome: 4 Convalecsent faecal carriage
Study or subgroup
FQ 2D
FQ 3D
n/N
n/N
Vinh 1996 VNM
0/34
1/32
Vinh 2005 VNM
0/89
0/107
123
139
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
100.0 %
0.31 [ 0.01, 7.45 ]

Not estimable
100.0 %
0.31 [ 0.01, 7.45 ]

0.01
0.1
Favours 2D
10
100
Favours 3D
Analysis 7.5. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 5 Fever clearance time.
Review:

Study or subgroup
FQ 2D
Mean
Difference
FQ 3D
Weight
Mean
Difference
Mean(SD)
Mean(SD)
Chinh 1997 VNM
47
97 (33)
53
97 (44)
36.8 %
0.0 [ -15.14, 15.14 ]
Vinh 1996 VNM
53
100 (64)
47
107 (60)
14.3 %
-7.00 [ -31.31, 17.31 ]
Vinh 2005 VNM
89
92 (48.13)
107
101 (44.86)
49.0 %
-9.00 [ -22.12, 4.12 ]
100.0 %
-5.41 [ -14.59, 3.78 ]
Total (95% CI)
189
IV,Fixed,95% CI
IV,Fixed,95% CI
207

-100
-50
Favours 2D
50
100
Favours 3D
108
Analysis 7.6. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 6 Duration of hospitalization.

Review:

Study or subgroup
FQ 2D
Mean
Difference
FQ 3D
Weight
Mean(SD)
Mean(SD)
Chinh 1997 VNM
47
7.6 (1.4)
53
7.8 (1.6)
45.4 %
-0.20 [ -0.79, 0.39 ]
Vinh 1996 VNM
53
12.1 (2.3)
47
12.7 (3.5)
11.3 %
-0.60 [ -1.78, 0.58 ]
Vinh 2005 VNM
89
7.6 (2.17)
107
8 (2.11)
43.2 %
-0.40 [ -1.00, 0.20 ]
100.0 %
-0.33 [ -0.73, 0.06 ]
Total (95% CI)
189
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
207

-4
-2
Favours 2D
Favours 3D
109
Analysis 7.7. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 7 Serious adverse events.
Review:

Study or subgroup
FQ 2D
Fq 3D
n/N
n/N
Chinh 1997 VNM
0/47
0/53
Not estimable
Vinh 1996 VNM
0/53
0/47
Not estimable
Vinh 2005 VNM
2/89
1/107
100.0 %
2.40 [ 0.22, 26.08 ]
189
207
100.0 %
2.40 [ 0.22, 26.08 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 2 (FQ 2D), 1 (Fq 3D)

0.005
0.1
Favours 2D
10
200
Favours 3D
Analysis 7.8. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 8 Non-serious adverse events.
Review:

Study or subgroup
Fluoroquinolone 2D
Fluoroquinolone 3D
n/N
n/N
Vinh 1996 VNM
0/53
2/47
Vinh 2005 VNM
0/89
0/107
142
154
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
100.0 %
0.18 [ 0.01, 3.61 ]

Not estimable
100.0 %
0.18 [ 0.01, 3.61 ]
Total events: 0 (Fluoroquinolone 2D), 2 (Fluoroquinolone 3D)

0.01
0.1
Favours FQ 2D
10
100
Favours FQ 3D
110

Review:

Outcome: 1 Relapse
Study or subgroup
FQ 3D
FQ 5D
n/N
n/N
0/79
1/75
100.0 %
0.32 [ 0.01, 7.65 ]
79
75
100.0 %
0.32 [ 0.01, 7.65 ]
Tran 1995 VNM
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 3D
10
100
Favours 5D
111
Analysis 8.2. Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 2 Fever Clearance time.
Review:

Outcome: 2 Fever Clearance time
Mean
Difference
Study or subgroup
FQ 3D
N
Mean(SD)
Mean(SD)
Tran 1995 VNM
103
60 (21.6)
92
72 (21.6)
Total (95% CI)
FQ 5D
103
Weight
Mean
Difference
100.0 %
-12.00 [ -18.07, -5.93 ]
100.0 %
-12.00 [ -18.07, -5.93 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
92

-100
-50
Favours 3D
50
100
Favours 5D
Review:

Study or subgroup
Tran 1995 VNM
Total (95% CI)
FQ 3D
FQ 5D
n/N
n/N
Risk Ratio
Weight
14/214
8/211
100.0 %
1.73 [ 0.74, 4.03 ]
214
211
100.0 %
1.73 [ 0.74, 4.03 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.05
0.2
Favours 3D
20
Favours 5D
112
Analysis 9.1. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 1 Microbiological Failure.

Review:

Outcome: 1 Microbiological Failure
Study or subgroup
Unal 1996 TUR
FQ 5D
FQ 7D
n/N
n/N
1/22
0/24
100.0 %
3.26 [ 0.14, 76.10 ]
22
24
100.0 %
3.26 [ 0.14, 76.10 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 5D
10
100
Favours 7D

Review:

Outcome: 2 Relapse
Study or subgroup
Unal 1996 TUR
FQ 5D
FQ 7D
n/N
n/N
1/22
0/24
100.0 %
3.26 [ 0.14, 76.10 ]
22
24
100.0 %
3.26 [ 0.14, 76.10 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 5D
10
100
Favours 7D
113
Review:

Mean
Difference
Study or subgroup
FQ 5D
N
Mean(SD)
Mean(SD)
Unal 1996 TUR
22
74.4 (1)
24
81.6 (1)
Total (95% CI)
FQ 7D
22
Weight
Mean
Difference
100.0 %
-7.20 [ -7.78, -6.62 ]
100.0 %
-7.20 [ -7.78, -6.62 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
24

-100
-50
50
Favours 5D
100
Favours 7D
Review:

Study or subgroup
FQ 5D
FQ 7D
n/N
n/N
3/22
4/24
100.0 %
0.82 [ 0.21, 3.25 ]
22
24
100.0 %
0.82 [ 0.21, 3.25 ]
Unal 1996 TUR
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 5D
10
100
Favours 7D
114

Review:

Study or subgroup
FQ 7D
FQ 10D or 14D
n/N
n/N
Risk Ratio
Weight
Kalo 1997 ALB
0/15
0/15
Not estimable
Total (95% CI)
15
15
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 0 (FQ 7D), 0 (FQ 10D or 14D)

0.01
0.1
Favours 7D
10
100
Favours 10 or 14D

Review:

Outcome: 2 Relapse
Study or subgroup
FQ 7D
FQ 10 or 14D
n/N
n/N
Risk Ratio
Weight
Kalo 1997 ALB
0/15
0/15
Not estimable
Total (95% CI)
15
15
Not estimable
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 0 (FQ 7D), 0 (FQ 10 or 14D)

0.01
0.1
Favours 7
10
100
Favours 10 or 14D
115
Analysis 11.1. Comparison 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days), Outcome
1 All outcomes.
Review:
Comparison: 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days)

Outcome: 1 All outcomes
Study or subgroup
Gatifloxacin
Chloramphenicol
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Clinical failure (need for rescue medication or persistence of fever until day 10)
Arjyal 2011 (1)
8/177
10/175
0.79 [ 0.32, 1.96 ]
0/175
4.94 [ 0.24, 102.24 ]
2 Microbiological failure (blood culture +ve on day 8)

Arjyal 2011
2/177
3 Relapse (reappearance of culture confirmed or syndromic enteric fever on days 11 to 31)

Arjyal 2011
4/177
7/175
0.56 [ 0.17, 1.90 ]
0/154
1/156
0.34 [ 0.01, 8.22 ]
99/418
0.58 [ 0.44, 0.78 ]

Arjyal 2011 (2)
6 Other adverse events (selected gastrointestinal adverse events)
Arjyal 2011 (3)
59/426
0.005
0.1
Favours gatifloxacin
10
200
(1) This data includes culture positive patients only

(2) 3 patients in the chloramphenicol arm had positive stool cuture during convalescence but only one remained positive at 3 months
(3) Note: The adverse event data from Arjyal 2010 includes all randomized patients including test negative
116

Review:

Outcome: 1 Relapse
Study or subgroup
FQ 10D
FQ 14D
n/N
n/N
Risk Ratio
Weight
Alam 1995 BGD
0/35
2/34
100.0 %
0.19 [ 0.01, 3.91 ]
Total (95% CI)
35
34
100.0 %
0.19 [ 0.01, 3.91 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.005
0.1
Favours 10D
10
200
Favours 14D
Review:

Mean
Difference
Study or subgroup
FQ 10D
FQ 14D
Mean(SD)
Mean(SD)
Alam 1995 BGD
35
100.8 (45.6)
34
117.6 (62.4)
Total (95% CI)
35
Weight
Mean
Difference
100.0 %
-16.80 [ -42.65, 9.05 ]
100.0 %
-16.80 [ -42.65, 9.05 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
34

-100
-50
Favours 10D
50
100
Favours 14D
117
Review:

Study or subgroup
FQ 10D
FQ 14D
n/N
n/N
Risk Ratio
Weight
Alam 1995 BGD
4/35
9/34
100.0 %
0.43 [ 0.15, 1.27 ]
Total (95% CI)
35
34
100.0 %
0.43 [ 0.15, 1.27 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

0.01
0.1
Favours 10D
10
100
Favours 14D
Analysis 13.1. Comparison 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days), Outcome 1 All
outcomes.
Review:
Comparison: 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days)

Study or subgroup
Gatifloxacin
Cefixime
n/N
n/N
Risk Ratio
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Clinical failure (need for rescue medication or persistence of fever until day 7)
Pandit 2007 NPL (1)
1/88
19/70
0.04 [ 0.01, 0.31 ]
2 Relapse (fever plus +ve blood culture within 1 month of successful treatment)
Pandit 2007 NPL
6/51
0.20 [ 0.04, 0.93 ]
0/88
1/70
0.27 [ 0.01, 6.43 ]
2/92
1/77
1.67 [ 0.15, 18.11 ]
1/77
19.25 [ 2.66, 139.30 ]
2/87
3 Microbiological failure (blood culture +ve on day 10)

Pandit 2007 NPL
Pandit 2007 NPL (2)
5 Other adverse events (may be incompletely reported)

Pandit 2007 NPL (3)
23/92
0.001 0.01 0.1

10 100 1000
Favours cefixime
118
(1) This data includes culture positive patients only

(2) 2 patients developed severe vomiting requiring IV reydration in the gatifloxacin group, 1 patient died in the cefixime group
(3) 23 patients in the gatifloxacin developed vomiting, 1 patient in the cefixime group developed a rash
Analysis 14.1. Comparison 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days), Outcome 1 All
outcomes.
Review:
Comparison: 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days)

Study or subgroup
Gatifloxacin
Azithromycin
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Clinical failure (need for rescue medication of persistence of fever until day 10)
6/145
6/140
0.97 [ 0.32, 2.92 ]
2 Relapse (symptoms and signs of typhoid fever within 1 month of successful treatment)
Dolecek 2008 VNM
0/127
8.35 [ 0.45, 153.52 ]
2/145
3/140
0.64 [ 0.11, 3.79 ]
1/137
0/131
2.87 [ 0.12, 69.82 ]
1/141
1.94 [ 0.18, 21.21 ]
4/137
3 Microbiological failure (blood culture +ve on day 7 to 9)

Dolecek 2008 VNM
6 Other adverse events (may be incompletely reported)
2/145
0.005
0.1
10
200
(1) This data incudes culture positive patients only

(2) Only 1 patient was shown to be a persistent carrier during follow-up
(3) One patient developed vomiting on day 3 and 1 diarrhoea on day 4 in gatifloxacin group, one patient developed a rash in azithromycin group
119
APPENDICES
Appendix 1. Detailed Search Strategy
Search set
CIDG SRa
CENTRAL
MEDLINEb
EMBASEb
typhoid fever
fluoroquinolone
QUINOLINES
QUINOLONE
typhoid
DERIVED ANTIINFECTIVE AGENT
enteric fever
amifloxacin
QUINOLONES
fluoroquinolones
paratyphoid fever
balofloxacin
ANTI-INamifloxacin
FECTIVE AGENTS,
QUINOLONE
enteric fever
Salmonella typhi
cetefloxacin
ANTI-INFECTIVE BALOFLOXACIN
AGENTS, FLUOROQUINOLONE
Salmonella typhi
Salmonella paratyphi
ciprofloxacin
FLUOROQUINOLONES
balofloxacin
clinafloxacin
fluoroquinolones
CETEFLOXACIN
enoxacin
amifloxacin
cetefloxacin
fleroxacin
balofloxacin
CIPROFLOXACIN
gatifloxacin
cetefloxacin
ciprofloxacin
10
gemifloxacin
CIPROFLOXACIN
CLINAFLOXACIN
11
grepafloxacin
ciprofloxacin
clinafloxacin
12
irloxacin
clinafloxacin
ENOXACIN
13
levofloxacin
ENOXACIN
enoxacin
14
lomefloxacin
enoxacin
FLEROXACIN
15
moxifloxacin
FLEROXACIN
fleroxacin
16
nordifloxacin
fleroxacin
GATIFLOXACIN
17
norfleroxacin
gatifloxacin
gatifloxacin
18
norfloxacin
gemifloxacin
GEMIFLOXACIN
LILACSb
typhoid fever
120
(Continued)
19
ofloxacin
grepafloxacin
gemifloxacin
20
oxociprofloxacin
irloxacin
GREPAFLOXACIN
21
pefloxacin
levofloxacin
grepafloxacin
22
premafloxacin
lomefloxacin
IRLOXACIN
23
prulifloxacin
moxifloxacin
irloxacin
24
rufloxacin
nordifloxacin
LEVOFLOXACIN
25
sitafloxacin
norfleroxacin
levofloxacin
26
sparfloxacin
NORFLOXACIN
LOMEFLOXACIN
27
temafloxacin
norfloxacin
lomefloxacin
28
tosufloxacin
ofloxacin
MOXIFLOXACIN
29
trovafloxacin
oxociprofloxacin
moxifloxacin
30
1/29 - OR
PEFLOXACIN
NORDIFLOXACIN
31
typhoid fever
pefloxacin
nordifloxacin
32
enteric fever
premafloxacin
NORFLEROXACIN -
33
paratyphoid fever
prulifloxacin
norfleroxacin
34
Salmonella typhi
rufloxacin
NORFLOXACIN
35
sitafloxacin
norfloxacin
36
31/35 - OR
sparfloxacin
OFLOXACIN
37
30 and 36
temafloxacin
ofloxacin
38
tosufloxacin
OXOCIPROFLOXACIN
39
trovafloxacin
oxociprofloxacin
40
1 - 39/OR
PEFLOXACIN
41
TYPHOID FEVER
pefloxacin
42
typhoid fever
PREMAFLOXACIN
121
(Continued)
43
enteric fever
premafloxacin
44
PARATYPHOID
FEVER
PRULIFLOXACIN
45
paratyphoid fever
prulifloxacin
46
SALMONELLA TY- RUFLOXACIN

PHI
47
Salmonella typhi
rufloxacin
48
SALMONELLA
PARATYPHI
SITAFLOXACIN
49
sitafloxacin
50
typhus
SPARFLOXACIN
51
41 - 50/OR
sparfloxacin
52
40 and 51
TEMAFLOXACIN
53
limit 52 to human
temafloxacin
54
tosufloxacin
55
1 - 54/OR
56
TYPHOID FEVER
57
typhoid fever
58
enteric fever
59
PARATYPHOID
FEVER
60
paratyphoid fever
61
SALMONELLA TY- PHI
62
Salmonella typhi
63
SALMONELLA
PARATYPHI
64
122
(Continued)
65
typhus
66
56 - 65/OR
67
55 and 66
68
limit 67 to human
a Cochrane
Infectious Diseases Group Specialized Register.

terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre
2011); upper case: MeSH or EMTREE heading; lower case: free text term.
b Search
Appendix 2. Description of drug resistance by study
Comparison
Trial
FluoroCristiano
quinolone vs 1995 ITA
chloramphenicol
Participants
Culture
positive
(site)
60
60 (blood)
enrolled and
randomized
S. Typhi/ Number
MDR
Paratyphi
(%)a with defined asb
MDR
Number
Notes on re(%*)a NaRc sistance
60/0
0
Fluoroquinolone:
30
Chloramphenicol: 30
Not stated
No
resistance to
chloramphenicol,
ampicillin, or cotrimoxazole
Not stated
MIC range
of pefloxacin
was < 0.016
to 0.5
Not stated
MIC range
of ciprofloxacin was < 1
Gasem 2003 100

55 (blood 50/5
IDN
enrolled and and/or bone
randomized marrow)
Not stated
No
resistance to
chloramphenicol
12.
8% resistant
to ampicillin
or
cotrimoxazole
Arjyal 2011
2(0.
58%) both
in the gatifloxacin arm
Resistance
251(72.2%)
to all first
line antibiotics: chloramphenicol, amoxicillin and
trimetho-
853
352 (blood)
enrolled and
randomized
124/53 Fluoroquinolone
125/50
Chloramphenicol
Two
S. Paratyphi
isolates were
chloramphenicol resistant.
123
(Continued)
prim-sulphamethoxazole
Gottuzzo
1992 N/A
Not stated
98
(not Not stated
stated)
Morelli
1992 ITA
156
156 (blood)
enrolled and
randomized
Phongmany
2005 LAO
107
50 (blood)
enrolled and
randomized
Not stated
Not stated
Not stated
156/0
Not stated
MIC range
for chloramphenicol
was 0.5 to 4
mg/L
Not stated
MIC
ranges were:
ofloxacin 0.
03 to 0.25;
pefloxacin 0.
06 to 0.5; ciprofloxacin 0.016 to
0.063;
enoxacin 0.
25;
norfloxacin 0.
063 to 0.25
50/0
Fluoroquinolone:
27
Chloramphenicol: 23
3/50 (6%)
Fluoroquinolone:
1/27
Chloramphenicol: 2/
23
Resistant to 0
all 3 (chloramphenicol, ampicillin, co-trimoxazole)
Chloramphenicol resistance: 4/
50
Fluoroquinolone:
1/27
Chloramphenicol: 3/
23d
Ampicillin:
2/50
Fluoroquinolone:
1/27
Chloramphenicol: 1/
23
Co-trimoxazole: 1/50
Fluoroquinolone:
0/27
Chloramphenicol: 1/
23
124
(Continued)
Yousaf 1992 85
85
(not Not stated
PAK
enrolled and stated)
randomized
Not stated
Not stated
Not stated
Not stated
Not stated
FluoroFlores 1994
quinolone vs MEX
ampicillin
Not stated
FluoroHajji 1988
quinolone vs MAR
cotrimoxazole
77
42
28/4
0
enrolled and (blood and/ (from blood
randomized or stool)
culture)
Not stated
0
1 isolate resistant to cotrimoxazole was in
pefloxacin
group
53
40 (blood)
enrolled and
randomized
Not stated
Not stated
No
resistance to cotrimoxazole
16 were resistant
to chloramphenicol
153 (58%)
of 263 S. Typhi
Fluoroquinolone:
87/137
Azithromycin: 66/126
Resistant to
253 (96%)
of 263 S. Typhi
Fluoroquinolone:
132/137
Azithromycin: 121/
126
All
5
S. Paratyphi
were susceptible
68 (78%) of
87
Fluoroquinolone:
35
Azithromycin: 33
Resistant to
46 (52.3%; of 87 strains
evaluated)
Fluoroquinolone:
21
Azithromycin: 25
Limson
1989 PHL
FluoroDolecek
quinolone vs 2008 VNM
azithromycin
40
(not 40/0
stated)
Fluoroquinolone:
20
Ampicillin:
20
Not stated
28/12
0
Fluoroquinolone:
15/5
Co-trimoxazole: 13/7
358
288 (blood 282/5
enrolled and or
bone Fluororandomized marrow)
quinolone:
144/1
Azithromycin: 138/4
Chinh 2000 97
91 (blood)
VNM
enrolled and
randomized
86/2
125
(Continued)
Girgis 1999
EGY
123
64 (62 by 60/4
enrolled and blood, 2 by Fluororandomized stool)
quinolone:
34/2
Azithromycin: 26/2
21/64
(33%)
Fluoroquinolone:
15
Azithromycin: 6
Resistant to Not stated

Parry 2007
VNM
160
130 (blood
enrolled and and/or bone
randommarrow)
ized (excluding fluoroquinolone
with
azithromycin combination arm)
125/0
Fluoroquinolone:
63/0
Azithromycin: 62/0
110/125
(88%)
Fluoroquinolone:
57/63
Azithromycin: 53/62
Resistant to
138
82 (blood)
enrolled and
randomized
82/0
Fluoroquinolone:
38
Cefixime:
44
70 (85%)
S. Typhi: 32
S. Paratyphi:
38
Resistant to 0
and tetracycline
119/50
Fluoroquinolone:
65/27
Cefixime:
54/23
Resistant to
60
47
enrolled and (44 by blood
randomized and/or bone
marrow, 3
by stool)
41/6
Fluoroquinolone:
21/1
Ceftriaxone:
20/5
26 (55%)
Fluoroquinolone:
14
Ceftriaxone:
12
Resistant to 0
and tetracycline
43 enrolled 42 (blood)
and 42 randomized
42/0
Fluoroquinolone:
20
22 (52%)
Fluoroquinolone:
11

all 3 (chloramphenicol, ampi-
FluoroPhuong
quinolone vs 1999 VNM
cefixime
Pandit 2007 390

169 (blood)
NPL
enrolled and
randomized
FluoroSmith 1994
quinolone vs VNM
ceftriaxone
Wallace
1993 BHR
117/125
(94%)
Fluoroquinolone:
62/63
Azithromycin: 55/62
136/163
(83%)
Fluoroquinolone:
71/89
Cefixime:
65/74
126
(Continued)
Ceftriaxone: Ceftriaxone: cillin, co-tri22

11
moxazole)
DifAlam 1995
ferent dura- BGD
tions of fluoroquinolone
76
72 (blood or 61/8
enrolled and bone
Fluororandomized marrow)
quinolone
10-day: 30/
5
Fluoroquinolone
14-day: 31/
3
36/69
(52%)
Fluoroquinolone
10-day: 18
Fluoroquinolone
14-day: 18
Resistance
to all drugs
used
conventionally against
S. Typhi and
S. Paratyphi
30
30 (blood)
(ampicillinresistant)
enrolled and
randomized
30/0
12/30
(40%)

Chinh 1997 107

101 (blood)
VNM
enrolled and
randomized
95/5
Fluoroquinolone
2-day: 43/4
Fluoroquinolone
3-day: 52/1
75/95
(79%)
Fluoroquinolone
2-day: 35
Fluoroquinolone
3-day: 40
Resistant to
and tetracycline
Tran 1995
VNM
438
en- 228 (blood)
rolled, 425
randomized
207/19
189
(2
other FluoroSalmonella) quinolone
3-day: 98
Fluoroquinolone
5-day: 91
Unal 1996
TUR
46 random- 46 (blood 19/27

ized
and/or bone Fluoromarrow)
quinolone
5-day: 8/14
Fluoroquinolone
7-day: 11/
13
Kalo 1997
ALB
6/46 (13%)
Fluoroquinolone
5-day: 3
Fluoroquinolone
7-day: 3
5/69 (7%)
Fluoroquinolone
10-day: 2
Fluoroquinolone
14-day: 3
(derived
from data
presented
for MIC for
ciprofloxacin)
5/95 (5%)
Fluoroquinolone
2-day: 1
Fluoroquinolone
3-day: 4
Resistant to Few
standard an- NaR strains
tibiotics
present,
number not
stated
Resistant to
Not stated
MIC for pefloxacin was
0.06 to 1
127
(Continued)
Vinh 1996
VNM
108
100 (blood)
enrolled and
randomized
100/0
Fluoroquinolone
2-day: 53
Fluoroquinolone
3-day: 47
84
Fluoroquinolone
2-day: 46
Fluoroquinolone
3-day: 38
Resistant to
and tetracycline
13 (13%)
Fluoroquinolone
2-day: 6
Fluoroquinolone
3-day: 7
Vinh 2005
VNM
235
202 (blood)
enrolled and
randomized
196/0
Fluoroquinolone
2-day: 89
Fluoroquinolone
3-day: 107
176/196
(90%)
Fluoroquinolone
2-day: 82/
89
Fluoroquinolone
3-day: 94/
107
Resistant to
4/161 (2. 5%)

Fluoroquinolone
2-day: 1/72
Fluoroquinolone
3-day: 3/89
MDR: multiple-drug-resistant strain; MIC: minimum inhibitory concentration; NaR: nalidixic acid resistant strain.
a Calculation: number with MDR or NaR divided by number culture positive.
b As stated or implied in text of report.
c Or MIC of fluoroquinolone if available (all ranges in mg/L).
d These participants were switched to fluoroquinolone when organisms were found resistant to assigned drug.
Appendix 3. Definitions of outcomes
Comparison
Specific FQ
FluoroCiprofloxacin
quinolones vs
chloramphenicol
Ciprofloxacin
Trial
Clinical fail- Microbiologure

ical failure
Relapse
Fever clear- Convaance time

lescent Faecal
Carriage
Gasem 2003
IDN
Not
Blood
culafebrile within ture positive at
7 days of treat- days 3 and 5
ment
Reappearance
of fever after
defervescence
during hospitalization (under 14 days)
DeOutcome not
fined as first reported
day that temperature fell <
37.5 C and
remained below that level
for 48 hours
Gottuzzo
1992 N/A
One partici- Outcome not Not defined

pant who de- reported
veloped a gastrointestinal
bleed in first
Outcome not Outcome not

reported
reported
128
(Continued)
36
hours of treatment was considered a failure
Ciprofloxacin
Morelli 1992
ITA
Persistence of Outcome not Not defined

fever
reported
Not defined
3 weeks during follow up
Ciprofloxacin Rizvi 2007

and Ofloxacin PAK
and
Cotrimoxazole
No significant Persistence of
response to S. Typhi and
therapy
S. Paratyphi
on day 7 or 14
or recurrence
of the initial
pathogen
at the end of
treatment
Ofloxacin
Phongmany
2005 LAO
Continuation Outcome not Outcome not Time

from Outcome not
of symptoms reported
reported
onset of treat- reported
and tympanic
ment
temperature >
to first record38 C for >
ing of a tym10 days after
panic temperstart of treatature < 38 C
ment or con(~ 37.5 C axtinuation
illary) which
of symptoms
remained < 38
and high tymC
panic temperfor 48 hours
ature > 39 C
(Fever Clearat 7 days after
ance
Time
start of treat38)
ment or development of
signs of severe
disease
Pefloxacin
Cristiano
1995 ITA
Not defined
Blood culture
positive at end
of treatment
(at 15 days)
Reapperance
Reported but Not reported
of signs and not defined
symptoms after initial disappearance
for at least 48
hours or reappearance
of pathogen in
blood
and/
or stool within
three weeks after end of
treatment
Within
Not defined
30 days after
end of treatment (the 2
relapses were
30 days
129
(Continued)
blood culture
negative
and were stool
culture
positive before
relapse)
Gatifloxacin
FluoroOfloxacin
quinolone vs
ampicillin
FluoroPefloxacin
quinolone
vs co-trimoxazole
Ciprofloxacin
Arjyal 2011
Not
specifically defined but denoted as part
of composite
end point of
treatment failure
Positive blood
culture for S.
Typhi
or S.Paratyphi
A on day 8
Reappearance of culture
confirmed or
syndromic enteric fever on
or after day 11
to day 31 in
patients who
were initially
categorized
as successfully
treated
Flores 1994
MEX
Persistence of signs
and symptoms
of infection 57 days after the
end of treatment
Persistence of Outcome not Outcome not Outcome not

S. Typhi from reported
reported
reported
blood culture
5-7 days after the end of
treatment
Yousaf 1992
PAK
Persistence or
reappearance of all presenting signs
and symptoms
or increase in
severity of at
least 1 sign
or symptom or
both
PersisOutcome not Outcome not Outcome not

tence of base- reported
reported
reported
line pathogen
at day 14
Hajji 1988
MAR
Fever
and Positive culpresence
of tures at days 4,
clinical symp- 15, and 30
toms and positive cultures
Limson 1989
PHL
Persistent
fever or no improvement in
symptoms af-
Reappearance
of fever, clinical symptoms,
and/or bacteraemia at days
4, 15, and 30
Time from the

first
dose of treatment given
until temperature was fro
the first time
37.5
o C and the patient remained
afebrile for at
least 48 hours
Faecal carriage
at the follow
up visits at 1, 3
and 6 months
Time for rectal 30 days

temperature
to be sustained
37.5 C for
2 days
Positive
Outcome not Outcome not Outcome not
cultures dur- reported
reported
reported
ing and after
therapy
130
(Continued)
ter 5 days of
therapy
FluoroGatifloxacin
quinolone vs
azithromycin
Dolecek 2008 PersisVNM

tence of fever
and symptoms
2 days after the
end of treatment, i.e. on
day 10
Positive blood
culture on day
7 to 9 after the
start of treatment
Symptoms
and signs suggestive of
typhoid fever
within
1 month after
completion of
treatment
(only culture
positive data
extracted)
Time
from
start of antibiotic treatment
to
when the axillary temperature first fell
37. 5 C
and remained
there for at
least 48 hours
Ciprofloxacin
Chinh 2000
VNM
Persistence of fever
and symptoms
for > 5 days after the end of
treatment or development of
severe complications (severe
gastrointestinal bleed, intestinal perforation, visible
jaundice, myocarditis, renal
failure, shock,
coma) during
treatment requiring change in
treatment
Isolation of S.
Typhi/S. Paratyphi
from
blood or other
sterile site after
completion of
treatment
Recurrence of signs
and symptoms
suggestive
of enteric fever
after discharge
at 4 to 6 weeks
of follow up
Time
Days 2 to 3
from start of after end of
treatment un- treatment
til body temperature fell <
37.5 C and
remained at
37.5 C for 48
hours
Ciprofloxacin
Girgis 1999
EGY
Lack of resolution of symptoms by day

7 or development of major complications of typhoid fever after 5 days of
therapy
Blood culture
positive for S. Typhi/S. Paratyphi on day 10
Recurrence of fever
with
signs/
symptoms of
typhoid fever
in 4 weeks of
therapy completion and culture positive
First day on 1 month

which maximum temperature 38
C and at this
level for 48
hours
Follow ups at
1, 3, and 6
months; participants who attended at least
2 consecutive
follow-up visits were evaluated
131
(Continued)
Ciprofloxacin
FluoroOfloxacin
quinolone vs
cefixime
Gatifloxacin
Parry 2007
VNM
Presence of fever
and at least 1
other typhoid
related symptom
for
> 7 days after
start of treatment or development of severe complications
(severe gastrointestinal bleeding,
perforation, visible
jaundice, myocarditis, pneumonia, renal failure,
shock,
or altered consciousness level, during treatment
requiring change in
therapy
Isolation of S.
Typhi
or S. Paratyphi
from blood or
sterile site after
completion of
treatment
Recurrence of
symptoms or
signs suggestive of enteric
fever within 4week
period after patient had been
discharged
well from hospital
accompanied by
positive blood
culture for S.
Typhi or S.
Paratyphi
Time
from start of
treatment until body temperature
reached 37.
5 C and remained at this
for 48 hours
After
end
of initial 7-day
treatment and
before
hospital discharge
(with
isolate having
the same susceptibility pattern as original
isolate)
Phuong 1999
VNM
Deterioration in
clinical condition or failure
of resolution
of symptoms
requiring further treatment
Blood culture
positive for S.
Typhi
after
completion of
treatment
Symptoms suggestive of typhoid

fever with a
positive blood
or bone marrow culture up
to 4 weeks after discharge
Time
from onset of
treatment until fever was
37.5 C or below for at least
24 hours
1
month mostly,
few seen after a
longer period
Pandit 2007
NPL
Any
Blood culture
severe compli- positive
on
cation, persis- day 10
tence
of
fever (> 38 C)
, persistence of
symptoms for
> 7 days after
start of treat-
Fever
with
blood culture
positive within a
month
of completing
treatment (patients given
rescue treat-
Time
1 month
to 1st drop in
oral temperature 37.5
C remaining
37.5 C for
48 hours
132
(Continued)
FluoroOfloxacin
quinolone vs
ceftriaxone
Ciprofloxacin
Different durations of fluoroquinolones
ment, requiring additional

or rescue treatment
ment or prolonged treatment were excluded)
Smith 1994
VNM
Acute treat- Blood culture

ment failure as positive at day
continu8
ing symptoms
and fever for at
least 7 days after starting the
treatment regimen
Recurrence of fever
and symptoms
in the period
up to 6 weeks
after discharge
with a positive blood or
bone marrow
culture b
Wallace 1993
BHR
Fever > 38 C Blood culture

after 7 days of positive at day
therapy
3
or who deteriorated clinically after 5
full days
ReadNot defined
mission for typhoid within
2 months of
discharge with
stool or blood
culture
positive
for S. Typhi of
the same antibiogram
(1 relapse had
both stool and
blood culture
positive)
Alam 1995
BGD
Lack of improvement or
deterioration
in clinical condition during
treatment
Growth
of S. Typhi or
S. Paratyphi in
blood in first
follow up (day
3)
Recurrence of
febrile illness
with growth of
S. Typhi or S.
Paratyphi
in blood culture after initial cure
Kalo 1997
ALB
Fever at day 5
Blood culture Relapse

Outcome not Days 7 to 12
positive at day during hospi- reported
4
talization and
2 month follow up
Time to defer- 4 to 6 weeks

vescence to <
37.5 C for at
least 48 hours
Days 1, 7, and
28; results unclear
Time to return Second

of
follow up (at 2
oral tempera- months)
ture to 37.5
C after initiation of therapy
and remained
so for at least
48 hours
133
(Continued)
Chinh 1997
VNM
Continuing fever and

symptoms for
7 days after the
start of treatment or deterioration in
clinical condition before 7
days that warranted further
treatment
Blood or bone
marrow culture positive
after end of
treatment before discharge
Recurrent fever
and symptoms
with
bone marrow
or blood culture
positive mostly up
to 6 weeks after discharge b
Tran 1995
VNM
Persistent fever and

symptoms for
> 7 days after
start of treatment
Blood or bone
marrow
culture positive after end
of treatment
Symptoms
Not defined
since
study
with positive
blood culture
Unal 1996
TUR
ContinFailued or worsen- ure to eradiing symptoms cate organism

after 7 days of
therapy
Similar signs
and symptoms
after
apparently being cured for
a month (the
participant
had a positive
stool culture)
Time for tem- 1 month; reperature to be sults unclear

below 37.5 C
for at least 48
hours
Vinh 1996
VNM
Continued fever and

symptoms for
> 7 days after
treatment
Positive blood
culture
or
bone marrow
culture for S.
Typhi taken >
48 hours after
the last dose of
treatment
Recurrence of fever
and symptoms
with
positive blood or
bone marrow
culture up to 6
weeks (26 participants followed up to
12 weeks) after discharge
Time
from
start of treatment until axillary temperature fell below
37.5 C and
remained below this level
for > 48 hours
Vinh 2005
VNM
Fever
and symptoms
persisting for
7 days after
start of therapy, or devel-
Blood culture
positive for same
organism
between 7 to
28 days after
Recurrence of
typhoid fever
symptoms
usually with positive blood cul-
PeImriod from start mediately afof treatment ter treatment

until temperature remained
at or below 37.
Time at which
fever fell below 37.5 C
for at least 24
hours
Usually
6 weeks (occasionally up to
12 weeks)
1 month
4 to 6 weeks
(for 66 participants); and
at 3 months
(for 26 participants)
134
(Continued)
opment of se- completion of ture after hos- 5 C for at

vere or com- therapy
pital discharge least 48 hours
plicated
until 28 days
disease
post discharge
(only data for
blood cultureconfirmed relapse
extracted)
S. Typhi/S. Paratyphi: Salmonella enterica serovar Typhi/Paratyphi.
a All definitions as stated or implied by trial authors.
b With an organism with the same sensitivity pattern, ribotype, and plasmid profile as the original isolate.
Appendix 4. Serious adverse events
Comparison
Trial
Intervention
Control
None reported
None reported
Gastrointestinal bleeding(1)
Severe leukopenia(1)
Cristiano 1995 ITA
Skin rash (1)
None
Morelli 1992 ITA
Ciprofloxacin: Rash (2)

Pefloxacin: Rash (2)
None
Gasem 2003 IDN
Ciprofloxacin: None
Chloramphenicol:
Intestinal
bleeding (1 participant)
Rash (1)
Phongmany 2005 LAO
None
None
Rizvi 2007 PAK
Ciprofloxacin: palpitation (1) ????

Ofloxacin: palpitation (2)
palpitation (1)
Arjyal 2011
none
Oral candidiasis (4)
Fluoroquinolone vs co-trimox- Hajji 1988 MAR

azole
Limson 1989 PHL
Pefloxacin: Phototoxicity (1)
Rash (1)
None
None
Fluoroquinolone vs ampicillin/ Yousaf 1992 PAK

amoxicillin
Flores 1994 MEX
None reported
None reported
None reported
None reported
Fluoroquinolone vs chloram- Yousaf 1992 PAK

phenicol
Gottuzzo 1992 N/A
135
(Continued)
Fluoroquinolone vs cefixime
Phuong 1999 VNM
Ofloxacin: Death (1)
None
Pandit 2007 NPL
Excessive vomiting requiring

intravenous therapy(1)
Death(1)
Not reported
Not reported
None reported
None reported
Fluoroquinolone vs ceftriaxone Wallace 1993 BHR

Smith 1994 VNM
Fluoroquinolone vs azithromy- Chinh 2000 VNM
cin
Gastrointestinal bleeding (1 partic- Gastrointestinal bleeding (1 participant)

ipant)
Dolecek 2008 VNM
Gastrointestinal bleeding (4 partic- None

ipants)
Rash (1)
Girgis 1999 EGY
None
None
Parry 2007 VNM
None
None
Appendix 5. Non-serious adverse events
Comparison
Trial
Fluoroquinolone vs Yousaf 1992 PAK

chloramphenicol
Clinical adverse events a
Laboratory adverse events a
Intervention
Intervention
Control
3 reported adverse 4 reported adverse None reported

events. No specific events. No specific
event
event
Gottuzzo 1992 N/A Rash (1)
None
None
Control
None reported
leukopenia (11)
Cristiano 1995 ITA Nausea

(3) Mild and transient None
, mild and transient epigastric pain (5)
epigastric pain (3),
transient skin rash
(1)
None
Morelli 1992 ITA
not reported
Ciprofloxacin: Skin Diarrhoea (3), Mild Not reported

rash (2), dizziness epigastric pain (6),
(4), flushing (4), abdominal pain (4)
epigastric pain (8)
Ofloxacin:
Mild epigastric pain
(4), flushing (4),
headache (2)
136
(Continued)
Pefloxacin:
Skin
Rash (2), headache
(6), epigastric pain
(10)
Gasem 2003 IDN
None
skin rash (1)
None reported
None reported
Phongmany 2005
LAO
None reported
None reported
None reported
None reported
Rizvi 2007 PAK
Ciprofloxcin: Nausea/
vomiting (10), diarrhoea (1), heartburn
(2), headache/dizziness (3), anorexia
(1), palpitation (1)
Ofloxacin: Nausea/
vomiting
(6), abdominal pain
(1), heartburn (4),
headache (2), palpitation (2)
ChloNone reported
ramphenicol: Nausea/vomiting(4), abdominal pain (1),
cough (1), palpitation(1), anaemia(2)
None reported
Arjyal 2011
Number
of
patients with events
(59/426)
Abdominal pain (8)
, acne (0),
anorexia (1), diarrhoea (5),
dizziness (2), nausea
(9), oral candidiasis
(0), vomiting (35),
weakness (0)
Number
of
patients with events
(99/418)
Abdominal pain (11)
, acne (2), anorexia
(9), diarrhoea (24),
dizziness (11), nausea (26), oral candidiasis (4), vomiting (36),
weakness (4)
Photosensitivity (1)
Generalized rash (1) Mild and transient Mild and transient

rise in transaminases rise in transaminases
(2)
(3)
Ciprofloxacin
Abdominal discomfort/diarrhoea (1)
Dizziness (1)
CotrimoxNone
azole: nausea or abdominal discomfort
(5)
Pruritus (1)
Fluoroquinolone vs Hajji 1988 MAR

cotrimoxazole
Limson 1989 PHL
Fluoroquinolone
Yousaf 1992 PAK
vs ampicillin/amoxicillin
Dysglycaemiab
Dysglycaemiab
Hyperglycaemia: 1/ Hyperglycaemia: 0/
400
402
Hypoglycaemia: 2/ Hypoglycaemia: 2/
400
402
Leucopeniac
Leucopeniac
Grade 1:1/188
Grade 1:4/403
Grade 2: 1/188
Grade 2: 3/403
3 reported adverse 11 events reported None reported

events. No specific to be mostly diar-
None
None reported
137
(Continued)
event
Flores 1994 MEX
rhoea, pruritus and

rashes
Moderate nausea (1) Epigastric pain (1)
None reported
None reported
Not reported
Not reported
Fluoroquinolone vs Phuong 1999 VNM Not reported

cefixime
Pandit 2007 NPL
Nausea/occasional
vomiting (23)
Not reported
Erythematous skin None

rash(1)
None
Fluoroquinolone vs Wallace 1993 BHR

ceftriaxone
Smith 1994 VNM
Not reported
Not reported
Not reported
Not reported
Pruritus (1)
skin rashes (2)
None
None
Fluoroquinolone vs Chinh 2000 VNM

azithromycin
Ofloxacin:
nausea (1); vomiting (3)
; abdominal pain (4)
; skin rash (0)
Azithromycin: nau- Ofloxacin: mild ele- Azithromycin: mild

sea (5); vomiting (5) vation in mean elevation in mean
; abdominal pain (4) transaminase levels transaminase levels
; skin rash (1)
Dolecek
VNM
Fluoroquinolones
2days vs 3days
Fluoroquinolone
3days vs 5days
2008 Gatifloxacin: vomit- Azithromycin: jaun- Gating (1); Diarrhoea dice (2)
ifloxacin: mild ele(1)
vations in median
transaminase levels
Azithromycin: nausea or vomiting (6);
lightheadedness (2);
dry throat or mouth
(3); loose stools (3);
constipation (2)
Girgis 1999 EGY
Ciprofloxacin: nausea or vomiting (4);

lightheadedness (2);
dry throat or mouth
(4); loose stools (3);
constipation (2)
Parry 2007 VNM
Ofloxacin: joint dis- Azithromycin: joint Ofloxacin: none

comfort
discomfort (1)
Azithromycin: none
Chinh 1997 VNM
2D: none
3D: none
2D: none
3D: none
Vinh 1996 VNM
2D: none
3D: none
2D: none
3D: none
Vinh 2005 VNM
2D: none
3D: none
2D: no significant 3D: no significant

increases in liver en- increases in liver enzymes
zymes
Tran 1995 VNM
3D: Insomnia (5), 5D: Insomnia (5), 3D: none

dizziness (5) epigas- dizziness (1) vomittric pain (2), nausea ing (1), rash (1)
(1), headache (1)
Ciprofloxacin:
thrombocytosis (1)
; mild increases in
aspartate transaminases levels (3)
Azithromycin: mild
elevations
in median transaminase levels
Azithromycin: thrombocytosis (4); mild increase in aspartate
amino transaminase
levels (2)
5D: none
138
(Continued)
Fluoroquinolone
5days vs 7days
Unal 1996 TUR
5D: Nausea and 7D: Nausea and 5D: None

vomiting (3)
vomiting (3)
7D:
Increased transaminase levels (1)
Fluoroquinolone
7days vs 10days
Kalo 1997 ALB
7D Nausea/abdom- 10D: Nausea/ ab- 7D: None

inal discomfort
dominal discomfort
10D:None
Fluoroquinolone
10days vs 14 days
Alam 1995 BGD
10D: Eleven events

occurred in four patients
namely
headache, malaise,
dizziness, insomnia,
skin rash, pruritus,
lethargy, weakness
14D:
10D:
Moderate
Eighteen events oc- eosinophilia (5)
curred in nine patients
namely
headache, malaise,
abdominal pain, dizziness, nausea, oral
mucosal pain, insomnia, photosensitivity, vomiting, vertigo, joint pain palpitation, restlessness
14D: Transient elevation of urea and

creatinine (1)
Moderate
eosinophilia (3)
a Number
of participants with adverse event.

grade 2 defined as non-fasting plasma glucose level between 161 and 250 mg/dL; hypoglycaemia grade 2 defined as
non-fasting plasma glucose between 40 and 54 mg/dL
c
Leucopenia GRADE 1:WBC count 2000-2500/mm3 and GRADE 2: WBC count 1500-1999/mm3
d Total number with listed adverse events was four but no specific number for each group
b Hyperglycaemia
WHATS NEW
Last assessed as up-to-date: 1 February 2011.
Date
Event
Description
5 October 2011
Amended
Amendment made to acknowledgements
139
HISTORY
Protocol first published: Issue 4, 2003
Review first published: Issue 2, 2005
Date
Event
Description
9 August 2011
New citation required and conclusions have changed
A new search was conducted and the structure of the review

altered. In previous versions the different types of fluoroquinolone were combined in the meta analyses in spite of
their dissimilarity. In this revision, we have analysed them
separately with the intention of highlighting the effectiveness of different fluoroquinolones
CONTRIBUTIONS OF AUTHORS
Emmanuel Effa and Zohra Lassi , considered the new search, extracted and enter data, updated the risk of bias assessment and Dave
Sinclair co-extracted data, assisted with restructuring and writing up of the review. Julia Critchley provided technical inputs and assisted
with the restructuring of the review. Prof Zulfiquar Bhutta, Prof Paul Garner, and Piero Olliaro guided the restructuring, examined the
data, provided technical direction and edited the manuscript. All authors contributed to the final manuscript.
DECLARATIONS OF INTEREST
None known. Professor ZA Bhutta has been part of trials of treatment for typhoid therapy in children, none of which involved
fluoroquinolones.
SOURCES OF SUPPORT
Internal sources
University of Calabar Teaching Hospital, Calabar, Nigeria.
Nigeria branch of South African Cochrane centre, Nigeria.
External sources
No sources of support supplied
140
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We changed the intervention from Fluoroquinolone antibiotic to Different fluoroquinolone antibiotic excluding norfloxacin or other
fluoroquinolones not currently in use
NOTES
The Contact Editor for this review was Dr Mical Paul.
INDEX TERMS
Medical Subject Headings (MeSH)
Anti-Bacterial Agents [adverse effects; therapeutic use]; Fluoroquinolones [adverse effects; therapeutic use]; Norfloxacin [therapeutic
use]; Paratyphoid Fever [ drug therapy]; Randomized Controlled Trials as Topic; Treatment Outcome; Typhoid Fever [ drug therapy]
MeSH check words

Adult; Child; Humans
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Cochrane Database of Systematic Reviews

Fluoroquinolones for treating typhoid and paratyphoid fever

Analysis 6.6. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization. . . .

Fluoroquinolones for treating typhoid and paratyphoid fever

Editorial group: Cochrane Infectious Diseases Group.

PLAIN LANGUAGE SUMMARY

Description of the condition

Diagnosis and treatment

The diagnosis of enteric fever can be difficult due to the non

Description of the intervention

How the intervention might work

Why it is important to do this review

Relapse; defined as the recurrence of symptoms with a

Fever clearance time; defined as the time in hours/days

Criteria for considering studies for this review

Clinical failure; defined as development of complications,

Serious adverse events; defined as adverse events leading to

Search methods for identification of studies

Searching other resources

We also checked the reference lists of all retrieved trials and

outcomes, such as clinical failure, we extracted the total number

Data collection and analysis

Assessment of risk of bias in included studies

Reference lists and review authors personal collections

Two review authors (EEE and ZSL) independently assessed the

Measures of treatment effect

Subgroup analysis and investigation of heterogeneity

We planned to investigate heterogeneity by conducting subgroup

Dealing with missing data

We planned to assess the robustness of the data by performing a

Assessment of reporting biases

Results of the search

Nine trials were conducted in Vietnam, two trials in each of Italy,

Trials that included patients diagnosed clinically tended to report

Three trials were exclusively in children (Vinh 1996 VNM;

There were considerable variations regarding the time points at

Risk of bias in included studies

Incomplete outcome data

Other potential sources of bias

Fluoroquinolones versus first-line antibiotics

Comparison 1. Fluoroquinolones versus chloramphenicol

Overall, a seven-day course of any fluoroquinolone appears at

and the fluoroquinolones used (ciprofloxacin and ofloxacin)

Relapse and convalescent faecal carriage

Fever clearance and duration of hospitalisation

Comparison 3. Fluoroquinolones versus amoxicillin or

Two small studies conducted in the 1990s, found that ofloxacin

Clinical and microbiological response

Relapse and convalescent faecal carriage

Fever clearance and duration of hospitalization

time to fever clearance for gatifloxacin (92 hours vs 138 hours, P

Comparison 4. Fluoroquinolones versus cefixime

Serious adverse events were low in two trials comparing ofloxacin

Comparison 5. Fluoroquinolones versus ceftriaxone

Two studies, conducted almost 20 years ago, compared five to

Clinical and microbiological response

Clinical and microbiological response

The proportion of clinical failures was lower with fluoroquinolones

Fever clearance time

There was a statistically significant reduction in the duration of

Comparison 6. Fluoroquinolones versus azithromycin

Azithromycin was superior to ofloxacin in reducing clinical

Clinical and microbiological response