723934

review-article2017
AOPXXX10.1177/1060028017723934Annals of PharmacotherapyWood and Swanson

Review Article
Annals of Pharmacotherapy

An Update on Aerosolized Antibiotics for

110
The Author(s) 2017
Reprints and permissions:
Treating Hospital-Acquired and Ventilator- sagepub.com/journalsPermissions.nav
DOI: 10.1177/1060028017723934
https://doi.org/10.1177/1060028017723934

Associated Pneumonia in Adults journals.sagepub.com/home/aop

G. Christopher Wood, PharmD1, and Joseph M. Swanson, PharmD1

Abstract
Objective: A significant percentage of patients with hospital-acquired pneumonia (HAP) and ventilator-associated
pneumonia (VAP) have poor outcomes with intravenous antibiotics. It is not clear if adding aerosolized antibiotics
improves treatment. This review is an update on using aerosolized antibiotics for treating HAP/VAP in adults. Data
Sources: PubMed search using the terms aerosolized antibiotics pneumonia, nebulized antibiotics pneumonia, and
inhaled antibiotics pneumonia. Reference lists from identified articles were also searched. Study Selection and Data
Extraction: Clinical studies of aerosolized antibiotics for treating HAP/VAP in adults from July 2010 to March 2017.
This article updates a previous review on this topic written in mid-2010. Data Synthesis: The size and quality of studies
have improved dramatically in the recent time period compared to previous studies. However, there still are not large
randomized controlled trials available. Colistin and aminoglycosides were the most commonly studied agents, and the most
common pathogens were Pseudomonas and Acinetobacter. The clinical efficacy of adding aerosolized antibiotics was mixed.
Approximately half of the studies showed better outcomes, and none showed worse outcomes. Aerosolized antibiotics
appear to be relatively safe, though pulmonary adverse events can occur. Attention to proper administration technique
in mechanically ventilated patients is required, including the use of vibrating plate nebulizers. Conclusions: Adding
aerosolized antibiotics to intravenous antibiotics may improve the outcomes of adult patients with HAP/VAP in some
settings. It seems reasonable to add aerosolized antibiotics in patients with multidrug-resistant organisms or who appear
to be failing therapy. Clinicians should pay attention to potential adverse events and proper administration technique.

Keywords
pneumonia, antibiotics, critical care, administration, aminoglycosides, bacterial infections, ventilators, mechanical, hospital-
acquired infections

Introduction aerosolized antibiotics to maximize drug concentrations at

Treating hospital-acquired pneumonia (HAP) and ventila-
tor-associated pneumonia (VAP) continues to be a chal-
lenge in critically ill patients. HAP/VAP is the most common
life-threatening infection in the intensive care unit (ICU)
and is associated with significant increases in length of stay,
days of mechanical ventilation, health care costs, and, in
some patients, increased mortality.1 Developing more effec-
tive antibiotic treatment regimens is a critical unmet need in
HAP/VAP management. For example, in a large meta-anal-
ysis of randomized controlled trials (RCTs) of VAP treat-
ment, 37% of the patients failed therapy with intravenous
(IV) antibiotics alone.2 Treatment is also complicated by the
increasing development of multidrug-resistant (MDR)
Pseudomonas, Acinetobacter, and enterobacteriacae, which
are associated with high mortality and have very few treat-
ment options.3
One potential factor for treatment failure is poor penetra-
tion of IV antibiotics into the lung. Thus, adding adjunctive
the site of infection has become more widely used over the
past 2 decades. Recent surveys suggest that approximately
50% of ICUs have used aerosolized antibiotics for VAP.4
Current guidelines suggest that aerosolized antibiotics can
be added for patients with highly resistant organisms or in
patients who are failing therapy.1 However, they also note
lack of high-quality data in this area, which include effi-
cacy, safety, and optimal dosing and administration.1
Critically, there are no large RCTs to date that show if
aerosolized antibiotics are effective. Data prior to 2011
were mostly retrospective studies without control groups.5
These were essentially large case series that seemed to show
1
University of Tennessee Health Science Center, Memphis, TN, USA
Corresponding Author:
G. Christopher Wood, Department of Clinical Pharmacy, University of
Tennessee Health Science Center College of Pharmacy, 881 Madison,
Room 335, Memphis, TN 38104, USA.
Email: cwood@uthsc.edu
2 Annals of Pharmacotherapy 00(0)
acceptable clinical responses in patients with highly resis-
tant or recurrent infections. However, without control
groups it is very difficult to determine if there was any ben-
efit from adding aerosolized antibiotics.
Fortunately, since that time the number and quality of
studies has increased significantly. Recent studies tend to be
larger, have control groups, and some have even used aero-
solized monotherapy without IV antibiotics. In addition,
there are new data optimizing delivery of aerosolized anti-
biotics in mechanically ventilated patients as well as safety
information. As such, the objective of this article is to pro-
vide an updated review on the use of aerosolized antibiotics
for treating HAP and VAP in adults.
Methods
Our investigative group published reviews in this area in
2000, 2007, and 2011.5-7 The current article is an update of
studies published after our last review was completed in
mid-2010. Studies were identified for this article using the
following search terms in PubMed: aerosolized antibiotics
pneumonia, nebulized antibiotics pneumonia, and aerosolized colistin, only one of the RCTs did so. In 2010,
inhaled antibiotics pneumonia. Reference lists from arti-
cles were used to identify more publications. Studies were
included from July 2010 through March 2017 if they
described the use of aerosolized antibiotics for the treat-
ment of HAP or VAP in adult patients, or the optimization
of the delivery of aerosolized antibiotics in mechanically
ventilated adult patients. Because ~90% of patients with
HAP are mechanically ventilated (ie, they have VAP), and
because the vast majority of patients in the studies discussed
had VAP, this article will focus on treating VAP. The new
HAP/VAP guidelines make an effort to differentiate HAP
and VAP; however, none of the identified studies analyzed
HAP and VAP separately.1 Only English language articles
were included; however, one English language abstract of
an article in Spanish was included based on relevance. Case
reports were not included.
Studies were informally graded according to the quality
of pneumonia diagnosis and the quality of the administra-
tion technique used. For pneumonia diagnosis, high qual-
ity included quantitative cultures obtained bronchoscopically,
medium quality included endotracheal aspirates with
semiquantitative cultures, and low quality included all
other culture techniques or a lack of cultures. For adminis-
tration technique, a major problem is the lack of detail
given, such that many studies were graded unclear.
Otherwise, high quality included either the use of an
advanced nebulizer (eg, vibrating plate) or a traditional neb-
ulizer with multiple elements of proper technique (eg, nebu-
lizer placement in the circuit, humidification turned off
during nebulization). Medium quality included less infor-
mation than the high quality studies. No studies were
considered low quality. Because the reporting of colistin
dosing varies by geographic location, all doses of colistin
are expressed in mg of colistin base activity (30 mg colistin
base activity = 80 mg colistimethate sodium prodrug =
approximately 1000000 units of colistimethate sodium
prodrug).8
Efficacy of Aerosolized Antibiotics
In the 2011 review, there were 23 studies and case reports
included from 1967 to 2010 that encompassed at total of
495 patientsmostly without controls.5 Since that time, 18
studies were identified with a total of 1751 patients, the vast
majority of which are from RCTs or observational studies
with control groups (Table 1).9-26 Thus, the ability to deter-
mine if there is a benefit from aerosolized antibiotics has
improved dramatically. The reader is referred to Table 1 for
details on study design and outcomes.
Randomized Controlled Trials
Interestingly, while most of the literature as a whole studied
Rattanaumpawan etal published a reasonably sized RCT (n
= 100) of aerosolized colistin added to standard IV antibiot-
ics for Pseudomonas and Acinetobacter HAP/VAP.9 Clinical
success was not significantly improved by aerosolized ther-
apy; however, microbiologic success was improved. This
study used low-dose colistin (75 mg BID) as opposed to
higher-dose colistin used in some other studies (150 mg
BID). Also, the administration technique was not well
described. It is unknown if these factors impacted the lack
of clinical benefit observed.
The other RCTs primarily studied aminoglycosides
(AMGs). Niederman etal published a Phase II pharmacoki-
netic RCT of a preservative-free aerosolized amikacin
product added to IV therapy.11 The administration technique
was excellent; however, no improvement was reported with
aerosolized therapy in this relatively small study (total n =
55), although the very high response rate in the control
group would make it very difficult to see a benefit for aero-
solized therapy. The study by Palmer etal took a somewhat
different approach.12 They included long-term ventilated
patients with bacterial colonization or pneumonia and
added aerosolized AMGs or vancomycin (the only study to
use that drug) to IV therapy depending on sensitivity results.
Microbiologic response and resistance development were
significantly improved in the study group. However, 2
important limitations are that clinical cure was not reported
and it is not clear which patients had pneumonia.
Perhaps the most important RCT to date was the recently
published IASIS trial of aerosolized amikacin/fosfomycin
administered with a high-quality technique.13 The primary
outcome was the change in clinical pulmonary infection
score, not clinical cure, though secondary composite
 Table 1. Recent Studies of Aerosolized Antibiotics for Treating HAP/VAP.
Quality of Diagnosis/
Study Patients Study Group Control Group Administration Results (Study vs Control) Adverse Events

Randomized controlled trials

Rattanaumpawan PA and AB VAP (50% N = 51 N = 49 Moderate/unclear Clinical success: 51% vs 53.1% (P = 0.84) Bronchospasm: 7.8% vs 2%
(2010)9 MDR) IV abx per C&S + aero IV abx per C&S Micro success: 60.9% vs 38.2% (P = 0.03) (P = 0.36)
colistin 75 mg Q12 Nephrotoxicity: 25.5% vs
22.4% (P = 0.82)
Niederman (2012)11 GNB VAP with MDR N = 36 N = 19 Low/high Clinical cure: 84% vs 87.5% (P = 0.467) Mild bronchospasm in 5.5%
risk factor IV abx based on C&S + aero IV abx based on C&S Micro cure: 68.8% vs 62.5% (P > 0.99) of study patients possibly
amikacin product 400 mg Mortality: 27.8% vs 10.5% (P = NR) or probably related to
Q12 or Q24 study drug
Palmer (2014)12 Long-term vent N = 24 N = 18 Low/high Micro response for all: 96% vs 9% (P > Resistance development:
patients with signs IV abx + aero AMG or aero IV abx based on C&S 0.0001); for MDR: 88% vs 9% (P < 0.0001) 12.5% vs 55% (P = 0.03)
of infection vanc (based on C&S) Mortality similar: 25% vs
11% (P = 0.43)
Kollef (2017)13 GNB VAP N = 71 N = 72 Low/high No difference in a number of clinical Bronchospasm: 1 patient in
IV carbapenem + aero IV carbapenem + endpoints each group
amikacin 300 mg/ aero placebo Micro response: 83% vs 59% (P = 0.002)
fosfomycin 120 mg BID Resistance development: 1.4% vs 11.1% (P
= 0.02)
Lu (2011)10 PA VAP (non-MDR) N = 20 N = 20 High/high Clinical success: 70% vs 55% (P = 0.33) No bronchospasm; hypoxia
Aero CTZ 15 mg/kg Q3 + IV CTZ + IV Mortality: 10% vs 5% (P = 0.55) in 15% of study group
aero amikacin 25 mg/kg/d amikacin
Observational studies with control groups
Korbila (2010)14 PA, AB, and Klebsiella N = 78 N = 43 Unclear/unclear Clinical cure: 79.5% vs 60.5% (P = 0.025) No serious adverse events
VAP Colistin IV 560 mg/d (mean) Colistin IV 512 mg/d Mortality: 39.7% vs 44.2% (P = 0.63) reported
+ aero colistin 80 mg Q12 (mean)
Ekren (2016)24 MDR PA and AB N = 69 N = 210 Unclear/unclear Clinical response: 66.7% vs 47.6% (P = 0.008) Nephrotoxicity: 63.8% vs
HAP (% VAP NR) Colistin IV 225 mg/d + aero Colistin IV 300 mg/d Micro response: 59.4% vs 41% (P < 0.001) 61.9% (P = 0.89)
(dose NR) Mortality similar: 65.2% vs 60.8% (P = 0.57)
Tumbarello (2013)21 MDR PA, AB, KP N = 104 N = 104 High/unclear Clinical cure: 69.2% vs 54.8% (P = 0.03) AKI during treatment: 25%
VAP Colistin IV 8 mg/kg/d + aero Colistin IV 8 mg/kg/d Micro cure: 63.4% vs 50% (P = 0.08) vs 22% (P = 0.62)
80 mg Q8 MV days: 8 vs 12 (P = 0.001)
Mortality: 43.3% vs 46.1 (P = 0.67)
Arnold (2012017 PB/AB VAP Total N = 19 N = 74 High/high 30-Day mortality (0% vs 17.6%) (P = 0.063), No adverse events
IV abx based on C&S IV abx based on C&S but better for APACHE II > 16 subgroup requiring discontinuation
(N = 10 tobramycin 300 mg report
BID, N = 9 colistin 150 mg
BID)
Doshi (2013)20 MDR PA, AB, KP N = 44 N = 51 Mixed (high and Clinical cure: 54.5% vs 39.2% (P = 0.13) NR
(95% VAP) Colistin IV 2.6 mg/kg/d Colistin IV 2.4 mg/ medium)/unclear Micro cure: 44.4% vs 40.7% (P = 0.8)
(mean) + aero 75-150 mg kg/d (mean) Mortality: 40% vs 70.4% (P = 0.055)
Q12 Aero showed improved clinical cure in
patients with high-quality cultures: 57.1% vs
31.3% (P = 0.033)
(continued)

3
4
Table 1. (continued)

Quality of Diagnosis/
Study Patients Study Group Control Group Administration Results (Study vs Control) Adverse Events

Demirdal (2016)23 AB HAP (67.5% VAP) N = 43 N = 80 High/unclear Clinical success: 37.5% vs 37.2% (P = 0.9) No neurotoxicity or
IV colistin 150 mg Q12 + IV colistin 150 mg Micro success: 50% vs 46.5% (P = 0.7) pulmonary events;
aero colistin 75 mg Q12 Q12 nephrotoxicity: 53.8% vs
48.8% (P = 0.6)
Chen (2014)22 MDR AB HAP or N = 81 N = 54 Mixed (high and Micro eradication: 54.3% vs 29.6% (P = NR
colonization IV abx per C&S + aero IV abx per C&S moderate)/unclear 0.005)
colistin 60 mg Q12 Mortality: 32.1% vs 40.7% (P = 0.3)
Kalin (2012)18 AB VAP N = 29 N = 16 Unclear/unclear Clinical cure: 14% vs 38% (P = 0.13) Nephrotoxicity: 41% vs
Colistin IV 2.5 mg/kg Q12 or Colistin IV 2.5 mg/kg Micro cure: 76% vs 67% (P = 0.73) 19% (P = 0.19)
Q6 + aero 150 mg Q12 Q12 or Q6 Mortality: 55% vs 44% (P = 0.65)
Naesens (2011)15 MDR PA HAP (30% N = 9: IV colistin 5 mg/kg/d N=5 Moderate/unclear Clinical cure: 86.7% (aero groups combined) No difference in
VAP) divided Q6-Q8 + aero IV colistin 5 mg/kg/d vs 40% (P = 0.07) nephrotoxicity; no serious
colistin 160 mg TID divided Q6-Q8 Mortality: 20% vs 100% (P = 0.003) adverse events reported
N = 6: Aero colistin 160 mg Clinical cure: 6/6 in aero only group
TID
Prez-Pedrero MDR AB VAP N=6 N = 12 Clinical cure: 100% vs 75% (P = NS) NR
(2011)16 IV colistin + aero colistin IV colistin (dose NR)
(doses NR)
Lu (2012)19 MDR PA/AB VAP Total N = 43: N = 122 High/high Clinical cure: 67.4% vs 66.4% (P = 0.65) Nephrotoxicity: 12% vs 8%
(study) vs Sensitive N = 28: Colistin aero 167 IV beta-lactam + IV (P = 0.47)
PA/AB VAP mg Q8 AMG or quinolone
(control) N = 15: Colistin aero 167 mg (3 d)
Q8 + IV AMG 3 d
Observational studies without control groups
Choi (2014)25 MDR AB (% VAP N = 8: IV abx per C&S + None Moderate/unclear Favorable response: 8/8 IV + aero group; 2/4 No bronchospasm or
NR) aero colistin 150 mg Q12 aero monotherapy group neurotoxicity; fever/
N = 4: Aero colistin 150 mg rash in 1 patient;
Q12 nephrotoxicity: 25%
Hsieh (2016)26 MDR AB HAP N = 57 None Unclear/unclear Clinical success: 57.8% Nephrotoxicity: 22.2%
(46.5% VAP) IV abx per C&S + aero Micro success: 78.9%
colistin 60 mg Q12 Mortality: 46.7%
Improved clinical success in patients with
eradication: 57.8% vs 25% (P = 0.04)

Abbreviations: VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia; PA, Pseudomonas aeruginosa; AB, Acinetobacter baumannii; MDR, multidrug-resistant; abx, antibiotics; C&S, culture and sensitivity report;
aero, aerosolized; CTZ, ceftazidime; GNB, Gram-negative bacilli; NR, not reported; NS, not statistically significant; AMG, aminoglycoside.
Wood and Swanson 5
clinical endpoints were reported. Unfortunately, no clinical
outcomes were improved with aerosolized therapy when
added to IV, though microbiological response and resis-
tance development among the VAP pathogens did improve
significantly. Factors that might have influenced the mostly
negative outcome of this study include the use of unconven-
tional outcome measures and inclusion of low-quality cul-
tures that might have allowed patients in the study that did
not actually have pneumonia.
The last RCT was a highly unusual study of aerosolized
ceftazidime/amikacin monotherapy (ie, no IV antibiotics)
versus IV ceftazidime/amikacin in 40 patients with
Pseudomonas VAP.10 This was unusual because almost all
studies up to that point had used aerosolized antibiotics in
addition to IV therapy, the use of a -lactam/AMG combi-
nation regimen, and very high doses. However, this study is
notable because of the high quality of aerosolized adminis-
tration and VAP diagnosis.10 There was no difference in out-
comes between groups, which suggested that high-dose
aerosolized combination therapy might be effective without
using IV antibiotics. This result needs to be confirmed in
larger RCTs.
Observational Studies With Control Groups
By far the most common design among this group of studies
was comparing IV colistin plus aerosolized colistin (study
group) to IV colistin alone (control). Most studies focused
on MDR Pseudomonas, MDR Acinetobacter, and occasion-
ally other MDR Gram-negatives such as Klesiella, though
some studies included a mix of MDR and sensitive patho-
gens. Most studies reported improved clinical responses in
groups receiving aerosolized therapy. Impressively, 2 rather
large studies by Korbila etal and Ekren etal both found
significantly improved clinical success by adding aerosol-
ized colistin to IV (total n = 121 and 279, respectively).14,24
However, perhaps the most important study in this group
was by Tumbarello etal.21 Strengths of this study include a
control group that was matched for age and severity of ill-
ness, large size (n = 208), high-quality VAP diagnosis, and
all patients having MDR pathogens. Clinical success was
significantly improved and duration of mechanical ventila-
tion was shorter with aerosolized colistin added to IV.
Two other studies failed to show an overall benefit for
aerosolized antibiotics, but did show a benefit in subgroups.
Arnold etal did not report the outcome of clinical success,
but they did report significantly decreased mortality for
adding aerosolized therapy (colistin or tobramycin) to IV in
a subgroup of more seriously ill patients with APACHE II
scores >16.17 This study is notable because the quality of
techniques for VAP diagnosis and aerosol administration
were high, and because mortality is a very difficult outcome
to affect in VAP. Similarly, Doshi etal found significantly
improved clinical success when adding aerosolized colistin
to IV in a subgroup of patients with high-quality cultures.20
This provides some reassurance that the treatment might
have been effective because that subgroup represents
patients who are the most likely to truly have had pneumo-
nia. These 2 studies are obviously limited by the use of sub-
group analyses.
However, another group of studies did not show any
additional benefit to adding aerosolized colistin to IV. The
studies by Chen etal and Demirdal etal were good sized
(total n = 135 and 123, respectively) and both studied
MDR Acinetobacter.22,23 The Demirdal etal article used a
matched control group.23 However, both suffered from
much lower clinical or microbiological success rates in
both the study and control groups than most other studies.
This might indicate that they found a particularly difficult
patient population to treat. Strengths of these 2 studies are
large size and medium to high VAP diagnostic quality;
however, limitations are unclear administration technique
and perhaps the low doses of aerosolized colistin used.
The relevance of the Chen etal study is more difficult to
determine because they showed improved microbiologic
success but did not report clinical success.22 A third study
was similar in that it focused on Acinetobacter VAP and
also found very poor success rates in both groups.18
However, this study was less important because it was
smaller (n = 45) and did not have clearly described diag-
nostic or administration techniques.
Two other negative studies were limited by very small
sample size. Naesens etal (n = 20) found a numerically
impressive improvement in clinical success for Pseudomonas
HAP/VAP that did not reach statistical significance.15
Interestingly, this study included 6 patients who received
aerosolized colistin monotherapy without IV antibiotics; and
all 6 patients were clinical successes. In the second study,
Prez-Pedrero etal (n = 18) reported no difference in the
high success rates for Acinetobacter VAP in both groups.16
Thus, it would have been very difficult for a potential benefit
of aerosolized antibiotics to be seen.
Last in this group is another study of aerosolized mono-
therapy from the same investigative group that performed
the aerosolized monotherapy RCT.10 Patients in the study
group had MDR Pseudomonas or Acinetobacter VAP and
received either high-dose aerosolized colistin alone or aero-
solized colistin plus 3 days of IV aminoglycosides at the
beginning of treatment.19 Both these study groups were
combined for the outcome analysis. The combined study
group had similar clinical success and mortality to the con-
trol group of patients with sensitive Pseudomonas or
Acinetobacter VAP treated with IV therapy. Weaknesses of
the study include a relatively small size of the study group,
as well as the unusual treatment regimens. As with these
investigators RCT, strengths include the high quality of
VAP diagnosis and aerosol administration, which makes the
findings even more intriguing.
6 Annals of Pharmacotherapy 00(0)
Retrospective Studies Without Control Groups
As noted earlier, these used to be the most common type of
study in this field; however, now it is the rarest. Choi etal
added aerosolized colistin to IV therapy in 8 patients with
MDR Acinetobacter and all were successful.25 Interestingly,
an additional 4 patients were treated with aerosolized colis-
tin monotherapy and 2/4 had a positive outcome. This study
is limited by the very small size and the lack of reporting of
how many patients had VAP versus colonization. Hsieh etal
also studied patients with MDR Acinetobacter. In this mod-
erately sized study, the authors reported acceptable effi-
cacy.26 However, the interesting finding was that patients
who had microbiologic eradication of the organism had a
significantly higher clinical success rate. The utility of
microbiologic eradication as an outcome is questionable,
but in this study it was related to clinical success.
Summary of Efficacy Studies
Unfortunately, there are no large RCTs to give a clear indi-
cation if aerosolized antibiotics add to the treatment of VAP.
The future publication of the ongoing large Phase III RCTs
of an aerosolized amikacin product (INHALE 1 and 2 trials)
will provide critical data in this area.27,28 In the meantime,
with the publication of larger and better designed studies
since 2010, there are some indications that adding aerosol-
ized antibiotics might improve efficacy. Perhaps the most
relevant studies are those with larger total size (n > 75), a
control group, and that reported clinical cure or mortality as
the primary outcome (ie, higher quality studies). Of those
8 higher quality studies, 5 studies demonstrated improved
outcomes with aerosolized antibiotics,14,17,20,21,24 while 3
studies did not show a benefit.9,13,23
There was not an obvious pattern of success or failure in
the higher quality studies. The distribution of treated patho-
gens and the dose of aerosolized colistin was not clearly
different between the successful and unsuccessful high-
quality studies. However, it is interesting that the 2 studies
that used high doses17,20 were among the successful
studies,14,17,20,21 and both unsuccessful studies9,23 used low
doses. This suggests that the dose could matter. Interestingly,
there might be some question about how well AMGs per-
formed. The amikacin/fosfomycin trial was the one higher
quality RCT with AMGs and it was negative.13 The smaller
RCT with amikacin was also negative, but with limitations
described previously.11 On the other hand, AMGs contrib-
uted to the success seen in the higher quality Arnold etal
study and the smaller Palmer etal study.12,17
Importantly, 2 recent meta-analyses both suggest that
aerosolized antibiotics are beneficial. The first focused on
adjunctive colistin and included 1 RCT and 7 observational
studies with control groups totaling 690 patients.29
Aerosolized colistin was associated with improvements in
clinical cure (odds ratio [OR] = 1.57; 95% confidence inter-
val [CI] = 1.14-2.15; P = 0.006), microbiologic cure (OR =
1.61; 95% CI = 1.11-2.35; P = 0.01), and infection-related
mortality (OR = 0.58; 95% CI = 0.34-0.96; P = 0.04). The
second included 6 RCTs and 6 observational studies with
control groups that included all aerosolized antibiotics (not
just colistin) and a total of 812 patients.30 This analysis also
showed an improvement in clinical cure (risk ratio [RR] =
1.23; 95% CI = 1.05-1.43), but not in microbiologic cure
(RR = 1.24; 95% CI = 0.95-1.62) or mortality (RR = 0.90;
95% CI = 0.76-1.08).
Last, the use of aerosolized monotherapy is highly inter-
esting. If effective, using aerosolized therapy alone to treat
VAP could potentially be a major advance in limiting patient
exposure to antibiotics and aiding overall antimicrobial
stewardship. Two studies from one center suggest that aero-
solized monotherapy resulted in equivalent outcomes to
conventional IV therapy.10,19 Critically, these investigators
used high doses and very detailed administration tech-
niques, which might have optimized delivery of antibiotics
to the distal lung fields and improved efficacy. Others
reported success in 6/8 patients treated with aerosolized
monotherapy.15,25 Despite this initial success, at this time
aerosolized monotherapy should only be used in clinical tri-
als at centers where optimal administration technique is
used. This is because aerosolized delivery of drug to the
lung can be widely variable, and may provide low concen-
trations if proper technique is not used.5,31 Also, there is a
danger that localized antibiotic therapy may not provide
protection if the VAP pathogen spreads to the bloodstream.
In summary, based on the newer data from mid-2010 for-
ward, there is now far better evidence that adjunctive aero-
solized antibiotics might improve outcomes in VAP. There
are obvious weaknesses in this body of literature including
a lack of large RCTs, and differences in patient populations,
severity of illness, drug selection, dosing, and administra-
tion techniques. Regardless, in 2016 the updated IDSA/ATS
VAP guidelines modestly expanded their recommendation
to consider using aerosolized antibiotics in patients with
MDR pathogens, or who are not responding clinically to IV
therapy.1 This is similar to a 2010 recommendation from the
Society of Infectious Diseases Pharmacists.32 Such usage
seems reasonable based on current efficacy data. The data at
this time are not strong enough to warrant routine usage in
all patients with VAP, and indeed, aerosolized antibiotics
were not used that way in recent studies.
Interestingly, a recent European guideline on aerosolized
antibiotics in VAP gave a weak recommendation not to use
them based primarily on a lack of high-quality evidence and
concern over adverse events.33 We certainly agree that large
RCTs are needed. However, we respectfully disagree with
their recommendation. We feel that the severity of the prob-
lem (ie, poor HAP/VAP response rates), a lack of treatment
options for some organisms, the current state of knowledge
Wood and Swanson 7
that suggests additional efficacy over IV therapy alone, and
relative safety (see below) tilt the risk-benefit equation in
favor of using them in selected situations.
If the decision is made to use aerosolized antibiotics,
drug selection should based on sensitivity testing.
Aminoglycosides should probably be used when possible
because they may have a better safety profile (see below)
and to reserve colistin for the most resistant organisms.
There is much less experience using cephalosporins but that
class could be an option. We urge caution in aerosolizing
drugs for which there is not published experience. For
instance, imipenem is not physically suitable for aerosoliza-
tion and doripenem may cause adverse events.32
Regarding dosing, ideal doses of aerosolized colistin and
aminoglycosides are not known. Recent pharmacokinetic
data suggest that higher doses of colistin (ie, 150 mg rather
than 80 mg) are needed to generate optimal lung concentra-
tions.34 Thus, based on current data the following doses
seem reasonable for aerosolized therapy of HAP/VAP:
colistin 150 mg BID, gentamicin or tobramycin 300 mg
BID, or amikacin 400 mg BID.5,34-36 Regarding duration of
therapy, a pragmatic recommendation is to simply continue
the aerosolized antibiotic for the duration of IV therapy.
Most clinical trials described in this review treated patients
that way. Total duration of therapy (IV + aerosolized) was
typically 7 to 21 days depending on the patients course.
Many patients were treated longer than 7 days because they
had MDR organisms.
Safety of Aerosolized Antibiotics
Another important aspect of using aerosolized antibiotics is
safety. Older studies did not provide much information on
adverse events such as cough, bronchospasm, and the
potential for increased nephrotoxicity, ototoxicity, or neuro-
toxicity from systemic absorption of colistin or AMGs.5
There was also a suggestion that colistin might cause more
bronchospasm than AMGs and that pretreatment with alb-
uterol might make aerosolized antibiotics better tolerated.5
In the newer studies, none reported coughing from aero-
solized therapy. In the 4 studies that specifically commented
on bronchospasm, a total of 7/178 patients (3.9%) receiving
aerosolized antibiotics had bronchospasm compared to 2/160
patients (1.3%) in control groups.9-11,13 One study reported a
decrease of pO2 by 25% during administration in 3/20 (15%)
patients with one patient requiring discontinuation of
treatment.10 Seven studies reported rates of nephrotoxicity
with none showing an increase in the aerosolized antibiotic
group.9,14,18,19,21,23,24 This is not surprising because most data
suggest that aerosolized colistin or aminoglycosides do not
generate significant serum concentrations unless patients
have renal dysfunction.5,36-39 Even in patients with varying
degrees of renal dysfunction, 2 newer studies reported the
mean maximum serum concentrations of amikacin were
below the trough range for all groups (0.94-2.46 mg/L)37,38
Four other studies reported no significant adverse events of
any kind.14,15,17,25
Another potential issue is clogging of the ventilator filter
on the expiratory side of the circuit. The study that used
very high doses of aerosolized antibiotics also reported
clogging of the expiratory filter on the ventilator in 3/20
(15%) patients.10 It is unclear if this was due to the very
high doses used or some other reason. Others have reported
the same issue.40 The new European aerosolized adminis-
tration guidelines recommend changing the filter with every
dose.41 It is unclear how realistic this might be, but attention
should be paid to this issue.
There are also drug compounding factors that affect tol-
erability of an aerosolized medication (Table 2). Critically,
colistin needs to be used immediately on reconstitution to
avoid breakdown products that can cause potentially fatal
reactions. Solutions are best tolerated if they have a pH of
4.0 to 8.0, osmolarity of 150 to 1200 mOsm/L, and a sodium
concentration of 77 to 154 mEq/L.5 Thus, using normal
saline or half-normal saline as a diluent is preferred over
D5W or sterile water for inhalation or injection. Using a
preservative-free formulation that is designed for inhalation
such as the tobramycin for inhalation product could theo-
retically be better tolerated than aerosolizing the IV formu-
lation.5 However, such a comparison has not been made in
VAP. Last, the volume of drug solution should ideally match
the fill volume of the nebulizer (usually 3-5 mL).5 If the
dose is in more volume than can be accommodated in one
nebulizer fill, then the remaining solution can be adminis-
tered immediately after. Attention should be paid to make
sure the full dose is administered.
In summary, using aerosolized antibiotics appears to
have a good safety profile. They do not appear to increase
nephrotoxicity compared to IV antibiotics alone, though
larger studies will need to confirm this finding. It is impor-
tant to note that there is a small percentage of patients that
will have pulmonary adverse events. There was not a clear
difference in bronchospasm between colistin and AMGs in
more recent studies though previous data suggested that
colistin caused more coughing and bronchospasm.5 If aero-
solized antibiotic therapy is to continue in patients with pul-
monary adverse events, it is reasonable to pretreat those
patients with aerosolized albuterol though the efficacy of
this practice is not well studied.5
Optimizing Delivery in Mechanically
Ventilated Patients
Using proper administration technique dramatically
improves the percentage of an aerosolized dose that reaches
the lung.5,31,32,34 Thus, it is critical to use proper technique.
Unfortunately, a recent survey found that only 28% of ICUs
used optimal technique (as defined by the authors) when
8 Annals of Pharmacotherapy 00(0)

Table 2. Optimizing Aerosolized Delivery in Mechanically Ventilated Patients.

Nebulizer choice
Vibrating plate nebulizers are preferred over jet or ultrasonic nebulizers
The median mass aerodynamic diameter of the nebulizer should be 1-5 m (data available from manufacturer)
Nebulizer placement
15 cm from the endotracheal tube (ET) on the inspiratory limb of the ventilator circuit
VPNs can also be placed at the ET tube
Ventilator issues
Humidification should be turned off during administration of each dose
If jet nebulizers are used, the ventilator should only nebulize during inspiration
Optional: Change the expiratory ventilator filter after each dose
Optional: Use tidal volume 8 mL/kg, respiratory rate 12-15/minute, inspiratory-expiratory ratio 50%, inspiratory pause 20% (may
require sedation)
Drug formulation issues
Use normal saline or normal saline as a diluent
Compound doses so that they fill the nebulizer being used (see manufacturers information)
Drug solutions should have pH 4.0-8.0, osmolarity 150-1200 mOsm/L, and sodium content 77-154 mEq/L
Colistin must be compounded immediately before use to avoid severe adverse events
Consider pretreating with aerosolized albuterol and/or using a preservative-free product in patients with pulmonary adverse
events

administering aerosolized antibiotics.4 A detailed review of
this area is beyond the scope of this article, and the reader is
referred to more extensive reviews on administration
including a new European guideline.31,41 However, a sum-
mary of important administration issues is summarized in
Table 2 and below.
Recently, it has become clear that vibrating plate (also
called vibrating mesh) nebulizers (VPN) are preferred
over traditional jet nebulizers or more rarely used ultra-
sonic nebulizers because they deliver much more drug to
the lung.41-43 Compared to ultrasonic nebulizers, VPNs
do not have as big of an advantage in terms of delivery.
However, VPNs have other advantages in terms of ease
of use, cost, the ability to nebulize only on inspiration,
and they do not increase the temperature of the aerosol
fluid which could affect drug stability.5 Other factors
affecting delivery include nebulizer placement, circuit
humidification, and ventilator settings (Table 2). Another
advantage of VPNs is that they are not as affected by
placement or humidification as jet nebulizers.42,43 In
some cases (eg, imipenem) the drug formulation is not
suitable for aerosolization.32
Using ventilator settings that optimize delivery is a more
difficult issue. Experimental studies suggest that volume-
controlled ventilation with a tidal volume of 8 mL/kg, respi-
ratory rate of 12 to 15, a 50% I:E ratio, and 20% inspiratory
pause time generates the best delivery, and this is recom-
mended by the European guideline.41 However, this will be
not realistic in many patients. Such settings may not be well
tolerated and might require additional sedation. Also, some
patients may not tolerate a change from their current venti-
lator settings. A more pragmatic approach may be to use the
other drug compounding and administration techniques
recommended in Table 2 and administer doses to most
patients at their current ventilator settings.
Cost Implications of Aerosolized
Antibiotic Therapy
Costs of aerosolized antibiotics for treating HAP/VAP have
not been addressed in any of the studies described. These
potentially include direct costs for drug and nebulizer
acquisition, and indirect costs such as pharmacy time for
drug preparation, respiratory therapy time for drug adminis-
tration, patient monitoring, and ventilator filter changes,
and possibly nursing time for dealing for pretreating patients
for managing adverse events. Fortunately, the vast majority
of studies have used drugs that are available generically and
relatively inexpensive. Vibrating mesh nebulizers are also
inexpensive. If approved for use, it is unknown how much
specially formulated antibiotics for inhalation will cost but
it is safe to assume that they will be more expensive based
on the higher cost of the tobramycin for inhalation product
used in cystic fibrosis. However, if aerosolized antibiotics
are found to improve outcomes such as treatment failure,
length of stay, duration of mechanical ventilation, or mor-
tality, then the pharmacoeconomics should be favorable.
Such analyses will need to be performed.
Conclusions
The amount and quality of data on using adjunctive aerosol-
ized antibiotics for treating HAP/VAP has improved signifi-
cantly over the past 6 years. While the efficacy data are
mixed, a number of studies do show a benefit and none
show worse outcomes when adding aerosolized therapy to
Wood and Swanson 9
IV therapy. As such, the recommendations to consider add-
ing aerosolized colistin or aminoglycosides to patients with
MDR isolates or who are not responding well to IV therapy
alone in the updated HAP/VAP guidelines seem reasonable.
Attention should be paid to using good administration tech-
nique to optimize the delivery of drug to the lung, as well as
monitoring for adverse events. Clearly, large RCTs are
needed to determine the ultimate role of aerosolized antibi-
otics in HAP/VAP therapy.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Wood is a consultant for Bayer Pharma AG and was an
investigator for the INHALE 1 study of an aerosolized antibiotic
for pneumonia sponsored by Bayer Pharma AG. Dr Swanson was
an investigator for the INHALE 1 study of an aerosolized antibi-
otic for pneumonia sponsored by Bayer Pharma AG.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Kalil AC, Metersky ML, Klompas M, etal. Management of
adults with hospital-acquired and ventilator-associated pneu-
monia: 2016 clinical practice guidelines by the Infectious
Diseases Society of America and the American Thoracic
Society. Clin Infect Dis. 2016;63:e61-e111.
2. Aarts MAW, Hancock JN, Heyland D, McLeod RS, Marchall
JC. Empiric antibiotic therapy for suspected ventilator-asso-
ciated pneumonia: a systematic review and meta-analysis of
randomized trials. Crit Care Med. 2008;36:108-117.
3. Zilberberg MA, Shorr AF, Micek ST, Vazquez-Guillamet C,
Kollef MH. Multi-drug resistance, inappropriate initial anti-
biotic therapy and mortality in gram-negative severe sepsis
and septic shock: a retrospective cohort study. Crit Care.
2014;18:596.
4. Sol-Lleonart C, Rouby JJ, Chastre J, etal. Intratracheal
administration of antimicrobial agents in mechanically venti-
lated adults: an international survey on delivery practices and
safety. Respir Care. 2016;61:1008-1014.
5. Wood GC. Aerosolized antibiotics for treating hospital-
acquired and ventilator-associated pneumonia. Expert Rev
Anti Infect Ther. 2011;9:993-1000.
6. Wood GC, Boucher BA. Aerosolized antimicrobial therapy in
acutely ill patients. Pharmacotherapy. 2000;20:166-181.
7. Wood GC, Swanson JM. Aerosolized antibiotics for the
prevention and treatment of hospital-acquired pneumonia.
Drugs. 2007;67:901-914.
8. Ortwine JK, Kaye KS, Li J, Pogue JM. Colistin: under-
standing and applying recent pharmacokinetic advances.
Pharmacotherapy. 2015;35:11-16.
9. Rattanaumpawan P, Lorsutthitham J, Ungprasert P,
Angkasekwinai N, Thamlikitkul V. Randomized controlled
trial of nebulized colistimethate sodium as adjunctive therapy
of ventilator-associated pneumonia caused by gram-negative
bacteria. J Antimicrob Chemother. 2010;65:2645-2649.
10. Lu Q, Yang J, Liu Z, etal. Nebulized ceftazidime and amikacin
in ventilator-associated pneumonia caused by Pseudomonas
aeruginosa. Am J Respir Crit Care Med. 2011;184:106-115.
11. Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE,
Garca MS. BAY41-6551 achieves bactericidal tracheal
aspirate amikacin concentrations in mechanically ventilated
patients with gram-negative pneumonia. Intensive Care Med.
2012;38:263-271.
12. Palmer LB, Smaldone GC. Reduction of bacterial resistance
with inhaled antibiotics in the intensive care unit. Am J Respir
Crit Care Med. 2014;189:1225-1233.
13. Kollef MH, Ricard JD, Roux D, etal. A randomized trial of
the amikacin fosfomycin inhalation system for the adjunc-
tive therapy of gram-negative ventilator-associated pneumo-
nia: IASIS trial. Chest. 2017;151:1239-1246. doi:10.1016/j.
chest.2016.11.026.
14. Korbila IP, Michalopoulos A, Rafailidis P, Nikita D, Samonis
G, Falagas ME. Inhaled colistin as adjunctive therapy to
intravenous colistin for the treatment of microbiologically
documented ventilator-associated pneumonia: a comparative
cohort study. Clin Microbiol Infect. 2010;16:1230-1236.
15. Naesens R, Vlieghe E, Verbrugghe W, Jorens P, Ieven M. A
retrospective observational study on the efficacy of colistin
by inhalation as compared to parenteral administration for
the treatment of nosocomial pneumonia associated with mul-
tidrug-resistant Pseudomonas aeruginosa. BMC Infect Dis.
2011;11:317.
16. Prez-Pedrero MJ, Snchez-Casado M, Rodriguez-Villar S.
Nebulized colistin treatment of multi-resistant Acinetobacter
baumannii pulmonary infection in critical ill patients [in
Spanish]. Med Intensiva. 2011;35:226-231.
17. Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aero-
solized antimicrobial therapy in the treatment of Pseudomonas
aeruginosa and Acinetobacter baumannii ventilator-associ-
ated pneumonia. Respir Care. 2012;57:1226-1233.
18. Kalin G, Alp E, Coskun R, Demiraslan H, Gndogan K,
Doganay M. Use of high-dose IC and aerosolized colistin for
the treatment of multidrug-resistant Acinetobacter baumannii
ventilator-associated pneumonia: do we really need this treat-
ment? J Infect Chemother. 2012;18:872-877.
19. Lu Q, Luo R, Bodin L, etal. Efficacy of high-dose nebulized
colistin in ventilator-associated pneumonia caused by multi-
drug-resistant Pseudomonas aeruginosa and Acinetobacter
baumannii. Anesthesiology. 2012;117:1335-1347.
20. Doshi NM, Cook CH, Mount KL, etal. Adjunctive aerosol-
ized colistin for multi-drug resistant gram-negative pneumo-
nia in the critically ill: a retrospective study. BMC Anesthesiol.
2013;13:45.
21. Tumbarello M, De Pascale G, Trecarichi EM, etal. Effect of
aerosolized colistin as adjunctive treatment on the outcomes
of microbiologically documented ventilator-associated pneu-
monia caused by colistin-only susceptible gram-negative bac-
teria. Chest. 2013;144:1768-1775.
22. Chen YM, Fang WF, Kao HC, etal. Influencing factors of
successful eradication of multidrug-resistant Acinetobacter
baumannii in the respiratory tract with aerosolized colistin.
Biomed J. 2014;37:269-283.
10 Annals of Pharmacotherapy 00(0)
23. Demirdal T, Sari US, Nemli SA. Is inhaled colistin beneficial
in ventilator-associated pneumonia or nosocomial pneumo-
nia caused by Acinetobacter baumannii? Ann Clin Microbiol
Antimicrob. 2016;15:11.
24. Ekren PK, Toreyin N, Sayiner A, Bacakoglu F. The role of
aerosolized colistin in the treatment of hospital-acquired
pneumonia: experience of multicenter from Turkey. Crit Care
Med. 2016;44:e304.
25. Choi HK, Kim YK, Kim HY, Uh Y. Inhaled colistin for
treatment of pneumonia due to colistin-only-susceptible
Acinetobacter baumannii. Yonsei Med J. 2014;55:118-125.
26. Hsieh TC, Chen FL, Ou TY, Jean SS, Lee WS. Role of aero-
solized colistin methanesulfonate therapy for extensively-drug-
resistant Acinetobacter baumannii complex pneumonia and
airway colonization. J Micro Immunol Infect. 2016;49:523-530.
27. National Library of Medicine. Inhaled amikacin solution
BAY41-6551 as adjunctive therapy in the treatment of gram-
negative pneumonia (INHALE 1) (ClinicalTrials.gov; NLM
Identifier: NCT01799993). Bethesda, MD: National Library
of Medicine. http://clinicaltrials.gov/show/NCT01799993.
Accessed July 19, 2017.
28. National Library of Medicine. Inhaled amikacin solution
BAY41-6551 as adjunctive therapy in the treatment of gram-
negative pneumonia (INHALE 2) (ClinicalTrials.gov; NLM
Identifier: NCT0805168). Bethesda, MD: National Library
of Medicine. http://clinicaltrials.gov/show/NCT00805168.
Accessed July 19, 2017.
29. Valachis A, Samonis G, Kofteridis DP. The role of aerosol-
ized colistin in the treatment of ventilator-associated pneumo-
nia: a systematic review and meta-analysis. Crit Care Med.
2014;43:527-533.
30. Zampieri FG, Nassar AP Jr, Gusmao-Flores D, Taniguchi LU,
Torres A, Ranzani OT. Nebulized antibiotics for ventilator-
associated pneumonia: a systematic review and meta-analy-
sis. Crit Care. 2015;19:150.
31. Rouby JJ, Bouhemad B, Monsel A, etal. Aerosolized anti-
biotics for ventilator-associated pneumonia: lessons from
experimental studies. Anesthesiology. 2012;117:1364-1380.
32. Le J, Ashley ED, Neuhauser MM, etal. Consensus summary
of aerosolized antimicrobial agents: application of guideline
criteria. Insights from the Society of Infectious Diseases
Pharmacists. Pharmacotherapy. 2010;30:562-584.
33. Rello J, Sol-Lleonart C, Rouby JJ, etal. Use of nebulized
antimicrobials for the treatment of respiratory infections in
invasively mechanically ventilated adults: a position paper
from the European Society of Clinical Microbiology and
Infectious Diseases [published online April 13, 2017]. Clin
Microbiol Infect. doi:10.1016/j.cmi.2017.04.011.
34. Athanassa ZE, Markantonis SL, Fousteri MZF, etal.
Pharmcokinetics of inhaled colistimethate sodium (CMS) in
mechanically ventilated critically ill patients. Intensive Care
Med. 2012;38:1779-1786.
35. Tobi [Prescribing information]. East Hanover, NJ: Novartis
Pharmaceuticals; 2015.
36. Luyt CE, Clavel M, Guntupalli K, etal. Pharmacokinetics and
lung delivery of PDDS-aerosolized amikacin (NKTR-061) in
intubated and mechanically ventilated patients with nosoco-
mial pneumonia. Crit Care. 2009;13:200.
37. Luyt CE, Eldon MA, Stass H, Gribben D, Corkery K, Chastre
J. Pharmacokinetics and tolerability of amikacin administered
as BAY41-6551 aerosol in mechanically ventilated patients
with gram-negative pneumonia and acute renal failure. J
Aerosol Med Pulm Drug Deliv. 2011;24:183-190.
38. Stass H, Corkery K, Gribben D, Eldon MA. Pharmcokinetics
and tolerability of BAY41-6551 in subjects with chronic kid-
ney disease. J Aerosol Med Pulm Drug Deliv. 2011;24:191-
199.
39. Boisson M, Jacobs M, Grgoire N, etal. Comparison of intra-
pulmonary and systemic pharmacokinetics of colistin meth-
anesulfonate (CMS) and colistin after aerosol delivery and
intravenous administration of CMS in critically ill patients.
Antimicrob Agents Chemother. 2014;58:7331-7339.
40. Mojoli F, Iotti FA, Imberti R, Braschi A. The importance of
protecting the mechanical ventilator during colistin methane-
sulfonate nebulization. Intensive Care Med. 2013;39:535-536.
41. Rello J, Rouby JJ, Sole-Lleonart C, etal. Key conceptional
consideration on nebulization of antimicrobial agents to
mechanically ventilated patients [published online March 25,
2017]. Clin Microbiol Infect. doi:10.1016/j.cmi.2017.03.018.
42. Ari A, Atalay OT, Harwood R, Sheard MM, Aljamhan EA,
Fink JB. Influence of nebulizer type, position, and bias flow
on aerosol drug delivery in simulated pediatric and adult
lung models during mechanical ventilation. Respir Care.
2010;55:845-851.
43. Ari A, Areabi H, Fink JB. Evaluation of aerosol generator
devices at 3 locations in humidified and non-humidified
circuits during adult mechanical ventilation. Respir Care.
2010;55:837-844.