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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
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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


the site of infection has become more widely used over the
Treating hospital-acquired pneumonia (HAP) and ventila- past 2 decades. Recent surveys suggest that approximately
tor-associated pneumonia (VAP) continues to be a chal- 50% of ICUs have used aerosolized antibiotics for VAP.4
lenge in critically ill patients. HAP/VAP is the most common Current guidelines suggest that aerosolized antibiotics can
life-threatening infection in the intensive care unit (ICU) be added for patients with highly resistant organisms or in
and is associated with significant increases in length of stay, patients who are failing therapy.1 However, they also note
days of mechanical ventilation, health care costs, and, in lack of high-quality data in this area, which include effi-
some patients, increased mortality.1 Developing more effec- cacy, safety, and optimal dosing and administration.1
tive antibiotic treatment regimens is a critical unmet need in Critically, there are no large RCTs to date that show if
HAP/VAP management. For example, in a large meta-anal- aerosolized antibiotics are effective. Data prior to 2011
ysis of randomized controlled trials (RCTs) of VAP treat- were mostly retrospective studies without control groups.5
ment, 37% of the patients failed therapy with intravenous These were essentially large case series that seemed to show
(IV) antibiotics alone.2 Treatment is also complicated by the
increasing development of multidrug-resistant (MDR) 1
University of Tennessee Health Science Center, Memphis, TN, USA
Pseudomonas, Acinetobacter, and enterobacteriacae, which
are associated with high mortality and have very few treat- Corresponding Author:
G. Christopher Wood, Department of Clinical Pharmacy, University of
ment options.3 Tennessee Health Science Center College of Pharmacy, 881 Madison,
One potential factor for treatment failure is poor penetra- Room 335, Memphis, TN 38104, USA.
tion of IV antibiotics into the lung. Thus, adding adjunctive Email: cwood@uthsc.edu
2 Annals of Pharmacotherapy 00(0)

acceptable clinical responses in patients with highly resis- dosing varies by geographic location, all doses of colistin
tant or recurrent infections. However, without control are expressed in mg of colistin base activity (30 mg colistin
groups it is very difficult to determine if there was any ben- base activity = 80 mg colistimethate sodium prodrug =
efit from adding aerosolized antibiotics. approximately 1000000 units of colistimethate sodium
Fortunately, since that time the number and quality of prodrug).8
studies has increased significantly. Recent studies tend to be
larger, have control groups, and some have even used aero-
Efficacy of Aerosolized Antibiotics
solized monotherapy without IV antibiotics. In addition,
there are new data optimizing delivery of aerosolized anti- In the 2011 review, there were 23 studies and case reports
biotics in mechanically ventilated patients as well as safety included from 1967 to 2010 that encompassed at total of
information. As such, the objective of this article is to pro- 495 patientsmostly without controls.5 Since that time, 18
vide an updated review on the use of aerosolized antibiotics studies were identified with a total of 1751 patients, the vast
for treating HAP and VAP in adults. 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
Methods improved dramatically. The reader is referred to Table 1 for
Our investigative group published reviews in this area in details on study design and outcomes.
2000, 2007, and 2011.5-7 The current article is an update of
studies published after our last review was completed in
Randomized Controlled Trials
mid-2010. Studies were identified for this article using the
following search terms in PubMed: aerosolized antibiotics Interestingly, while most of the literature as a whole studied
pneumonia, nebulized antibiotics pneumonia, and aerosolized colistin, only one of the RCTs did so. In 2010,
inhaled antibiotics pneumonia. Reference lists from arti- Rattanaumpawan etal published a reasonably sized RCT (n
cles were used to identify more publications. Studies were = 100) of aerosolized colistin added to standard IV antibiot-
included from July 2010 through March 2017 if they ics for Pseudomonas and Acinetobacter HAP/VAP.9 Clinical
described the use of aerosolized antibiotics for the treat- success was not significantly improved by aerosolized ther-
ment of HAP or VAP in adult patients, or the optimization apy; however, microbiologic success was improved. This
of the delivery of aerosolized antibiotics in mechanically study used low-dose colistin (75 mg BID) as opposed to
ventilated adult patients. Because ~90% of patients with higher-dose colistin used in some other studies (150 mg
HAP are mechanically ventilated (ie, they have VAP), and BID). Also, the administration technique was not well
because the vast majority of patients in the studies discussed described. It is unknown if these factors impacted the lack
had VAP, this article will focus on treating VAP. The new of clinical benefit observed.
HAP/VAP guidelines make an effort to differentiate HAP The other RCTs primarily studied aminoglycosides
and VAP; however, none of the identified studies analyzed (AMGs). Niederman etal published a Phase II pharmacoki-
HAP and VAP separately.1 Only English language articles netic RCT of a preservative-free aerosolized amikacin
were included; however, one English language abstract of product added to IV therapy.11 The administration technique
an article in Spanish was included based on relevance. Case was excellent; however, no improvement was reported with
reports were not included. aerosolized therapy in this relatively small study (total n =
Studies were informally graded according to the quality 55), although the very high response rate in the control
of pneumonia diagnosis and the quality of the administra- group would make it very difficult to see a benefit for aero-
tion technique used. For pneumonia diagnosis, high qual- solized therapy. The study by Palmer etal took a somewhat
ity included quantitative cultures obtained bronchoscopically, different approach.12 They included long-term ventilated
medium quality included endotracheal aspirates with patients with bacterial colonization or pneumonia and
semiquantitative cultures, and low quality included all added aerosolized AMGs or vancomycin (the only study to
other culture techniques or a lack of cultures. For adminis- use that drug) to IV therapy depending on sensitivity results.
tration technique, a major problem is the lack of detail Microbiologic response and resistance development were
given, such that many studies were graded unclear. significantly improved in the study group. However, 2
Otherwise, high quality included either the use of an important limitations are that clinical cure was not reported
advanced nebulizer (eg, vibrating plate) or a traditional neb- and it is not clear which patients had pneumonia.
ulizer with multiple elements of proper technique (eg, nebu- Perhaps the most important RCT to date was the recently
lizer placement in the circuit, humidification turned off published IASIS trial of aerosolized amikacin/fosfomycin
during nebulization). Medium quality included less infor- administered with a high-quality technique.13 The primary
mation than the high quality studies. No studies were outcome was the change in clinical pulmonary infection
considered low quality. Because the reporting of colistin 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 to IV in a subgroup of patients with high-quality cultures.20
outcomes were improved with aerosolized therapy when This provides some reassurance that the treatment might
added to IV, though microbiological response and resis- have been effective because that subgroup represents
tance development among the VAP pathogens did improve patients who are the most likely to truly have had pneumo-
significantly. Factors that might have influenced the mostly nia. These 2 studies are obviously limited by the use of sub-
negative outcome of this study include the use of unconven- group analyses.
tional outcome measures and inclusion of low-quality cul- However, another group of studies did not show any
tures that might have allowed patients in the study that did additional benefit to adding aerosolized colistin to IV. The
not actually have pneumonia. studies by Chen etal and Demirdal etal were good sized
The last RCT was a highly unusual study of aerosolized (total n = 135 and 123, respectively) and both studied
ceftazidime/amikacin monotherapy (ie, no IV antibiotics) MDR Acinetobacter.22,23 The Demirdal etal article used a
versus IV ceftazidime/amikacin in 40 patients with matched control group.23 However, both suffered from
Pseudomonas VAP.10 This was unusual because almost all much lower clinical or microbiological success rates in
studies up to that point had used aerosolized antibiotics in both the study and control groups than most other studies.
addition to IV therapy, the use of a -lactam/AMG combi- This might indicate that they found a particularly difficult
nation regimen, and very high doses. However, this study is patient population to treat. Strengths of these 2 studies are
notable because of the high quality of aerosolized adminis- large size and medium to high VAP diagnostic quality;
tration and VAP diagnosis.10 There was no difference in out- however, limitations are unclear administration technique
comes between groups, which suggested that high-dose and perhaps the low doses of aerosolized colistin used.
aerosolized combination therapy might be effective without The relevance of the Chen etal study is more difficult to
using IV antibiotics. This result needs to be confirmed in determine because they showed improved microbiologic
larger RCTs. 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
Observational Studies With Control Groups However, this study was less important because it was
By far the most common design among this group of studies smaller (n = 45) and did not have clearly described diag-
was comparing IV colistin plus aerosolized colistin (study nostic or administration techniques.
group) to IV colistin alone (control). Most studies focused Two other negative studies were limited by very small
on MDR Pseudomonas, MDR Acinetobacter, and occasion- sample size. Naesens etal (n = 20) found a numerically
ally other MDR Gram-negatives such as Klesiella, though impressive improvement in clinical success for Pseudomonas
some studies included a mix of MDR and sensitive patho- HAP/VAP that did not reach statistical significance.15
gens. Most studies reported improved clinical responses in Interestingly, this study included 6 patients who received
groups receiving aerosolized therapy. Impressively, 2 rather aerosolized colistin monotherapy without IV antibiotics; and
large studies by Korbila etal and Ekren etal both found all 6 patients were clinical successes. In the second study,
significantly improved clinical success by adding aerosol- Prez-Pedrero etal (n = 18) reported no difference in the
ized colistin to IV (total n = 121 and 279, respectively).14,24 high success rates for Acinetobacter VAP in both groups.16
However, perhaps the most important study in this group Thus, it would have been very difficult for a potential benefit
was by Tumbarello etal.21 Strengths of this study include a of aerosolized antibiotics to be seen.
control group that was matched for age and severity of ill- Last in this group is another study of aerosolized mono-
ness, large size (n = 208), high-quality VAP diagnosis, and therapy from the same investigative group that performed
all patients having MDR pathogens. Clinical success was the aerosolized monotherapy RCT.10 Patients in the study
significantly improved and duration of mechanical ventila- group had MDR Pseudomonas or Acinetobacter VAP and
tion was shorter with aerosolized colistin added to IV. received either high-dose aerosolized colistin alone or aero-
Two other studies failed to show an overall benefit for solized colistin plus 3 days of IV aminoglycosides at the
aerosolized antibiotics, but did show a benefit in subgroups. beginning of treatment.19 Both these study groups were
Arnold etal did not report the outcome of clinical success, combined for the outcome analysis. The combined study
but they did report significantly decreased mortality for group had similar clinical success and mortality to the con-
adding aerosolized therapy (colistin or tobramycin) to IV in trol group of patients with sensitive Pseudomonas or
a subgroup of more seriously ill patients with APACHE II Acinetobacter VAP treated with IV therapy. Weaknesses of
scores >16.17 This study is notable because the quality of the study include a relatively small size of the study group,
techniques for VAP diagnosis and aerosol administration as well as the unusual treatment regimens. As with these
were high, and because mortality is a very difficult outcome investigators RCT, strengths include the high quality of
to affect in VAP. Similarly, Doshi etal found significantly VAP diagnosis and aerosol administration, which makes the
improved clinical success when adding aerosolized colistin findings even more intriguing.
6 Annals of Pharmacotherapy 00(0)

Retrospective Studies Without Control Groups clinical cure (odds ratio [OR] = 1.57; 95% confidence inter-
val [CI] = 1.14-2.15; P = 0.006), microbiologic cure (OR =
As noted earlier, these used to be the most common type of 1.61; 95% CI = 1.11-2.35; P = 0.01), and infection-related
study in this field; however, now it is the rarest. Choi etal mortality (OR = 0.58; 95% CI = 0.34-0.96; P = 0.04). The
added aerosolized colistin to IV therapy in 8 patients with second included 6 RCTs and 6 observational studies with
MDR Acinetobacter and all were successful.25 Interestingly, control groups that included all aerosolized antibiotics (not
an additional 4 patients were treated with aerosolized colis- just colistin) and a total of 812 patients.30 This analysis also
tin monotherapy and 2/4 had a positive outcome. This study showed an improvement in clinical cure (risk ratio [RR] =
is limited by the very small size and the lack of reporting of 1.23; 95% CI = 1.05-1.43), but not in microbiologic cure
how many patients had VAP versus colonization. Hsieh etal (RR = 1.24; 95% CI = 0.95-1.62) or mortality (RR = 0.90;
also studied patients with MDR Acinetobacter. In this mod- 95% CI = 0.76-1.08).
erately sized study, the authors reported acceptable effi- Last, the use of aerosolized monotherapy is highly inter-
cacy.26 However, the interesting finding was that patients esting. If effective, using aerosolized therapy alone to treat
who had microbiologic eradication of the organism had a VAP could potentially be a major advance in limiting patient
significantly higher clinical success rate. The utility of exposure to antibiotics and aiding overall antimicrobial
microbiologic eradication as an outcome is questionable, stewardship. Two studies from one center suggest that aero-
but in this study it was related to clinical success. solized monotherapy resulted in equivalent outcomes to
conventional IV therapy.10,19 Critically, these investigators
Summary of Efficacy Studies used high doses and very detailed administration tech-
niques, which might have optimized delivery of antibiotics
Unfortunately, there are no large RCTs to give a clear indi- to the distal lung fields and improved efficacy. Others
cation if aerosolized antibiotics add to the treatment of VAP. reported success in 6/8 patients treated with aerosolized
The future publication of the ongoing large Phase III RCTs monotherapy.15,25 Despite this initial success, at this time
of an aerosolized amikacin product (INHALE 1 and 2 trials) aerosolized monotherapy should only be used in clinical tri-
will provide critical data in this area.27,28 In the meantime, als at centers where optimal administration technique is
with the publication of larger and better designed studies used. This is because aerosolized delivery of drug to the
since 2010, there are some indications that adding aerosol- lung can be widely variable, and may provide low concen-
ized antibiotics might improve efficacy. Perhaps the most trations if proper technique is not used.5,31 Also, there is a
relevant studies are those with larger total size (n > 75), a danger that localized antibiotic therapy may not provide
control group, and that reported clinical cure or mortality as protection if the VAP pathogen spreads to the bloodstream.
the primary outcome (ie, higher quality studies). Of those In summary, based on the newer data from mid-2010 for-
8 higher quality studies, 5 studies demonstrated improved ward, there is now far better evidence that adjunctive aero-
outcomes with aerosolized antibiotics,14,17,20,21,24 while 3 solized antibiotics might improve outcomes in VAP. There
studies did not show a benefit.9,13,23 are obvious weaknesses in this body of literature including
There was not an obvious pattern of success or failure in a lack of large RCTs, and differences in patient populations,
the higher quality studies. The distribution of treated patho- severity of illness, drug selection, dosing, and administra-
gens and the dose of aerosolized colistin was not clearly tion techniques. Regardless, in 2016 the updated IDSA/ATS
different between the successful and unsuccessful high- VAP guidelines modestly expanded their recommendation
quality studies. However, it is interesting that the 2 studies to consider using aerosolized antibiotics in patients with
that used high doses17,20 were among the successful MDR pathogens, or who are not responding clinically to IV
studies,14,17,20,21 and both unsuccessful studies9,23 used low therapy.1 This is similar to a 2010 recommendation from the
doses. This suggests that the dose could matter. Interestingly, Society of Infectious Diseases Pharmacists.32 Such usage
there might be some question about how well AMGs per- seems reasonable based on current efficacy data. The data at
formed. The amikacin/fosfomycin trial was the one higher this time are not strong enough to warrant routine usage in
quality RCT with AMGs and it was negative.13 The smaller all patients with VAP, and indeed, aerosolized antibiotics
RCT with amikacin was also negative, but with limitations were not used that way in recent studies.
described previously.11 On the other hand, AMGs contrib- Interestingly, a recent European guideline on aerosolized
uted to the success seen in the higher quality Arnold etal antibiotics in VAP gave a weak recommendation not to use
study and the smaller Palmer etal study.12,17 them based primarily on a lack of high-quality evidence and
Importantly, 2 recent meta-analyses both suggest that concern over adverse events.33 We certainly agree that large
aerosolized antibiotics are beneficial. The first focused on RCTs are needed. However, we respectfully disagree with
adjunctive colistin and included 1 RCT and 7 observational their recommendation. We feel that the severity of the prob-
studies with control groups totaling 690 patients.29 lem (ie, poor HAP/VAP response rates), a lack of treatment
Aerosolized colistin was associated with improvements in options for some organisms, the current state of knowledge
Wood and Swanson 7

that suggests additional efficacy over IV therapy alone, and below the trough range for all groups (0.94-2.46 mg/L)37,38
relative safety (see below) tilt the risk-benefit equation in Four other studies reported no significant adverse events of
favor of using them in selected situations. any kind.14,15,17,25
If the decision is made to use aerosolized antibiotics, Another potential issue is clogging of the ventilator filter
drug selection should based on sensitivity testing. on the expiratory side of the circuit. The study that used
Aminoglycosides should probably be used when possible very high doses of aerosolized antibiotics also reported
because they may have a better safety profile (see below) clogging of the expiratory filter on the ventilator in 3/20
and to reserve colistin for the most resistant organisms. (15%) patients.10 It is unclear if this was due to the very
There is much less experience using cephalosporins but that high doses used or some other reason. Others have reported
class could be an option. We urge caution in aerosolizing the same issue.40 The new European aerosolized adminis-
drugs for which there is not published experience. For tration guidelines recommend changing the filter with every
instance, imipenem is not physically suitable for aerosoliza- dose.41 It is unclear how realistic this might be, but attention
tion and doripenem may cause adverse events.32 should be paid to this issue.
Regarding dosing, ideal doses of aerosolized colistin and There are also drug compounding factors that affect tol-
aminoglycosides are not known. Recent pharmacokinetic erability of an aerosolized medication (Table 2). Critically,
data suggest that higher doses of colistin (ie, 150 mg rather colistin needs to be used immediately on reconstitution to
than 80 mg) are needed to generate optimal lung concentra- avoid breakdown products that can cause potentially fatal
tions.34 Thus, based on current data the following doses reactions. Solutions are best tolerated if they have a pH of
seem reasonable for aerosolized therapy of HAP/VAP: 4.0 to 8.0, osmolarity of 150 to 1200 mOsm/L, and a sodium
colistin 150 mg BID, gentamicin or tobramycin 300 mg concentration of 77 to 154 mEq/L.5 Thus, using normal
BID, or amikacin 400 mg BID.5,34-36 Regarding duration of saline or half-normal saline as a diluent is preferred over
therapy, a pragmatic recommendation is to simply continue D5W or sterile water for inhalation or injection. Using a
the aerosolized antibiotic for the duration of IV therapy. preservative-free formulation that is designed for inhalation
Most clinical trials described in this review treated patients such as the tobramycin for inhalation product could theo-
that way. Total duration of therapy (IV + aerosolized) was retically be better tolerated than aerosolizing the IV formu-
typically 7 to 21 days depending on the patients course. lation.5 However, such a comparison has not been made in
Many patients were treated longer than 7 days because they VAP. Last, the volume of drug solution should ideally match
had MDR organisms. 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-
Safety of Aerosolized Antibiotics tered immediately after. Attention should be paid to make
Another important aspect of using aerosolized antibiotics is sure the full dose is administered.
safety. Older studies did not provide much information on In summary, using aerosolized antibiotics appears to
adverse events such as cough, bronchospasm, and the have a good safety profile. They do not appear to increase
potential for increased nephrotoxicity, ototoxicity, or neuro- nephrotoxicity compared to IV antibiotics alone, though
toxicity from systemic absorption of colistin or AMGs.5 larger studies will need to confirm this finding. It is impor-
There was also a suggestion that colistin might cause more tant to note that there is a small percentage of patients that
bronchospasm than AMGs and that pretreatment with alb- will have pulmonary adverse events. There was not a clear
uterol might make aerosolized antibiotics better tolerated.5 difference in bronchospasm between colistin and AMGs in
In the newer studies, none reported coughing from aero- more recent studies though previous data suggested that
solized therapy. In the 4 studies that specifically commented colistin caused more coughing and bronchospasm.5 If aero-
on bronchospasm, a total of 7/178 patients (3.9%) receiving solized antibiotic therapy is to continue in patients with pul-
aerosolized antibiotics had bronchospasm compared to 2/160 monary adverse events, it is reasonable to pretreat those
patients (1.3%) in control groups.9-11,13 One study reported a patients with aerosolized albuterol though the efficacy of
decrease of pO2 by 25% during administration in 3/20 (15%) this practice is not well studied.5
patients with one patient requiring discontinuation of
treatment.10 Seven studies reported rates of nephrotoxicity Optimizing Delivery in Mechanically
with none showing an increase in the aerosolized antibiotic
group.9,14,18,19,21,23,24 This is not surprising because most data
Ventilated Patients
suggest that aerosolized colistin or aminoglycosides do not Using proper administration technique dramatically
generate significant serum concentrations unless patients improves the percentage of an aerosolized dose that reaches
have renal dysfunction.5,36-39 Even in patients with varying the lung.5,31,32,34 Thus, it is critical to use proper technique.
degrees of renal dysfunction, 2 newer studies reported the Unfortunately, a recent survey found that only 28% of ICUs
mean maximum serum concentrations of amikacin were 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 recommended in Table 2 and administer doses to most
this area is beyond the scope of this article, and the reader is patients at their current ventilator settings.
referred to more extensive reviews on administration
including a new European guideline.31,41 However, a sum-
Cost Implications of Aerosolized
mary of important administration issues is summarized in
Table 2 and below. Antibiotic Therapy
Recently, it has become clear that vibrating plate (also Costs of aerosolized antibiotics for treating HAP/VAP have
called vibrating mesh) nebulizers (VPN) are preferred not been addressed in any of the studies described. These
over traditional jet nebulizers or more rarely used ultra- potentially include direct costs for drug and nebulizer
sonic nebulizers because they deliver much more drug to acquisition, and indirect costs such as pharmacy time for
the lung.41-43 Compared to ultrasonic nebulizers, VPNs drug preparation, respiratory therapy time for drug adminis-
do not have as big of an advantage in terms of delivery. tration, patient monitoring, and ventilator filter changes,
However, VPNs have other advantages in terms of ease and possibly nursing time for dealing for pretreating patients
of use, cost, the ability to nebulize only on inspiration, for managing adverse events. Fortunately, the vast majority
and they do not increase the temperature of the aerosol of studies have used drugs that are available generically and
fluid which could affect drug stability.5 Other factors relatively inexpensive. Vibrating mesh nebulizers are also
affecting delivery include nebulizer placement, circuit inexpensive. If approved for use, it is unknown how much
humidification, and ventilator settings (Table 2). Another specially formulated antibiotics for inhalation will cost but
advantage of VPNs is that they are not as affected by it is safe to assume that they will be more expensive based
placement or humidification as jet nebulizers.42,43 In on the higher cost of the tobramycin for inhalation product
some cases (eg, imipenem) the drug formulation is not used in cystic fibrosis. However, if aerosolized antibiotics
suitable for aerosolization.32 are found to improve outcomes such as treatment failure,
Using ventilator settings that optimize delivery is a more length of stay, duration of mechanical ventilation, or mor-
difficult issue. Experimental studies suggest that volume- tality, then the pharmacoeconomics should be favorable.
controlled ventilation with a tidal volume of 8 mL/kg, respi- Such analyses will need to be performed.
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
Conclusions
not realistic in many patients. Such settings may not be well The amount and quality of data on using adjunctive aerosol-
tolerated and might require additional sedation. Also, some ized antibiotics for treating HAP/VAP has improved signifi-
patients may not tolerate a change from their current venti- cantly over the past 6 years. While the efficacy data are
lator settings. A more pragmatic approach may be to use the mixed, a number of studies do show a benefit and none
other drug compounding and administration techniques show worse outcomes when adding aerosolized therapy to
Wood and Swanson 9

IV therapy. As such, the recommendations to consider add- of ventilator-associated pneumonia caused by gram-negative
ing aerosolized colistin or aminoglycosides to patients with bacteria. J Antimicrob Chemother. 2010;65:2645-2649.
MDR isolates or who are not responding well to IV therapy 10. Lu Q, Yang J, Liu Z, etal. Nebulized ceftazidime and amikacin
alone in the updated HAP/VAP guidelines seem reasonable. in ventilator-associated pneumonia caused by Pseudomonas
aeruginosa. Am J Respir Crit Care Med. 2011;184:106-115.
Attention should be paid to using good administration tech-
11. Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE,
nique to optimize the delivery of drug to the lung, as well as
Garca MS. BAY41-6551 achieves bactericidal tracheal
monitoring for adverse events. Clearly, large RCTs are aspirate amikacin concentrations in mechanically ventilated
needed to determine the ultimate role of aerosolized antibi- patients with gram-negative pneumonia. Intensive Care Med.
otics in HAP/VAP therapy. 2012;38:263-271.
12. Palmer LB, Smaldone GC. Reduction of bacterial resistance
Declaration of Conflicting Interests with inhaled antibiotics in the intensive care unit. Am J Respir
The authors declared the following potential conflicts of interest Crit Care Med. 2014;189:1225-1233.
with respect to the research, authorship, and/or publication of this 13. Kollef MH, Ricard JD, Roux D, etal. A randomized trial of
article: Dr Wood is a consultant for Bayer Pharma AG and was an the amikacin fosfomycin inhalation system for the adjunc-
investigator for the INHALE 1 study of an aerosolized antibiotic tive therapy of gram-negative ventilator-associated pneumo-
for pneumonia sponsored by Bayer Pharma AG. Dr Swanson was nia: IASIS trial. Chest. 2017;151:1239-1246. doi:10.1016/j.
an investigator for the INHALE 1 study of an aerosolized antibi- chest.2016.11.026.
otic for pneumonia sponsored by Bayer Pharma AG. 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
Funding
documented ventilator-associated pneumonia: a comparative
The authors received no financial support for the research, author- cohort study. Clin Microbiol Infect. 2010;16:1230-1236.
ship, and/or publication of this article. 15. Naesens R, Vlieghe E, Verbrugghe W, Jorens P, Ieven M. A
retrospective observational study on the efficacy of colistin
References by inhalation as compared to parenteral administration for
the treatment of nosocomial pneumonia associated with mul-
1. Kalil AC, Metersky ML, Klompas M, etal. Management of
tidrug-resistant Pseudomonas aeruginosa. BMC Infect Dis.
adults with hospital-acquired and ventilator-associated pneu-
2011;11:317.
monia: 2016 clinical practice guidelines by the Infectious
16. Prez-Pedrero MJ, Snchez-Casado M, Rodriguez-Villar S.
Diseases Society of America and the American Thoracic
Nebulized colistin treatment of multi-resistant Acinetobacter
Society. Clin Infect Dis. 2016;63:e61-e111.
baumannii pulmonary infection in critical ill patients [in
2. Aarts MAW, Hancock JN, Heyland D, McLeod RS, Marchall
Spanish]. Med Intensiva. 2011;35:226-231.
JC. Empiric antibiotic therapy for suspected ventilator-asso-
17. Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aero-
ciated pneumonia: a systematic review and meta-analysis of
solized antimicrobial therapy in the treatment of Pseudomonas
randomized trials. Crit Care Med. 2008;36:108-117. aeruginosa and Acinetobacter baumannii ventilator-associ-
3. Zilberberg MA, Shorr AF, Micek ST, Vazquez-Guillamet C, ated pneumonia. Respir Care. 2012;57:1226-1233.
Kollef MH. Multi-drug resistance, inappropriate initial anti- 18. Kalin G, Alp E, Coskun R, Demiraslan H, Gndogan K,
biotic therapy and mortality in gram-negative severe sepsis Doganay M. Use of high-dose IC and aerosolized colistin for
and septic shock: a retrospective cohort study. Crit Care. the treatment of multidrug-resistant Acinetobacter baumannii
2014;18:596. ventilator-associated pneumonia: do we really need this treat-
4. Sol-Lleonart C, Rouby JJ, Chastre J, etal. Intratracheal ment? J Infect Chemother. 2012;18:872-877.
administration of antimicrobial agents in mechanically venti- 19. Lu Q, Luo R, Bodin L, etal. Efficacy of high-dose nebulized
lated adults: an international survey on delivery practices and colistin in ventilator-associated pneumonia caused by multi-
safety. Respir Care. 2016;61:1008-1014. drug-resistant Pseudomonas aeruginosa and Acinetobacter
5. Wood GC. Aerosolized antibiotics for treating hospital- baumannii. Anesthesiology. 2012;117:1335-1347.
acquired and ventilator-associated pneumonia. Expert Rev 20. Doshi NM, Cook CH, Mount KL, etal. Adjunctive aerosol-
Anti Infect Ther. 2011;9:993-1000. ized colistin for multi-drug resistant gram-negative pneumo-
6. Wood GC, Boucher BA. Aerosolized antimicrobial therapy in nia in the critically ill: a retrospective study. BMC Anesthesiol.
acutely ill patients. Pharmacotherapy. 2000;20:166-181. 2013;13:45.
7. Wood GC, Swanson JM. Aerosolized antibiotics for the 21. Tumbarello M, De Pascale G, Trecarichi EM, etal. Effect of
prevention and treatment of hospital-acquired pneumonia. aerosolized colistin as adjunctive treatment on the outcomes
Drugs. 2007;67:901-914. of microbiologically documented ventilator-associated pneu-
8. Ortwine JK, Kaye KS, Li J, Pogue JM. Colistin: under- monia caused by colistin-only susceptible gram-negative bac-
standing and applying recent pharmacokinetic advances. teria. Chest. 2013;144:1768-1775.
Pharmacotherapy. 2015;35:11-16. 22. Chen YM, Fang WF, Kao HC, etal. Influencing factors of
9. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, successful eradication of multidrug-resistant Acinetobacter
Angkasekwinai N, Thamlikitkul V. Randomized controlled baumannii in the respiratory tract with aerosolized colistin.
trial of nebulized colistimethate sodium as adjunctive therapy Biomed J. 2014;37:269-283.
10 Annals of Pharmacotherapy 00(0)

23. Demirdal T, Sari US, Nemli SA. Is inhaled colistin beneficial invasively mechanically ventilated adults: a position paper
in ventilator-associated pneumonia or nosocomial pneumo- from the European Society of Clinical Microbiology and
nia caused by Acinetobacter baumannii? Ann Clin Microbiol Infectious Diseases [published online April 13, 2017]. Clin
Antimicrob. 2016;15:11. Microbiol Infect. doi:10.1016/j.cmi.2017.04.011.
24. Ekren PK, Toreyin N, Sayiner A, Bacakoglu F. The role of 34. Athanassa ZE, Markantonis SL, Fousteri MZF, etal.

aerosolized colistin in the treatment of hospital-acquired Pharmcokinetics of inhaled colistimethate sodium (CMS) in
pneumonia: experience of multicenter from Turkey. Crit Care mechanically ventilated critically ill patients. Intensive Care
Med. 2016;44:e304. Med. 2012;38:1779-1786.
25. Choi HK, Kim YK, Kim HY, Uh Y. Inhaled colistin for 35. Tobi [Prescribing information]. East Hanover, NJ: Novartis
treatment of pneumonia due to colistin-only-susceptible Pharmaceuticals; 2015.
Acinetobacter baumannii. Yonsei Med J. 2014;55:118-125. 36. Luyt CE, Clavel M, Guntupalli K, etal. Pharmacokinetics and
26. Hsieh TC, Chen FL, Ou TY, Jean SS, Lee WS. Role of aero- lung delivery of PDDS-aerosolized amikacin (NKTR-061) in
solized colistin methanesulfonate therapy for extensively-drug- intubated and mechanically ventilated patients with nosoco-
resistant Acinetobacter baumannii complex pneumonia and mial pneumonia. Crit Care. 2009;13:200.
airway colonization. J Micro Immunol Infect. 2016;49:523-530. 37. Luyt CE, Eldon MA, Stass H, Gribben D, Corkery K, Chastre
27. National Library of Medicine. Inhaled amikacin solution
J. Pharmacokinetics and tolerability of amikacin administered
BAY41-6551 as adjunctive therapy in the treatment of gram- as BAY41-6551 aerosol in mechanically ventilated patients
negative pneumonia (INHALE 1) (ClinicalTrials.gov; NLM with gram-negative pneumonia and acute renal failure. J
Identifier: NCT01799993). Bethesda, MD: National Library Aerosol Med Pulm Drug Deliv. 2011;24:183-190.
of Medicine. http://clinicaltrials.gov/show/NCT01799993. 38. Stass H, Corkery K, Gribben D, Eldon MA. Pharmcokinetics
Accessed July 19, 2017. and tolerability of BAY41-6551 in subjects with chronic kid-
28. National Library of Medicine. Inhaled amikacin solution
ney disease. J Aerosol Med Pulm Drug Deliv. 2011;24:191-
BAY41-6551 as adjunctive therapy in the treatment of gram- 199.
negative pneumonia (INHALE 2) (ClinicalTrials.gov; NLM 39. Boisson M, Jacobs M, Grgoire N, etal. Comparison of intra-
Identifier: NCT0805168). Bethesda, MD: National Library pulmonary and systemic pharmacokinetics of colistin meth-
of Medicine. http://clinicaltrials.gov/show/NCT00805168. anesulfonate (CMS) and colistin after aerosol delivery and
Accessed July 19, 2017. intravenous administration of CMS in critically ill patients.
29. Valachis A, Samonis G, Kofteridis DP. The role of aerosol- Antimicrob Agents Chemother. 2014;58:7331-7339.
ized colistin in the treatment of ventilator-associated pneumo- 40. Mojoli F, Iotti FA, Imberti R, Braschi A. The importance of
nia: a systematic review and meta-analysis. Crit Care Med. protecting the mechanical ventilator during colistin methane-
2014;43:527-533. sulfonate nebulization. Intensive Care Med. 2013;39:535-536.
30. Zampieri FG, Nassar AP Jr, Gusmao-Flores D, Taniguchi LU, 41. Rello J, Rouby JJ, Sole-Lleonart C, etal. Key conceptional
Torres A, Ranzani OT. Nebulized antibiotics for ventilator- consideration on nebulization of antimicrobial agents to
associated pneumonia: a systematic review and meta-analy- mechanically ventilated patients [published online March 25,
sis. Crit Care. 2015;19:150. 2017]. Clin Microbiol Infect. doi:10.1016/j.cmi.2017.03.018.
31. Rouby JJ, Bouhemad B, Monsel A, etal. Aerosolized anti- 42. Ari A, Atalay OT, Harwood R, Sheard MM, Aljamhan EA,
biotics for ventilator-associated pneumonia: lessons from Fink JB. Influence of nebulizer type, position, and bias flow
experimental studies. Anesthesiology. 2012;117:1364-1380. on aerosol drug delivery in simulated pediatric and adult
32. Le J, Ashley ED, Neuhauser MM, etal. Consensus summary lung models during mechanical ventilation. Respir Care.
of aerosolized antimicrobial agents: application of guideline 2010;55:845-851.
criteria. Insights from the Society of Infectious Diseases 43. Ari A, Areabi H, Fink JB. Evaluation of aerosol generator
Pharmacists. Pharmacotherapy. 2010;30:562-584. devices at 3 locations in humidified and non-humidified
33. Rello J, Sol-Lleonart C, Rouby JJ, etal. Use of nebulized circuits during adult mechanical ventilation. Respir Care.
antimicrobials for the treatment of respiratory infections in 2010;55:837-844.