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Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

Contents lists available at ScienceDirect

Pulmonary Pharmacology & Therapeutics


journal homepage: www.elsevier.com/locate/ypupt

The efficacy and safety of inhaled antibiotics for pneumonia: A systematic


review and meta-analysis
Zengzeng Zhang a,1 , Hong Li a,1 , Yutao Hu a , Binhui Sun a , Tingting Ke a , Qihuan Wu a ,
Xiang Lian a,**, Wei Yu b,*
a
Department of Infectious Diseases, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Xiangshan First People’s Hospital Medical and Health Group,
Ningbo Fourth Hospital, Ningbo, China
b
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for
Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: The aim of this study was to evaluate the efficacy and safety of inhaled antibiotics for adults with
inhaled antibiotics pneumonia by meta-analysis.
Aminoglycosides Methods: Literature retrieval was completed through five databases (PubMed, Embase, Cochrane Library, Web of
Polymyxins
Science and Scopus) by the deadline of May 31, 2024. The process of study selection and data extraction were
Ventilator-associated pneumonia
Clinical cure
performed independently by two reviewers. The quality of observational studies and randomized controlled trial
(RCT) studies were evaluated by Newcastle Ottawa scale and Jadad scale, respectively. The primary outcomes
included mortality, clinical cure, and microbiological cure. Secondary outcomes were recurrence and renal
impairment.
Results: There were 30 studies were analyzed, including 12 RCT studies and 18 observational studies. Inhaled
antibiotics did not significantly reduce mortality in RCT studies (odds ratio (OR) = 1.06, 95 % confidence in-
terval (CI): 0.80–1.41). Inhaled antibiotics were associated with higher rates of clinical cure (OR = 1.47 95%CI:
0.82–2.66 in RCT studies and OR = 2.09, 95%CI: 1.36–3.21 in observational studies) and microbiological cure
(OR = 7.00 in RCT studies and OR = 2.20 in observational studies). Subgroup analysis showed patients received
inhaled antibiotics combined with intravenous administration and inhaled amikacin had better improvements of
mortality, clinical cure and microbiological cure. Inhaled antibiotics were not associated with recurrence. The
pooled OR of renal impairment were 0.65 (95%CI: 0.27–1.13; I-squared = 43.5 %, P = 0.124) and 0.63(95%CI:
0.26–1.11; I-squared = 69.0 %, P = 0.110) in RCT studies and observational studies, respectively.
Conclusions: Inhaled antibiotics decreased risk of renal impairment and achieved significant improvements of
clinical and microbiological cure in patients with pneumoniae.

1. Introduction resistant pathogens and preventing the emergence of resistant strain


due to better lung permeability [3–5].
The typical treatment of pneumoniae involves administration of So far, the inhalation devices include pressurized metered dose
antibiotics by intravenous or oral route. In addition, inhaled antibiotics inhaler (pMDI), dry powder inhalers (DPIs) and nebulizers. In nebu-
are one potential means of treating pneumoniae as well, especially for lizers, there were three different types of drug nebulization systems,
cystic fibrosis and ventilator-associated pneumonia (VAP) [1,2] The such as ultrasonic, jet and mesh [6]. The available clinical application or
aerosol therapy is used to deliver suspended solid or liquid in a gas research nebulized antibiotics include 15 kinds of antibiotics, like
directly to the airways. Potential advantages of inhaled antibiotics aztreonam, colistimethate, tobramycin, amikacin and so on [6,7].
include decreasing the airway bacterial load, eradicating multi-drug Different antibiotics, devices and inhaled methods could influence the

* Corresponding author.
** Corresponding author.
E-mail addresses: 614404701@qq.com (X. Lian), wyu@zju.edu.cn (W. Yu).
1
These authors have contributed equally to this work.

https://doi.org/10.1016/j.pupt.2024.102315
Received 16 April 2024; Received in revised form 15 June 2024; Accepted 12 July 2024
Available online 14 July 2024
1094-5539/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-
nc/4.0/).
Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

success of aerosol therapy. The vast majority of case reports, retro- estimated by median and interquartile range [13].
spective studies and randomized controlled trial (RCT) studies suggest The heterogeneity was estimated with I-squared (I2) by archived
that nebulized antibiotics have the advantages of improving patient cure version of the Cochrane Handbook: 0 %–40 % (might represent mild
rates, reducing mortality rates, and reducing side effects [4,5,8,9]. heterogeneity and might cause little concern), 30 %–60 % (may repre-
However, several studies have yielded inconsistent results [10,11]. sent moderate heterogeneity), 50 %–90 % (may represent substantial
Therefore, the efficiency of inhaled antibiotics needs to be comprehen- heterogeneity), 75 %–100 % (considerable heterogeneity). Subgroup
sively explored. In the present study, a systematic review and analysis was performed according to different antibiotics and adminis-
meta-analysis was conducted to evaluate effectiveness and safety of trations. The influence of a single study on the overall results was
inhaled antibiotics among adult patients with pneumoniae on mortality, evaluated by sensitivity analysis. P value at the 0.05 level was consid-
clinical recovery, microbiological eradication, and nephrotoxicity, in ered to be statistically significant. Publication bias was evaluated by
order to help guide clinical practice. Begg’s funnel plot. STATA version 12 (STATA Corp, College Station, TX,
USA) was used for above statistical analyses.
2. Methods
3. Results
2.1. Search strategy
3.1. Search results and quality assessment
The current meta-analysis was conducted by reference to Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) A total of 3974 references were identified according to the pre-set
[12]. Five databases were searched up to May 31, 2024, including retrieval strategy. After duplicate removal and abstract screening, 306
PubMed, Embase, Cochrane Library, Web of Science and Scopus. Med- articles were assessed for eligibility through further full-text review.
ical Subject Headings (MeSH) was used for search strategy, which Then 276 articles were excluded due to incompatible with inclusion
combined with the following keywords: “Inhalation”, “Inhaling”, criteria. Finally, 12 RCT studies and 18 observational studies were
“Inhaled”, “Respiratory inspiration”, “Aerosolized”, “Nebulized”, “Res- included in this systematic review. The detailed selection process of the
piratory tract infections”, “Pneumonia”, “Lung inflammation”, “Tra- study is presented in Fig. 1.
cheobronchitis”, “Colistin”, “Polymyxin B”, “Aminoglycosides”, The characteristics of all studies are shown in Table 1 and Supple-
“Amikacin”, “Tobramycin”, and “Colistimethate sodium (CMS)”. mentary Table 1. There were 1348 patients in 12 included RCT studies
[4,5,8,9,11,14–38]. Six studies investigated the efficacy of amikacin as
2.2. Selection criteria inhaled antibiotic. In addition, two studies explored polymyxin and two
studies reported the data of tobramycin. Among trial groups, there were
Two independent reviewers identified the eligible literatures ac- 10 trials were only conducted with inhaled antibiotics, patients in other
cording to the following inclusion criteria: (1) Study design: case-control trials were received inhaled antibiotics combined with other routes. In
study or cohort study or RCT; (2) Interest: Included patients were over the control groups, 8 studies used inhaled placebo and others used
18 years old, had been diagnosed with respiratory tract infections or intravenous administration.
lung inflammation; (3) Comparison or control: the case group should Among 18 observational studies, 16 literatures concerned inhaled
include inhaled administration, the control group received treatment polymyxins (13 studies of colistin and 3 studies of polymyxin B), and 2
methods other than nebulization, or only aerosolize placebo; (4) Pri- literatures reported the outcomes of amikacin. There were 5 trials
mary outcomes: the primary outcomes included at least one of the evaluated inhaled antibiotics alone and 13 trials using inhaled antibi-
following indices: mortality, clinical cure (the disappearance of otics combined with intravenous administration. All patients in control
infection-related symptoms and signs or improvement of radiological groups were received intravenous administration alone.
findings and laboratory features by the end of treatments), and micro- According to the Newcastle-Ottawa scale and Jadad score, all articles
biological cure (no growth in the final culture by the end of treatments); are eligible for inclusion (Table 1).
(5) Other factors of interest: clinical recurrence, microbial recurrence,
and renal impairment. 3.2. Characteristics of continuous variable

2.3. Data collection and quality assessment The age, APACHE II score, treatment duration and length of ICU stay
were collected as continuous variable (Table 1 and Supplementary
After excluding duplicate literature and further screening based on Table 1). These factors were not statistically significant between trial
the type of article, two investigators (ZZZ and HL) selected relevant and the control groups in both RCT studies and the observational
articles by title and abstract, independently. Any controversies were studies. It is of note that treatment duration and length of ICU stay is
resolved through discussion with a third reviewer (YTH). The extracted lower in patients with inhaled antibiotics although there is no statistical
details included first author, year of publication, continent of the study difference (Supplementary Table 2).
population, trial design, drugs, administrations, characteristics of par-
ticipants, the primary outcomes and other factors of interest. 3.3. Mortality
Two investigators (BHS and TTK) evaluated the quality of observa-
tional research articles based on the Newcastle Ottawa scale, and the A total of 1295 patients in 11 RCT studies were assessed mortality.
quality of RCT studies were assessed according to the Jadad scale by The pooled result showed OR was 1.06 (95 % confidence interval (CI):
other two investigators (QHW and XL). Disagreements were resolved by 0.80–1.41; I-squared = 0.0 %, P = 0.666) with low heterogeneity,
a third reviewer (WY). indicating no significant improvement in mortality for patients with
inhaled antibiotics (Fig. 2a). According to different antibiotics and ad-
2.4. Statistical analysis ministrations, subgroup analysis also showed the similar results (Fig. 2c
and Supplementary Table 3). Notably, the OR for patients received
A random-effects model was used in our meta-analysis. Dichotomous extended infusion of meropenem and inhaled amikacin was 0.55 (95%
data were used to assess odds ratio (OR) for measuring the relation CI: 0.16–1.93) [20].
between inhaled antibiotics and primary outcomes. For continuous There were 16 observational studies including 1636 patients re-
variable, standardized mean difference (SWD) was calculated by mean ported the data of mortality. The pooled OR was 0.64 (95%CI:
and standard deviation (SD). The related data without mean ± SD were 0.50–0.82; I-squared = 8.8 %, P < 0.001), showing the significant

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Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

Fig. 1. Flow diagram of studies selection.

improvement in mortality (Fig. 2b). The subgroup analysis demon- 95%CI: 1.30–262.81, I-squared = 76.1 %) (Fig. 4c).
strated that the combination of inhaled antibiotics with intravenous The pooled OR was 2.20 (95%CI: 1.59–3.06; I-squared = 32.8 %, P <
administration (OR: 0.61, 95%CI: 0.46–0.81) effectively decreased 0.001) in 13 observational studies (Fig. 4b). OR-Galbraith plots showed
mortality compared to intravenous administration alone (OR: 0.78, 95% low heterogeneity (Supplementary Fig. 1f). Subgroup analysis showed
CI: 0.45–1.35) (Fig. 2d). In addition, patients received amikacin had inhaled antibiotics alone (OR: 2.10, 95%CI: 0.89–4.93, I-squared = 45.9
better survival outcomes than colistin and polymyxin. %) or combined with intravenous administration (OR: 2.26, 95%CI:
All points in OR-Galbraith plots lied within the confidence bounds, 1.55–3.27, I-squared = 36.0 %) had similar effect on bacterial clearance
representing low heterogeneity (Supplementary Figs. 1a–b). rate. Superior microbiological efficacy during treatment in the patients
receiving inhaled amikacin (OR: 3.68, 95%CI: 1.21–11.20, I-squared =
3.4. Clinical cure 0.0 %) compared to those receiving colistin (OR: 1.94, 95%CI:
1.29–2.91, I-squared = 38.8 %) or polymyxin B (OR: 2.84, 95%CI:
The pooled OR of clinical cure was 1.47 (95%CI: 0.82–2.66, I- 1.51–5.34, I-squared = 16.8 %) (Fig. 4d).
squared = 59.7 %, P = 0.196) in 7 RCT studies (Fig. 3a). The OR-
Galbraith plots signified Hassan’s study might be the most important 3.6. Recurrence
cause of heterogeneity (Supplementary Fig. 1c). Subgroup analysis
found inhaled antibiotics combined with intravenous administration The rates of clinical recurrence were reported in 2 RCT studies and 3
(OR: 3.14, 95%CI: 1.07–9.27, I-squared = 0.0 %) or inhaled antibiotics observational studies. The pooled OR of recurrence were 1.06 and 1.20
alone (OR:1.85, 95%CI: 0.57–6.00, I-squared = 77.1 %) obviously in- in RCT studies and observational studies, respectively (Supplementary
crease clinical cure rate than intravenous administration alone. Ami- Table 4). Inhaled antibiotics did not reduce the clinical recurrence rate.
kacin showed the highest improvement of clinical cure rate (OR: 2.04, It is noteworthy that the pooled OR of microbial recurrence rate was
95%CI: 1.01–4.12, I-squared = 55.6 %) (Fig. 3c). 2.26 in 4 observational studies.
The results of 11 observational studies were similar to RCT studies.
The pooled OR was 2.09 (95%CI: 1.36–3.21; I-squared = 58.1 %, P = 3.7. Renal impairment
0.001) (Fig. 3b). The OR-Galbraith plots showed Dalia’s and Kalin’s
studies were the sources of heterogeneity (Supplementary Fig. 1d). Included data of renal impairment retrieved from 5 RCT studies and
Inhaled antibiotics alone or combined with intravenous administration 12 observational studies. The pooled OR were 0.65 (95%CI: 0.27–1.13;
improved clinical cure rate (Fig. 3d). Among different inhaled antibi- I-squared = 43.5 %, P = 0.124) and 0.63(95%CI: 0.26–1.11; I-squared =
otics, patients received amikacin (OR: 6.83, 95%CI: 1.36–34.20, I- 69.0 %, P = 0.110) in RCT studies and observational studies, respec-
squared = 75.2 %) had significantly more favourable clinical outcome tively (Supplementary Table 4).
than colistin (OR: 1.70, 95%CI: 1.12–2.57, I-squared = 40.8 %) and
polymyxin B (OR: 2.03, 95%CI: 0.95–4.33, I-squared = 0.0 %) (Fig. 3d). 3.8. Sensitivity analysis

3.5. Microbiological cure Sensitivity analysis was employed to evaluate the influence of the
single study on the overall results of the meta-analysis. Microbiological
Among 4 RCT studies, the pooled OR of microbiological cure was cure rate in the RCT group showed instability (Supplementary Fig. 2e),
7.00 (95%CI: 0.95–51.71; I-squared = 80.9 %, P = 0.056) with while the other pool results showed reliable sensitivity due to deleting
considerable heterogeneity (Fig. 4a). According to OR-Galbraith plots, each trial with low change (Supplementary Fig. 2a-d,f). The instability
Angermair’s and Palmer’s studies might be the source of heterogeneity of microbiological cure rate is due to the results of trial groups in
(Supplementary Fig. 1e). Favourable microbiological outcome was Palmer’s and Angermair’s studies much better than that of placebo as
significantly greater in patients received inhaled antibiotics (OR: 18.51, control groups.

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Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

Table 1
Characteristics of included studies and participants.
First author Disease Age (years) Drug Treatments Bacteria Quality Ref.
score
case control case control case control

Randomized controlled trial studies


Bilton D Pneumonia 61.9 63.7 ± Tobramycin Placebo Aerosolized + Aerosolized + P. aeruginosa 6 [14]
± 11.7 oral oral
11.4 ciprofloxacin ciprofloxacin
Palmer LB VAP 62.3 62.7 ± Different Placebo Aerosolized Aerosolized Gram-negative and 6 [15]
± 20.1 antibiotics gram-positive
20.4 bacteria
Rattanaumpawan VAP 70.2 66.2 ± Colistimethate Placebo Aerosolized Aerosolized Gram-negative 5 [11]
P ± 15.8 bacteria
18.5
Lu Q VAP 58.0 60.0 ± Ceftazidime + Ceftazidime Aerosolized Intravenous P. aeruginosa 7 [16]
± 17.0 amikacin + amikacin
15.0
Palmer LB Pneumonia 57.7 60.6 ± Different Placebo Aerosolized Aerosolized MDR bacteria 5 [4]
± 18.2 antibiotics
23.1
Abdellatif S VAP 50.0 53.0 ± Colistin Colistin Aerosolized Intravenous Gram-negative 7 [17]
± 17.0 bacteria
16.0
Kollef MH VAP 57.7 61.9 ± Amikacin + Placebo Aerosolized Aerosolized Gram-negative 6 [18]
± 11.5 fosfomycin bacteria
15.2
Liu C VAP 68.1 64.7 ± Amikacin Placebo Aerosolized Aerosolized MDR gram- 4 [5]
± 10.6 negative bacteria
16.7
Ammar MA VAP 55.5 54.9 ± Amikacin Amikacin Aerosolized + Intravenous MDR gram- 4 [19]
± 3.9 4.3 intravenous amikacin + negative bacteria
colistin and meropenem
meropenem
Hassan NA VAP or HAP 49.8 51.4 ± Amikacin Amikacin Aerosolized Intravenous MDR gram- 5 [20]
± 9.8 9.9 negative bacteria
Niederman MS Pneumonia 64.2 63.9 ± Amikacin Placebo Aerosolized Aerosolized MDR gram- 7 [21]
± 17.5 negative bacteria
16.1
Angermair S VAP 64.9 64.2 ± Tobramycin Placebo Aerosolized Aerosolized Gram-negative 5 [22]
± 10.7 bacteria
14.8
Observational studies
Kofteridis DP VAP 62.4 62.0 ± Colistin Colistin Aerosolized + Intravenous MDR gram- 7 [23]
± 15.1 intravenous negative bacteria
14.9
Korbila IP VAP 59.2 60.9 ± Colistin Colistin Aerosolized + Intravenous Gram-negative 8 [8]
± 15.7 intravenous bacteria
19.2
Naesens R Pneumonia NR NR Colistin Colistin Aerosolized/ Intravenous MDR P. aeruginosa 6 [9]
Aerosolized +
intravenous
Pérez-Pedrero MJ HAP or 55.5 60.1 ± Colistin Colistin Aerosolized Intravenous MDR gram- 5 [24]
Tracheobronchitis ± 17.4 negative bacteria
19.8
Kalin G VAP 50.1 48.2 ± Colistin Colistin Aerosolized + Intravenous MDR A. baumannii 4 [25]
± 22.2 intravenous
19.8
Doshi NM Pneumonia 60.9 57.3 ± Colistin Colistin Aerosolized + Intravenous MDR gram- 5 [26]
± 15.6 intravenous negative bacteria
15.3
Tumbarello M VAP 62.9 63.9 ± Colistin Colistin Aerosolized + Intravenous Gram-negative 7 [27]
± 21.0 intravenous bacteria
21.0
Zah Bogovict T VAP 72.4 72.5 ± Colistin Colistin Aerosolized + Intravenous MDR gram- 4 [28]
± 12.9 intravenous negative bacteria
11.9
Zhu JD VAP 42.4 41.9 ± Amikacin Amikacin Aerosolized Intravenous A. baumannii 4 [29]
± 6.8 5.9
Jang JY VAP 67.5 60.0 ± Colistin Colistin Aerosolized Intravenous MDR A. baumannii 5 [30]
± 15.2
12.6
Kim YK VAP 68.9 63.6 ± Colistin Colistin Aerosolized Intravenous Carbapenem- 5 [31]
± 16.6 resistant
14.2 A. baumannii
Choe J VAP or HAP NR NR Colistin Colistin Aerosolized + Intravenous Carbapenem- 6 [32]
intravenous resistant gram-
negative bacteria
(continued on next page)

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Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

Table 1 (continued )
First author Disease Age (years) Drug Treatments Bacteria Quality Ref.
score
case control case control case control

El Fawy VAP 58.0 59.3 ± Amikacin Amikacin Aerosolized + Intravenous Klebsiella, 7 [33]
± 17.4 intravenous Acinetobacter,
14.4 Pseudomonas,
Citrobacter,
Staphylocci,
Provedinetia,
Proteus,
Enterobacter
Ahn SH Pneumonia 69.6 66.6 ± Colistin Colistin Aerosolized Intravenous MDR A.baumannii, 4 [34]
± 14.5 MDR P.aeruginosa
16.0
Almangour TA Pneumonia 54.0 54.0 ± Colistin Colistin Aerosolized + Intravenous MDR gram- 6 [35]
± 18.0 intravenous negative bacteria
20.0
Hasan MJ VAP 64.1 63.9 ± Polymyxin B Polymyxin B Aerosolized + Intravenous K. pneumoniae 5 [36]
± 14.3 intravenous
16.1
Zhou L Pneumonia 59.2 66.8 ± Polymyxin B Polymyxin B Aerosolized + Intravenous MDR gram- 4 [37]
± 13.6 intravenous negative bacteria
14.2
Liu J VAP 67.0 64.0 ± Polymyxin B Polymyxin B Aerosolized + Intravenous Extensively drug- 5 [38]
± 17.0 intravenous resistant gram-
17.0 negative bacteria

VAP, ventilator-associated pneumonia; HAP, hospital acquired pneumonia; MDR, multi-drug resistant; NR, no report; Ref., references.

Fig. 2. Forest plots and subgroup analysis of mortality. (a)forest plots of mortality in RCT studies; (b)forest plots of mortality in observational studies; (c)subgroup
analysis of mortality in RCT studies; (d)subgroup analysis of mortality in observational studies. IN, Inhaled antibiotics; IV, intravenous administration.

3.9. Publication bias option for the treatment of chronic airway diseases, minimizing the
adverse effects of systemic antibiotic therapy [1,2]. However, the effi-
The publication bias was assessed by funnel plot asymmetry ciency of inhaled antibiotics is not consistent, especially for improve-
(Supplementary Fig. 3). There was no potential publication bias in this ment of survival rate. This systematic review and meta-analysis
study. demonstrated there is no significant decrease in mortality whether using
aerosolized antibiotics or not in RCT studies. However, favourable
4. Discussion clinical cure and microbiological cure were observed for patients
received inhaled antibiotics, especially for amikacin. The pooled OR of
The use of inhaled antibiotics has been proposed as a promising renal impairment in patients was less than 0.7.

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Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

Fig. 3. Forest plots and subgroup analysis of clinical cure. (a)forest plots of clinical cure in RCT studies; (b)forest plots of clinical cure in observational studies; (c)
subgroup analysis of clinical cure in RCT studies; (d)subgroup analysis of clinical cure in observational studies. IN, Inhaled antibiotics; IV, intravenous
administration.

Fig. 4. Forest plots and subgroup analysis of microbiological cure. (a)forest plots of microbiological cure in RCT studies; (b)forest plots of microbiological cure in
observational studies; (c)subgroup analysis of microbiological cure in RCT studies; (d)subgroup analysis of microbiological cure in observational studies. IN, Inhaled
antibiotics; IV, intravenous administration.

Use of inhaled antibiotics is part of the standard treatment in cystic and worsening bacterial resistance may affect the prognosis of the pa-
fibrosis, while the evidence for patients with other bronchiectasis or tients with VAP or in ICU [41]. Therefore, although the current studies
pneumoniae was inconsistent [11,23,39]. Our data suggest that inhaled failed to achieve endpoint of significant mortality decrease, it is
antibiotics did not consistently achieve reduction in mortality in RCT important to compel us to optimize the antibiotics treatments and future
studies. The pooled OR of mortality in RCT studies (1.06, 95%CI: trial designs in the critically ill.
0.80–1.41) was higher than in observational studies (OR 0.64, 95%CI: Results of inhaled antibiotics as adjunctive therapy to intravenous
0.50–0.82), which is consistent with previous study for VAP (OR 0.89, antibiotics or alone for pneumonia from RCT and retrospective studies
95 % CI 0.64–1.25) [40]. This may be due to the inclusion of different are inconclusive [11,18,23]. The clinical and microbiological signifi-
patients in our study, especially for VAP. The severity of patient illness cance of inhaled antibiotics was observed in our study. The subgroup

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Z. Zhang et al. Pulmonary Pharmacology & Therapeutics 86 (2024) 102315

analysis in the present study revealed that the combination of inhaled Investigation, Data curation. Yutao Hu: Supervision, Methodology,
and intravenous route was more effective in reducing mortality than Investigation, Data curation. Binhui Sun: Validation, Investigation,
only intravenous route. Therefore, for patients with poor efficacy of Data curation. Tingting Ke: Supervision, Investigation, Data curation.
intravenous antibiotics alone, adjunctive inhaled antibiotics can also be Qihuan Wu: Validation, Supervision, Data curation. Xiang Lian:
considered as a last resort [21]. In addition, this meta-analysis showed Writing – review & editing, Software, Conceptualization. Wei Yu:
amikacin was more effective in improving clinical cure and microbio- Writing – review & editing, Resources, Investigation, Funding acquisi-
logical cure. In addition to therapeutic purpose, inhaling amikacin also tion, Data curation, Conceptualization.
showed the preventive effects on VAP. Current study demonstrated
preventive inhaled amikacin could reduce the incidence of
ventilator-associated pneumonia during 28 days of follow-up [2]. Declaration of competing interest
To our knowledge, multiple factors could affect the efficacy of
inhaled antibiotics, such as devices, physical and chemical properties of None.
antibiotics and underlying disease [6]. Most recent systematic reviews Title: The efficacy and safety of inhaled antibiotics for pneumonia: A
pointed out the types of devices used in inhaled antibiotics could greatly Systematic Review and Meta-Analysis
affect efficacy [6]. However, subgroup analysis was not conducted ac-
cording to the different nebulization devices due to the lack of detailed Data availability
information in the included studies. The influence of nebulization de-
vices is worth further attention and exploration. No data was used for the research described in the article.
Previous studies and our results showed an acceptable safety profile
of inhaled antibiotics [42]. Nephrotoxicity is a common adverse effect of Acknowledgements
the clinically used aminoglycosides and polymyxins during systematic
administration [43,44]. Current evidence demonstrated inhaled route of NA.
administration could reduce risk of toxicity or systemic adverse effects
encountered with antibiotics administered via other routes [42,45]. Our Appendix A. Supplementary data
date also indicated that the choice of inhaled antibiotics reduced
nephrotoxicity as well. Supplementary data to this article can be found online at https://doi.
The present study has several limitations. First, different treatments org/10.1016/j.pupt.2024.102315.
and limited study quality resulted in heterogeneity. Secondly, the
number of RCT studies for same antibiotics in specific infections were References
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