Respiratory Investigation 62 (2024) 200–205

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Respiratory Investigation
journal homepage: www.elsevier.com/locate/resinv

Review

Carbapenem vs. non-carbapenem antibiotics for ventilator-associated

pneumonia: A systematic review with meta-analysis
Hisayuki Shuto a, 1, Kosaku Komiya a, b, *, Kazuya Tone c, Hiroyuki Matsumoto a, Hiroshi Moro d,
Nobuaki Shime e
a
Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
b
Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
c
Department of Respiratory Medicine, The Jikei University School of Medicine Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa, Chiba, 277-8567, Japan
d
Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan, 951-8510, Japan
e
Department of Emergency and Critical Care Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan

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

Keywords: Background: Carbapenem is recommended as one of the first-line regimens for ventilator-associated pneumonia
Ventilator-associated pneumonia (VAP), but no recent systematic review has fully investigated its efficacy. This systematic review aims to evaluate
Carbapenem the efficacy of carbapenem compared with non-carbapenem for VAP treatment.
Empiric therapy
Methods: We performed a systematic review and meta-analysis of studies comparing the efficacy and the safety
between carbapenem and non-carbapenem with activity to Pseudomonas aeruginosa in the treatment for VAP. The
main outcome was mortality, and the additional outcomes were the clinical cure of pneumonia, length of
intensive care unit stay, recurrence, adverse effects, and the development of resistant bacteria. This study was
conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)
guidelines.
Results: Of the initial 1,730 publications, 9 randomized control trials were enrolled. In the meta-analysis, no
difference was observed between the carbapenem and non-carbapenem regimens in improving mortality (odds
ratio, 0.83; 95 % confidence interval (CI) 0.67–1.02). While the carbapenem regimen was superior to the non-
carbapenem regimen in studies reporting the resolution of pneumonia (odds ratio, 1.09; 95 % CI 1.01–1.17),
the effectiveness of carbapenem treatment was not evident in studies assessing the other outcomes.
Conclusions: Carbapenem might have no superiority in survival when treating VAP. Moreover, non-carbapenem
antibiotics with activities to P. aeruginosa have a potential option to avoid inducing carbapenem-resistant
pathogens.

methicillin-resistant Staphylococcus aureus (MRSA) for high-risk patients

[3,4]. Carbapenem has a wide antibiotic spectrum for Gram-negative
1. Introduction rod and is a first-line drug in the treatment for VAP. However, the
inadequate or frequent use of carbapenem may induce
Ventilator-associated pneumonia (VAP) may occur in 10 % of carbapenem-resistant pathogens, which could result in a global health
ventilated patients, and its mortality is estimated to be 13 % [1]. The threat. Thus, the indication for antibiotic therapy using carbapenem
success in initial therapy was reported to indicate an improvement in the needs to be fully investigated, and other alternative antibiotic options
prognosis of patients with VAP [2]. The 2016 clinical practice guidelines should also be considered [5].
of the Infectious Diseases Society of America (IDSA) and the American The recommendations in the 2016 IDSA/ATS guidelines are based on
Thoracic Society (ATS) for the management of adults with the results from their own systematic reviews, which reported that the
hospital-acquired pneumonia (HAP) and VAP recommend the use of carbapenem regimen significantly improved the survival rate of patients
antibiotics covering Gram-negative rod, including Pseudomonas aerugi­ with VAP compared with the non-carbapenem regimen [3]. In contrast,
nosa, and the consideration of the combined use of antibiotics against

* Corresponding author. Oita University Faculty of Medicine 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.
E-mail address: komiyakh1@oita-u.ac.jp (K. Komiya).
1
These authors equally contributed to this study.

https://doi.org/10.1016/j.resinv.2023.12.006
Received 9 September 2023; Received in revised form 27 November 2023; Accepted 16 December 2023
Available online 7 January 2024
2212-5345/© 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
H. Shuto et al. Respiratory Investigation 62 (2024) 200–205

This systematic review focused on the empiric therapy for VAP. Thus,
Abbreviations definitive therapy after the pathogens were isolated from the respiratory
samples was excluded. The trials that compared monotherapy with
ALAT Asociación Latinoamericana del Tórax combination therapy were also excluded because they do not provide
ATS American Thoracic Society results regarding the superiority or inferiority of carbapenem in com­
CI Confidence interval parison with single non-carbapenem agents. By contrast, the study
ERS European Respiratory Society designed as additional agents mandatory or allowed (e.g. anti-MRSA
ESCMID European Society of Clinical Microbiology and drugs) for both intervention and comparison groups were included.
Infectious Diseases Furthermore, we excluded studies in which VAP was not clearly differ­
ESICM European Society of Intensive Care Medicine entiated from HAP.
HAP Hospital-acquired pneumonia
ICU Intensive care unit 2.2. Data extraction and assessing the risk of bias
IDSA Infectious Diseases Society of America
MJ McKenzie JE The titles, abstracts, and full texts of the articles were screened and
MRSA Methicillin-resistant Staphylococcus aureus further independently assessed by two respiratory infectious disease
PRISMA Preferred Reporting Items for Systematic reviews and specialists (H.S. and K.T.). Disagreements were resolved by a third
Meta-Analyses reviewer of the other authors. We obtained the following information
VAP Ventilator-associated pneumonia from the included studies: study design, sample size, treatment regi­
mens, and the number of each outcome among patients.
We conducted a meta-analysis using the Review Manager (Revman,
London, UK) for the outcomes for which two or more studies provided
the results of a systematic review conducted by the Cochrane review data. The outcomes were pooled using Mantel-Haenszel risk ratios, and
team in the same year indicated that carbapenem was not effective in the precision of the estimates was expressed as the 95 % confidence
improving the mortality rate, while it was found to increase the clinical interval (CI). Statistical heterogeneity was assessed using the Higgins I2
cure rate [6]. Although several comparison studies have been addi­ tests. A random-effects model was used when significant heterogeneity
tionally conducted since these reviews were performed, no updated was found. Publication bias was assessed by the examination of funnel
systematic review has been published yet. Currently, the Japanese plots.
Respiratory Society is revising the guidelines for the management of The risk of bias was assessed according to the scales of version 2 of
pneumonia in adults, and the committee members raised the following the Cochrane risk-of-bias tool for randomized trials (RoB2) for the RCT
clinical question: “Is the carbapenem regimen more highly recom­ [10]. The trials were assessed for eight factors related to the potential
mended than the non-carbapenem regimen in the treatment for VAP?” biases as follows: random sequence generation (selection bias), alloca­
The aim of this study is to conduct a systematic review of the studies tion concealment (selection bias), blinding of participants and personnel
comparing the carbapenem regimen with the non-carbapenem regimen (performance bias), blinding of outcome assessment (detection bias):
for VAP treatment. self-reported outcomes, blinding of outcome assessment (detection
bias): objective measures, incomplete outcome data (attrition bias): all
2. Materials and methods outcomes, selective reporting (reporting bias), and other bias.

This study was conducted in accordance with the Preferred Report­ 3. Results
ing Items for Systematic reviews and Meta-Analyses (PRISMA) guide­
lines [7]. To ensure a timely publication, this review has not been 3.1. Database search
registered in any database in advance. The authors have no conflicts of
interest to declare. A total of 1,730 articles were identified through PubMed and
ICHUSHI. We then excluded 1,705 manuscripts as the abstracts did not
2.1. Search criteria meet the inclusion criteria. We excluded 16 of the remaining 25 records
after retrieving and inspecting the full text. The reasons for exclusion
Since this systematic review was conducted in the process of revising were as follows: mismatched exposure or outcomes (n = 4), unavailable
the guidelines for the management of pneumonia in adults by the Jap­ data specific for VAP (n = 10), and subanalysis or post hoc analysis of
anese Respiratory Society, we used PubMed and Igaku Chuo Zasshi the original study (n = 2). Finally, nine RCTs were included in the final
(ICHUSHI), which is being updated by the Japan Medical Abstracts analysis [11–19]. Fig. 1 shows the process of the study selection.
Society (JAMAS), and accessible full text written in English or Japanese
was included. The search strategy was developed in PubMed and then 3.2. Details of eligible studies and assessing the risk of bias
subsequently translated for ICHUSHI. Full strategies are provided in the
Supplementally file. We accessed these databases on 8 August 2023, and While the carbapenem regimens studied were MEPM (n = 4), IPM/
screened the articles published before 31 May 2023, to maintain cilastatin (CS) (n = 3), DRPM (n = 1), and IPM/CS/relebactam (REL) (n
reproducibility of the search. = 1), the comparison regimens included tazobactam (TAZ)/piperacillin
We included randomized control trials (RCTs) that compared the (PIPC) (n = 2), tigecycline (n = 2), TAZ/ceftolozane (CTLZ) (n = 1),
efficacy and/or safety of the carbapenem regimen with that of the non- avibactam (ACI)/ceftazidime (CAZ) (n = 1), levofloxacin (LVFX) (n =
carbapenem regimen for VAP patients aged over 18 years old. VAP was 1), colistin (n = 1), and cefiderocol (n = 1), as summarized in Table 1. In
defined as a “pneumonia that develops more than 48 h after endotra­ a trial by Shorr et al. amikacin (AMK) was administered to the carba­
cheal intubation” [8]. Carbapenem included meropenem (MEPM), imi­ penem group and CAZ to the LVFX group [11]. Similarly, Freire et al.
penem (IPM), and doripenem (DRPM). The non-carbapenem group, allowed the combination use with CAZ in the tigecycline group [13].
which was the comparison group, was limited to antibiotic agents with Anti-MRSA agents were mandatory for both the carbapenem group and
activity to P. aeruginosa because the guidelines recommend its coverage non-carbapenem group in five studies [14–16,18,19], allowed in two
for VAP treatment [3,9]. The main outcome was mortality, whereas the studies [12,17], and no requirement [11]. A study by Freire et al.
secondary outcomes were clinical cure of pneumonia, length of ICU stay, allowed the combination treatment with VCM only for the carbapenem
recurrence, adverse effects, and the development of resistant bacteria. group [13].

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Fig. 1. Flow diagram of the study selection.

Table 1
A summary of included studies.
Study Patients Carbapenem* Non- Combination therapy Outcome
carbapenem*

Titov 2021 VAP, HAP IPI/REL (n = TAZ/PIPC (n = LZD was mandatory for both groups. 28-day
91) 101) mortality
Clinical cure
Wunderink VAP, HAP, MEPM (n = 64) Cefiderocol (n = LZD was mandatory for both groups. 28-day
2021 HCAP 59) mortality
Clinical cure
Kollef 2019 VAP, HAP MEPM (n = TAZ/CTLZ (n = LZD was mandatory for both groups. 28-days
256) 263) AMK was allowed for both groups. mortality
Clinical cure
Cisneros 2019 VAP MEPM (n = Colistin (n = 120) LVFX was mandatory for both groups. 28-day
112) VCM or LZD was allowed for both groups. mortality
Clinical cure
Adverse
events
Relapse
Torres 2018 VAP, HAP MEPM (n = AVI/CAZ (n = AMK and either VCM or LZD were mandatory for both groups. Clinical cure
128) 118)
Ramirez 2013 VAP, HAP IPM/CS (n = Tigecycline (n = VCM and either TOB or AMK were mandatory for the carbapenem group. Clinical cure
16) 25) CAZ and either TOB or AMK were mandatory for the non-carbapenem group.
Freire 2010 VAP, HAP IPM/CS (n = Tigecycline (n = VCM was allowed for the carbapenem group. Short-term
122) 131) CAZ was allowed for the non-carbapenem group. death†
Clinical cure
Days of ICU
stay
Réa-Neto VAP, HAP DRPM (n = 62) TAZ/PIPC (n = VCM or AMK was allowed for both groups. Clinical cure
2008 61)
Shorr 2005 VAP, HAP IPM/CS (n = LVFX (n = 111) In the case of Pseudomonas aeruginosa infection or suspected, AMK was mandatory for Clinical cure
111) the carbapenem group and CAZ for the non-carbapenem group. Adverse
events

AVI/CAZ, avibactam/ceftazidime; AMK, amikacin; CAZ, ceftazidime; DRPM, doripenem; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneu­
monia; IPM/REL, imipenem/cilastatin/relebactam; IPM/CS, imipenem/cilastatin; LVFX, levofloxacin; MEPM, meropenem; TAZ/PIPC, tazobactam/piperacillin; TOB,
tobramycin; VAP, ventilator-associated pneumonia; VCM, vancomycin.
*, the number of cases of VAP patients only is listed. †, death at the test of cure assessment 10–21 days after 7–10 days of treatment.

As shown bias risk using RoB2 in Fig. 2, three trials were not blinded test of cure 10–21 days after 7–10 days of treatment [13]. The
[11,12,17]. Two studies conducted by Ramirez et al. and Cisneros et al. meta-analysis indicated the superiority of carbapenem, but no signifi­
have been halted since the desired number of participants was not cant difference was observed between the carbapenem and
reached [14,17]. All studies except for one [17] received funds from the non-carbapenem regimens (relative risk, 0.83; 95 % CI, 0.67–1.02; I2 =
associated pharmaceutical companies. 0 %) as shown in Fig. 3. A funnel plot symmetry was observed for
in-hospital mortality.

3.3. In-hospital mortality

3.4. Clinical cure rate
Five studies [13,16–19] assessed the in-hospital mortality; four
assessed the 30-day mortality [16–19]; and one assessed the death at the The clinical cure rate was analyzed in all included studies. The meta-

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Fig. 2. ‘Risk of bias’ summary: review authors’ judgments about each risk of bias item for each included study.

Fig. 3. Forest plot and funnel plot: carbapenem versus non-carbapenem for in-hospital mortality.

analysis showed a significant superiority of the carbapenem regimen groups [11,17], but these trials did not confirm whether the adverse
compared with the non-carbapenem regimen with zero heterogeneity effects were caused by antibiotics. The meta-analysis indicated no sig­
(Fig. 4), but the advantage was limited: the risk ratio was 1.09 (95 % CI nificant difference (relative risk, 1.00; 95 % CI, 0.79–1.27; I2 = 0 %) as
1.01–1.17) and risk difference was 0.06 (95 % CI 0.01–0.10). Further­ shown in Fig. 5.
more, the funnel plot appeared to be asymmetrical with a larger number
of studies with a high risk ratio.
3.6. Recurrence of pneumonia

Recurrence was compared in only one RCT [17]. This study did not
3.5. Length of intensive care unit stay
show any statistical significance between MEPM and colistin in the
recurrence of pneumonia (RR 0.73, 95 % CI 0.13–4.24).
Only one study assessed the length of ICU stay [13]. This study
presented the non-statistical significance (p = 0.937) without providing
the actual number of outcomes in both groups. 3.7. Development of resistant bacteria

3.5.1. Adverse effects No study assessed the resistant bacteria before or after antibiotic
Two RCTs compared the rate of severe adverse effects between the treatment.

Fig. 4. Forest plot and funnel plot: carbapenem versus non-carbapenem for clinical cure rate.

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Fig. 5. Forest plot and funnel plot: carbapenem versus non-carbapenem for adverse effects.

4. Discussion antibacterial activity to P. aeruginosa. Furthermore, no significant dif­

ference in the adverse effects among carbapenem, TAZ/PIPC, and
Five RCTs have been newly added to this systematic review since the TAZ/CTLZ was observed [12,16,18]. Further studies that assess not only
latest IDSA/ATS guidelines and the Cochrane review were published [3, efficacy but also the development of antibiotic resistance and adverse
6]. The results indicated that the carbapenem regimen does not seem to effects are required.
improve the in-hospital mortality compared with the non-carbapenem It should be discussed that anti-MRSA drug is mandatory for the
regimen, although it may slightly increase the clinical cure rate. Addi­ combination treatment of both the carbapenem and non-carbapenem
tionally, even including these newly published studies, the obtained groups in all trials except for one [11]. If MRSA is a significant causa­
data is not sufficient to conclude the role of carbapenem on the length of tive pathogen for patients with VAP who were included in these studies,
ICU stay, adverse effects, recurrence, and the development of antibiotic the use of anti-MRSA drugs for both groups would deteriorate the
resistance. detection power of statistical significance. However, some studies have
The current systematic review suggests that carbapenem regimens shown that MRSA isolated from the respiratory samples may mostly
do not necessarily improve the in-hospital mortality for patients with denote colonization but not infection. For example, more than 90 % of
VAP compared with some non-carbapenem regimens. However, the 95 patients with healthcare-associated pneumonia and MRSA isolated from
% CI ranged from 0.67 to 1.02, which denoted no significance but did sputum were successfully cured without anti-MRSA drug therapy [21].
not provide solid coherence. In fact, a recent systematic review that A database study from the USA also indicated that MRSA coverage
focused on the efficacy of carbapenem for the empiric treatment of HAP, therapy did not improve the prognosis of hospitalized patients with
including VAP, demonstrated that carbapenem regimens were associ­ community-acquired pneumonia [22]. Although no sufficient evidence
ated with lower mortality than non-carbapenem regimens, largely can confirm the efficacy of anti-MRSA drugs in treating VAP, “MRSA
driven by VAP studies [20]. This systematic review additionally showed pneumonia” is unlikely to account for the majority of VAP.
that the superiority of the carbapenem regimens was observed mainly in The strength of this systematic review was that it updated the latest
trials that used ceftazidime as control. The efficacy of the carbapenem IDSA/ATS guidelines and the Cochrane review. In particular, no suffi­
regimens can be susceptible to characteristics of targeted patients and cient data can support the description of the role of carbapenem on
control regimens. Comparative drugs varied depending on the trial, a mortality in patients with VAP in 2016. However, some limitations in
detailed information of comparison arm needs to be considered. Of the this study should be noted. First, this systematic review searched articles
comparison drugs in the current meta-analysis, AVI/CAZ, cefiderocol, only through PubMed and ICHUCHI because quick conduct is required
tigecycline, and colistin were fundamentally restricted to be used for in the process of the management of pneumonia by the Japanese Res­
highly resistant pathogens (e.g., multidrug resistant P. aeruginosa). In piratory Society. Second, three of nine trials were performed with an
this regard, these drugs would not be recommended as the first-line open label, which could have led to performance and detection biases.
empiric therapy for the treatment of patients with VAP whereas the Third, the evaluation methods for the outcomes other than mortality
other comparison agents, such as TAZ/PIPC, TAZ/CTLZ, and LVFX, can may be varied (e.g., clinical cure). Since the novel finding in this sys­
be selected as the first regimen. tematic review was the impact of carbapenem vs. non-carbapenem on
When investigating the antibacterial activity for P. aeruginosa of each in-hospital mortality, these biases may be ignorable. Finally, this review
antibiotics used in these included studies, the results of the drug sus­ included the regimens limited to cover P. aeruginosa as a comparison
ceptibility test need to be considered. Rea-Neto et al. have provided arm. It is evident that no RCT comparing regimens with or without ac­
information of the isolated pathogens at baseline [12]. While DRPM was tivity to P. aeruginosa exists for VAP treatment. Therefore, it has not been
found to sufficiently cover the isolated pathogens, including determined whether P. aeruginosa coverage is mandatory in the treat­
P. aeruginosa, TAZ/PIPC did not have any activity to 34 % of ment for patients with VAP.
P. aeruginosa. Moreover, 50 % of Klebsiella pneumoniae was resistant to In conclusion, this review showed that the carbapenem regimen
TAZ/PIPC [12]. In fact, the isolation of ESBL-producing Gram-negative might not significantly improve the in-hospital mortality compared with
rod, including Klebsiella. pneumoniae, is gradually increasing [23], and the non-carbapenem regimen, although it may slightly raise the clinical
TAZ/PIPC is known to be inferior to carbapenem [24]. LVFX does not cure rate. The increasing isolation of carbapenem-resistant pathogens is
have a sufficient antibacterial activity to P. aeruginosa; thus, the study a significant health threat. The easy selection of carbapenem regimens
conducted by Shorr et al. required the combination of CAZ with LVFX in for VAP treatment should be avoided, and alternative regimens,
the case of P. aeruginosa infection or suspected [11]. In contrast, including TAZ/CTLZ or TAZ/PIPC, need to be considered.
TAZ/CTLZ was shown to have the non-inferiority to MEPM in the
treatment of HAP, including VAP, and has an adequate ability to kill Author contribution
P. aeruginosa [16]. The post hoc analysis indicated that TAZ/CTLZ was
less likely to induce the antibiotic-resistant P. aeruginosa than MEPM HS, KK, KT, and NS designed this study. HS and KT searched articles
[25]. A cross-resistance was observed between carbapenem and PIPC, and extracted the information for this systematic review. HS conducted
rather than TAZ/CTLZ [26]. Considering this fact, it would be reason­ meta-analysis. HS and KK drafted the manuscript. KT, HM, HM, and NS
able to conclude that TAZ/CTLZ should be used as another first treat­ advised and helped to draft the manuscript.
ment of choice for patients with VAP, especially in the case of
P. aeruginosa infection or suspected. However, there is still insufficient
data to conclude that carbapenem is inferior to other drugs with

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Informed consent Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and
Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).
Eur Respir J 2017:50.
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this study. revised tool for assessing risk of bias in randomised trials. Bmj 2019;366:l4898.
[11] Shorr AF, Zadeikis N, Jackson WL, Ramage AS, Wu SC, Tennenberg AM, et al.
Levofloxacin for treatment of ventilator-associated pneumonia: a subgroup analysis
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[12] Réa-Neto A, Niederman M, Lobo SM, Schroeder E, Lee M, Kaniga K, et al. Efficacy
The datasets analyzed during this study are available from the cor­ and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia:
a randomized, open-label, multicenter study. Curr Med Res Opin 2008;24:
responding author on reasonable request. 2113–26.
[13] Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al.
Declaration of competing interest Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-
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[14] Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC.
The authors have no conflicts of interest. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage
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Acknowledgments [15] Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime-
avibactam versus meropenem in nosocomial pneumonia, including ventilator-
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