Impact of carbapenem versus non-carbapenem treatment on the rates of superinfection: A meta-analysis of randomized controlled trials

doi:10.1016/j.jiac.2018.08.004

Journal of Infection and Chemotherapy

Volume 24, Issue 11, November 2018, Pages 915-920

https://doi.org/10.1016/j.jiac.2018.08.004 Get rights and content

Abstract

Imipenem and meropenem are the recommended antipseudomonal carbapenems for nosocomial pneumonia per clinical practice guidelines. However, these agents have a relatively broader spectrum of activity than other antibiotics and need to be reserved. Carbapenems might cause higher rate of superinfection. The aim of this study was to compare the rate of superinfection between patients who received imipenem or meropenem versus those who received non-carbapenem treatment. PubMed, EMBASE, Cochrane Library databases and two trial registries were searched for relevant randomized controlled trials of hospitalized adults with pneumonia through February 24, 2017 without date or language restrictions. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects models. The primary outcome was based on the intention-to-treat analysis while clinically evaluable patients were analyzed as secondary outcome. Eight RCTs were included in this meta-analysis. A statistically higher risk of superinfection with low heterogeneity (RR = 1.690, 95% CI 1.247–2.291, p = 0.001, I² = 0%) was associated with the two carbapenems compared to non-carbapenems. However, in comparison with non-carbapenems, superinfection with imipenem was significantly higher (RR = 1.694, 95% CI 1.234–2.325, p = 0.001, I² = 0%), while it was non-significant with meropenem (RR = 1.647, 95% CI 0.552–4.919, p = 0.371, I² = 0%). Superinfection was statistically higher in both double-blind and open-label studies and when carbapenems were compared to other antipseudomonal beta-lactams. This meta-analysis identified significantly higher superinfection with imipenem compared to non-carbapenems. The findings confirm the theory of higher superinfections with broader spectrum agents and provide additional support for reserving carbapenems for the treatment of infections caused by multidrug-resistant organisms.

Introduction

The 2016 Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) guidelines for implementing antibiotic stewardship program (ASP) recommended monitoring evidence of adverse events related to antibiotics and considering these factors in antibiotic selection [1], [2]. Moreover, the guidelines recommended specific ASP interventions designed to decrease the use of antibiotics that are associated with a high risk of Clostridium difficile infection (CDI). The development of CDI is one type of superinfection but the guidelines have not addressed other superinfections likely due to limited data available on antibiotic-induced superinfections.

Broad-spectrum antibiotic therapy is a risk factor for increased rates of superinfection [3]. In addition, longer antibiotic therapy duration for ventilator-associated pneumonia (VAP) is associated with higher rates of susceptible and multidrug-resistant superinfection [4]. Imipenem and meropenem are the recommended antipseudomonal carbapenems for nosocomial pneumonia per the current clinical practice guidelines but they need to be reserved [4]. These agents might cause higher rate of superinfection because of having a relatively broader spectrum of activity than other antibiotics. Randomized controlled trials (RCTs) reduce selection bias but unfortunately do not consistently report rates of superinfection. It is very unlikely that one study would be adequately powered to detect a statistically significant difference of superinfection rate. Therefore, the objective of this meta-analysis is to compare the rate of superinfection between patients who received imipenem or meropenem versus those who received non-carbapenem antibiotics for treatment of pneumonia.

Section snippets

Materials and methods

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (appendix. eTable 2). This study is registered with PROSPERO, number CRD42017058062.

Results

The search process identified 431 articles (PubMed 122; Embase 142; Cochrane Library 167) [Fig. 1]. After removal of duplicates, a total of 253 articles were screened. Twenty-four full-text articles were assessed for eligibility after screening by title and/or abstract and eight RCTs (with 1874 patients) were included [6], [7], [8], [9], [10], [11], [12], [13]. A total of 814 ITT-patients treated with carbapenems (imipenem, 641; meropenem, 173) were compared to 855 patients treated with

Discussion

The emergence and development of superinfection during therapy with broad spectrum antibiotics are major concerns for the use of these agents [3]. Antibiotics alter the normal protective microflora and its ecological balance in the host, resulting in overgrowth of opportunistic pathogens and superinfections [14]. We attempted to shed light on the development of superinfection when using carbapenems and non-carbapenems therapy in pneumonia patients based on data from RCTs. We specifically

Conflicts of interest

None.

Acknowledgements

None.

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However, the selective pressure caused by the use of carbapenems is likely responsible, to some degree, for the increase in carbapenem-resistant infections, which carry mortality rates of 30–50% [12]. In addition, previous meta-analyses reported higher risks of Clostridioides difficile and superinfection with carbapenems compared with other β-lactams [13,14]. Our meta-analysis did not identify a significant difference between eravacycline and carbapenems in clinical cure of cases caused by ESBL-producing Enterobacteriaceae.
This study was conducted to evaluate the efficacy and safety of eravacycline, a recently approved fluorocycline for treatment of complicated intra-abdominal infections (cIAIs).
PubMed, EMBASE and three trial registries were searched for randomised controlled trials (RCTs) comparing the efficacy and safety of eravacycline versus comparators. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using random-effects models. The study outcomes included clinical response, all-cause mortality and adverse events (AEs).
Three RCTs (1128 patients) with cIAIs were included. There were no significant differences in clinical response in the modified intention-to-treat (ITT) (OR, 0.91, 95% CI 0.62–1.35; I² = 0%), microbiological ITT (OR, 0.93, 95% CI 0.61–1.41; I² = 0%) and clinically evaluable (OR, 0.98, 95% CI 0.55–1.75; I² = 0%) populations or in all-cause mortality (OR, 1.18, 95% CI 0.16–8.94; I² = 0%). Eravacycline was associated with significantly greater odds of total AEs (OR, 1.55, 95% CI 1.20–1.99; I² = 0%) and nausea (OR, 5.29, 95% CI 1.77–15.78; I² = 1.70%) but the increase in vomiting was non-significant (OR, 1.44, 95% CI 0.73–2.86; I² = 1.70%). There were no significant differences in serious AEs or discontinuation due to AEs.
This meta-analysis of RCTs found similar clinical efficacy and mortality for eravacycline compared with carbapenems for treatment of cIAIs. However, the odds of total AEs and specifically nausea was higher with eravacycline, while no significant differences were observed in vomiting (although numerically higher), serious AEs or discontinuation due to AEs.
Superinfection rate among the patients treated with carbapenem versus piperacillin/tazobactam: Retrospective observational study
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This novel study of the comparative rates of superinfection between carbapenem and piperacillin/tazobactam found no differences. Eljaaly et al. summarized randomized clinical trials comparing superinfection for carbapenem and Non carbapenem antibiotics in general and concluded that carbapenem was associated with around a threefold (70%) increase in the risk of developing superinfection [3]. This finding is particularly notable because our study found higher percentages of superinfection in both groups (28.77% carbapenem and 20.96% piperacillin/tazobactam) than in groups reported by Eljaaly et al. (11.79% carbapenem and 6.67% Non-carbapenem antibiotics).
Superinfection is a new isolate pathogen after 48 h of antibiotic treatment or within one week of treatment discontinuation. In many studies carbapenem and piperacillin–tazobactam were associated with high risk of superinfection.
To evaluate the rate of superinfections during carbapenem and piperacillin/tazobactam treatment. Also, to identify risk factors for superinfections.
A Retrospective observational study was conducted in King Abdulaziz Medical City. Approval from the institutional Review Board was obtained. The study included all adult patient treated with carbapenem or piperacillin/tazobactam for more than 72 h. Univariate and multivariate analysis was conducted to compare piperacillin/tazobactam versus carbapenems and to identify the associated risk factor to develop superinfection.
507 patients were included in this study. The mean age of the patients was 61 years ± 19.33. Of these, 278 received carbapenems and 229 received piperacillin/tazobactam. In univariate analysis superinfections were significantly higher with carbapenems compared with piperacillin–tazobactam (28.77% versus 20.96%; P value = 0.044). After adjustment of cofounders in multivariate analysis, presence of tracheostomy, endotracheal ventilation, foley catheter and duration of antibiotic were associated with higher risk to developed superinfection adjusted odd ratio (aOR) 3.23 (95% CI,1.39–7.52) P < 0.01, aOR 2.556 (95% CI,1.30–5.02) P < 0.01, aOR 2.20 (95% CI,1.35–3.61) P < 0.001, aOR 1.051(95% CI,1.02–1.08) P < 0.001 respectively, but not carbapenems use aOR 1.052 (95% CI,0.657–1.685).
The use of carbapenems were not associated with higher risk to developed superinfection. The most important risk factors associated with superinfection were presence of tracheostomy, endotracheal mechanical ventilation, Foley catheter and the duration of antibiotics.
Antimicrobial resistance of gram-negative bacteria: A six-year longitudinal study in a hospital in Saudi Arabia
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The emergence of carbapenem resistant organism is of a concern throughout the globe. It was shown that the use of carbapenems as compared to non-carbapenem was associated with a higher rate of superinfection and a relative risk of 1.694 [24]. There is no single optimal method for the detection of carbapenemase resistance and this pose a challenge for many laboratories [25].
Increasing prevalence of antimicrobial resistance is a major concern especially in light of lack of new antimicrobial agents. Here, we present antibiotic resistance pattern of gram-negative bacteria (GNB) over six years (2013–2018) in a hospital in Saudi Arabia.
The study included a report of the cumulative antibiogram of GNB. Interpretation of the antibacterial susceptibility tests was based on the Clinical and Laboratory Standards Institute guidelines and VITEK® 2 system.
There was a total of 32,890 GNB isolates and the most common were: Escherichia coli (69.8%), Klebsiella pneumoniae (17.2%) and Pseudomonas aeruginosa (12.8%). Antimicrobial susceptibility of P. aeruginosa and E. coli did not change overtime, however, susceptibility to ceftazidime decreased from 92% to 85% in P. aeuroginosa. Yearly antimicrobial susceptibility did not change significantly overtime for K. pneumoniae. ESBL isolates among K. peumoniae and E. coli was about 26% and 20%, respectively (p = 0.0068). For ESBL E. coli, the least effective antibiotics were ciprofloxacin (26%) and trimethoprim-sulfamethoxazole (34%). For ESBL K. pneumoniae, gentamicin, ciprofloxacin, trimethoprim-sulfamethoxazole, and nitrofurantoin had poor activity. For K. pneumoniae, both ciprofloxacin (90%) and trimethoprim-sulfamethoxazole (86%) had better coverage than for E. coli. K. pneumoniae showed less susceptibility to nitrofurantoin than E. coli (20% vs. 92%).
Antibiotic resistance among P. aeruginosa and E. coli did not change overtime (2013–2018) and the rate of ESBL-producing E. coli and K. pneumoniae was high. Thus, continued surveillance is needed.
Outcomes of treating AmpC-producing Enterobacterales bacteraemia with carbapenems vs. non-carbapenems
2020, International Journal of Antimicrobial Agents
AmpC β-lactamases are found in Enterobacter species, Serratia species, Citrobacter freundii, Providencia species and Morganella morganii (‘ESCPM’). Carbapenems are commonly used to treat severe ‘ESCPM’ infections. Carbapenem-sparing agents are needed because of increasing carbapenem resistance worldwide. Use of cefepime and piperacillin-tazobactam has limited supportive clinical data. We evaluated the efficacy of non-carbapenems vs. carbapenems in ‘ESCPM’ bacteraemia.
A retrospective cohort study was conducted on patients with ‘ESCPM’ bacteraemia. Primary outcome was 30-day mortality. Analyses were performed on patients who received carbapenems vs. piperacillin-tazobactam or cefepime monotherapy as empirical and definitive therapy. Propensity score for carbapenem therapy was adjusted for in multivariate analyses for 30-day mortality.
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Adjusted multivariate analyses for empirical and definitive antibiotic treatment models yielded risk factors for 30-day mortality, including higher Pitt bacteraemia score (empirical: adjusted OR [aOR] 1.21 for each point increase, 95% confidence interval [CI]:1.01-1.45; definitive: aOR 1.33 for each point increase, 95% CI:1.06-1.69) and age (empirical: aOR 1.04 for each year increase, 95% CI:1.01-1.08). Empirical piperacillin-tazobactam (aOR 0.29, 95% CI:0.07-1.27) and definitive cefepime (aOR 0.65, 95% CI:0.12-3.55) were not associated with 30-day mortality.
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^☆: All authors meet the ICMJE authorship criteria.

¹: Department of Clinical Pharmacy, King Abdulaziz University P.O. Box 80200, Jeddah, postal code 21441, Saudi Arabia ext: 20675.

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Original ArticleImpact of carbapenem versus non-carbapenem treatment on the rates of superinfection: A meta-analysis of randomized controlled trials☆

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conflicts of interest

Acknowledgements

Respir Med

Lancet Infect Dis

Implementing an antibiotic stewardship program: guidelines by the infectious Diseases society of America and the society for Healthcare Epidemiology of America

Clin Infect Dis

Impact of requiring re-authorization of restricted antibiotics on day three of therapy

J Antimicrob Chemother

Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials

Clin Infect Dis

Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious Diseases society of America and the American thoracic society

Clin Infect Dis

Chapter 8: assessing risk of bias in included studies

Efficacy of meropenem as monotherapy in the treatment of ventilator-associated pneumonia

J Chemother

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group

Antimicrob Agents Chemother

Original Article
Impact of carbapenem versus non-carbapenem treatment on the rates of superinfection: A meta-analysis of randomized controlled trials☆