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Carbapenem-sparing beta-lactam/beta-lactamase inhibitors versus carbapenems for bloodstream infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis
The prognosis of bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) is poor.
•
Therapeutical response and mortality were compared between beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) and carbapenems.
•
BLBLIs are noninferior to carbapenems for the treatment of BSIs due to ESBL-PE.
•
BLBLIs perform better in definitive therapy rather than empirical therapy.
•
BLBLIs are an effective alternative carbapenem-sparing option for ESBL-PE BSIs.
Abstract
Objectives
Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat, and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) are considered as one reliable carbapenem-sparing antibiotic. However, it is still controversial whether BLBLIs are truly noninferior to carbapenems. Therefore, we conducted this meta-analysis to compare the efficacy of BLBLIs with carbapenems for ESBL-PE BSIs.
Methods
A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 2021 to enroll studies comparing BLBLIs with carbapenems for ESBL-PE BSIs. A subgroup analysis was performed based on the choice of therapy (empirical, definitive, and mixed therapy). The protocol was registered in the International Prospective Register of Systematic Reviews (#CRD42022316011).
Results
A total of 2786 patients from one randomized clinical trial and 25 cohorts were included. There was no statistically significant difference between BLBLIs and carbapenems groups in therapeutical response (odds ratio [OR] = 1.19, P = 0.45) and mortality (OR = 1.06, P = 0.68). Furthermore, although the statistical difference was also not found in the subgroup analysis, BLBLIs performed better in definitive therapy than empirical therapy than carbapenems, with a numerically higher therapeutical response (OR = 1.42 vs 0.89) and a mildly lower mortality (OR = 0.85 vs 1.14).
Conclusion
BLBLIs were noninferior to carbapenems for ESBL-PE BSIs, especially in definitive therapy. BLBLIs may be a valid alternative to spare the use of carbapenems.
Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat with increasing morbidity, huge health care costs, and poor clinical outcomes, such as prolonged hospital stay and high mortality [
]. As class A beta-lactamase enzymes, ESBL can hydrolyze the beta-lactam ring and thereby confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and aztreonam [
]. Besides, coresistance to other types of antibiotics, such as aminoglycosides, fluoroquinolones, and tetracycline, is also frequently observed in ESBL-PE due to the coexistence of various modifying enzymes on the same plasmid [
], consequently limiting the available therapeutic options for infections caused by ESBL-PE. According to a guide specifically on the treatment of ESBL-PE in 2022, carbapenems are still recommended as the first-choice regimens for the treatment of serious infections due to ESBL-PE, such as BSIs [
]. However, with the widespread consumption of carbapenems, the alarming emergence of carbapenems resistance has increased dramatically in recent years, especially in Enterobacteriaceae, which represents a bigger challenge in the clinic [
]. Therefore, it is thought-provoking whether the therapeutical advantages brought by carbapenems would be attenuated by the accompanied selection pressure on carbapenems resistance.
Recently, the interest in beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) as a strategy to spare the use of carbapenems for ESBL-PE infections treatment has been developed [
]. Beta-lactamase inhibitors, such as tazobactam, clavulanate, sulbactam, and avibactam, have shown great efficacy for ESBL enzymes in vitro and in vivo [
]. Furthermore, many clinical cohort studies have been conducted and found that BLBLIs are not inferior to carbapenems for the treatment of BSIs caused by ESBL-PE [
A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae.
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-β-lactamase-producing Enterobacteriaceae in hematological patients with neutropenia.
]. However, one randomized clinical trial (RCT; MERINO trial) performed in 2018 questions the role of BLBLIs in ESBL-PE BSIs. As the only RCT comparing the efficacy of BLBLIs with carbapenems so far, it claims that piperacillin-tazobactam (PTZ) has a statistically higher mortality than meropenem (MEM) [
Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial.
]. Nevertheless, there are some issues in the RCT, increasing the possibility of poor outcomes in BLBLI treatment group. For example, the ESBL-PE was defined as nonsusceptible to ceftriaxone without ESBL-producing confirmation testing [
Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial.
]. Thus, it may falsely presume other ceftriaxone-resistant organisms to be ESBL-producers, such as AmpC and OXA-1-producing organisms, in which MEM is still effective, whereas BLBLIs were ineffective against these organisms [
]. Besides, the minimum inhibitory concentration of all strains in the RCT was assessed using strip tests, which would increase the false susceptibility of strains to PTZ, as warned by European Committee on Antimicrobial Susceptibility Testing, thus attenuating the efficacy of PTZ in treatment for ESBL-PE infections [
]. Furthermore, a recent secondary analysis of the MERINO trial has proven such issues mentioned previously and finds the mortality difference is less pronounced for PTZ than MEM in BSIs caused by ESBL strains, after restricting strains to ESBL-PE instead of ceftriaxone-nonsusceptible Enterobacteriaceae and excluding the strains resistant to PTZ [
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
Given the controversial alternative use of BLBLIs in previous studies, partly caused by misjudgment of ESBL-PE and discrepancies in the susceptibility of treatment agents, we therefore conducted the meta-analysis to systematically compare the clinical outcomes of carbapenem-sparing BLBLIs versus carbapenems for ESBL-PE BSIs. In the current study, the inclusion criteria to ESBL-production were restricted with phenotypic confirmation or standard molecular testing and the subgroup analysis was performed based on choice of therapy according to susceptibility of antibiotics, with the hope to deal with such controversial causes mentioned previously.
2. Methods
2.1 Data sources
A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 25, 2021, using the following key terms “extended-spectrum β-lactamase or ESBL”, “Imipenem or Ertapenem or Meropenem or Carbapenem”, and “Bloodstream infections or BSIs or Bacteremia or Sepsis”. We also searched the references of relevant literatures to supplement our search. All included studies were restricted to English. The study protocol is published through the International Prospective Register of Systematic Reviews (#CRD42022316011).
2.2 Study selection
The studies were considered eligible if they fulfilled the following criteria: (i) adult patients (aged >16 years) diagnosed with BSIs caused by ESBL-PE; (ii) ESBL-production was determined using Clinical and Laboratory Standards Institute or European Committee on Antimicrobial Susceptibility Testing methods and confirmed by phenotypic or standard molecular testing; (iii) patients were administrated with BLBLIs and carbapenems, respectively, as a treatment and a control agent; and (iv) at least one of the efficacy outcomes of targeted agents were extractable in both the BLBLIs and carbapenems arms. The studies were excluded if they limited carbapenems as the only treatment agents for definitive therapy when switching from empirical therapy. Besides, studies merely defining ESBL-PE as a resistance to third-generation cephalosporins without confirmation testing were also excluded, as well as a secondary analysis of published data, which has been included in the study, reviews, in vitro studies, errata, and conference abstracts without primary data.
2.3 Qualitative assessment
The quality of eligible cohort studies was assessed using the Newcastle-Ottawa Scale (NOS) [
] through three domains, including nine scores in total: selection of participants, comparability of study group, and evaluation of outcome. The studies with an NOS score ≥6 were considered as high quality. For the included RCT, the quality was judged by the Cochrane Collaboration risk-of-bias tool [
], with a focus on the seven items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Each item was classified respectively as low, unclear, or high risk.
2.4 Data extraction
Basic information of studies was extracted as following: authors, year of publication, location, study design, choice of therapy, source of BSIs, inclusion and exclusion criteria, sample size, sex, age, organisms’ types of ESBL-PE, treatment regimens, and reported outcomes. These data were independently extracted by two researchers (QYX and HZ) and any discrepancies were resolved through discussion with a third reviewer (YC).
2.5 Outcome analysis
The outcomes of this meta-analysis included therapeutic response and mortality. Therapeutic response was defined as partial or complete resolution of signs and symptoms related to the infections (e.g., improving of fever, leukocytosis, tachycardia, tachypnea, and others). Mortality was defined as all-cause mortality at hospital discharge or the longest follow-up period reported by screened studies. Predefined subgroup analyses were also performed in the study to evaluate the efficacy of BLBLIs compared with carbapenems for the treatment of BSIs due to ESBL-PE during different choice of therapy (empirical, definitive, and mixed therapy). Empirical therapy was defined as the use of antimicrobial agents was given based on clinical suspicion before the results of blood cultures and susceptibility tests were reported, whereas definitive therapy was defined as antibiotics prescribed according to the available results mentioned previously. The group of mixed therapy included studies evaluating outcomes without classification or mention of the choice of therapy. Furthermore, if the same patients were nonmutually exclusively analyzed in both empirical and definitive therapy in one cohort study, we preferred to include the basic characteristics and outcomes of definitive therapy in our meta-analysis.
2.6 Data analysis and statistical methods
The meta-analysis was performed with Review Manager statistical software (Version: 5.1) to produce forest and funnel plots. The pooled efficacy of outcomes presented by odds ratio (OR) with 95% confidence interval (CI) was calculated by Mantel-Haenszel method with a random-effects or fixed-effects model based on the heterogeneity among studies. In the test for overall effect, a two-tailed P <0.05 was considered to be statistically significant, indicating that the treatment agent we studied was different from the control agent. The heterogeneity was assessed by the Cochrane I2 statistic, in which P <0.10 or I2 >50% indicated that these included studies were statistically heterogeneous and should be evaluated by the random-effects model. Furthermore, the existence of publication bias was evaluated by performing funnel plots when analyzing the outcomes of more than 10 studies.
3. Results
3.1 Study identification
The selection process for eligible studies is shown in Figure 1. A total of 26 studies (one RCT [
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.
Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae.
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-β-lactamase-producing Enterobacteriaceae in hematological patients with neutropenia.
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
]) consisting of 2786 patients were included in the final meta-analysis. The basic characteristics of the included articles are listed in Table 1. Among these studies, 12 of all studies were grouped into the empirical therapy subgroup [
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae.
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-β-lactamase-producing Enterobacteriaceae in hematological patients with neutropenia.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.
Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
Question: *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). A total of 4198 potential studies were found, where 2974 studies of them were from PubMed, 1096 studies were from Embase and 128 studies were from Cochrane.Question: **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.Reply: No automation tools was used and all irrelevant studies were excluded by human in the present study.Thanks for your careful check.
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-β-lactamase-producing Enterobacteriaceae in hematological patients with neutropenia.
A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae.
Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.
Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
Only one RCT was included in our study and it had a low risk in all seven modules according to the Cochrane Collaboration risk-of-bias tool. The overall quality of cohort studies was evaluated as low risk of bias by the NOS (Table 2).
Table 2NOS for assessing the quality of studies in meta-analysis.
Study
Selection
Comparability
Outcome
Scores
Representativeness of the exposed cohort
Selection of the non-exposed cohort
Ascertainment of exposure
Demonstration that outcome of interest was not present at the start of study
Comparability of cohorts based on the design or analysis
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-β-lactamase-producing Enterobacteriaceae in hematological patients with neutropenia.
A multinational, preregistered cohort study of β-lactam/β-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae.
Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts.
Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
Notes: Risk of bias was evaluated by the NOS with a total score of nine points. Each item of “Selection” and “Outcome” has a maximum of one point, while “Comparability” has a maximum of two points. One filled star (★, one point) would be awarded when a study met the requirements of each item; otherwise, an empty star (☆) would be given which means no point is awarded. Studies with an NOS score ≥ 6 are considered to be of high quality.
There were 10 studies containing 1095 patients evaluating the therapeutic response for the treatment of BSIs due to ESBL-PE and there was no remarkable difference identified between BLBLIs and carbapenems group by the fixed-effects model (OR = 1.19, 95% CI = [0.76, 1.84], P = 0.45) without significate heterogeneity (P = 0.44, I2 = 0%), as shown in Figure 2. Furthermore, although all subgroup analysis revealed no statistically remarkable difference comparing BLBLIs with carbapenems based on the choice of therapy, the rate of therapeutic response of BLBLIs was numerically higher than that of carbapenems in definitive therapy (OR = 1.42, 95% CI = [0.74, 2.75], P = 0.29), whereas the results were on the contrary in empirical therapy, with a mildly lower therapeutic response in BLBLIs arms (OR = 0.89, 95% CI = [0.37, 2.13], P = 0.80). It suggested that BLBLIs maybe have a better performance in definitive therapy than empirical therapy for ESBL-PE caused BSIs treatment.
Figure 2Forest plot showing the odds ratio with 95% CI of therapeutic response for BLBLIs vs carbapenems in patients with bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. BLBLIs, beta-lactam/beta-lactamase inhibitor combinations; CI, confidence interval.
The rate of mortality comparing BLBLIs with carbapenems was provided in 25 studies involving 2543 participants by the fixed-effects model without statistical heterogeneity (P = 0.45, I2 = 1%) and no significant difference was found in the two groups (OR = 1.06, 95% CI = [0.82, 1.37], P = 0.68; Figure 3). Similarly, there was no statistical difference in all subgroup analyses (empirical therapy: OR = 1.14, P = 0.50; definitive therapy: OR = 0.85, P = 0.44; mixed therapy: OR = 1.78, P = 0.16). However, the OR values showed an opposite trend in the different therapy patterns, numerically showing a lower mortality of BLBLIs than carbapenems and favoring its application in definitive therapy instead of empirical therapy. Furthermore, the publication bias was analyzed using the funnel plot, as shown in Figure 4, revealing a basically symmetrical distribution of all included studies on both sides of the funnel plot, which indicated a relatively small possibility of publication bias.
Figure 3Forest plot showing the odds ratio with 95% CI of mortality for BLBLIs vs carbapenems in patients with bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. BLBLIs, beta-lactam/beta-lactamase inhibitor combinations; CI, confidence interval.
Figure 4Publication bias indicators of mortality for beta-lactam/beta-lactamase inhibitor combinations vs carbapenems in patients with bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. OR, odds ratio.
In the current meta-analysis, one RCT and 25 cohorts involving 2786 patients were included, and the findings showed that BLBLIs were virtually equivalent to carbapenems for the treatment of BSIs due to ESBL-PE. Compared with two previously published meta-analysis, our study additionally evaluated the efficacy comparison of therapeutical response, restricted inclusion criteria of ESBL-production, and included newly updated RCT and cohorts. In addition, we also found that BLBLIs performed better in definitive therapy than empirical therapy compared with carbapenems, despite having no statistical difference in the two subgroup analyses, which might be accounted for by the different susceptibility of organisms to treatment agents. Overall, these results indicated that BLBLIs might be a reasonable alternative to carbapenems for BSIs caused by ESBL-PE, especially as a definitive therapy. However, due to some limitations in the study, such as only one available RCT, scarcity of demographic characteristics, and heterogeneous data in the clinic, more RCTs are needed to further validate our findings.
Although the noninferior result of mortality in the current study was generally in alignment with two previous published meta-analysis in 2017 [
Comparison between carbapenems and β-lactam/β-lactamase inhibitors in the treatment for bloodstream infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis.
Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
Comparison between carbapenems and β-lactam/β-lactamase inhibitors in the treatment for bloodstream infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis.
Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
], which only compared the mortality in patients diagnosed with BSIs due to ESBL-PE. The mortality was referred to the all-cause mortality in the cohorts included by our and the two previous meta-analysis [
Comparison between carbapenems and β-lactam/β-lactamase inhibitors in the treatment for bloodstream infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis.
Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
], it was generally influenced by substantial confounding factors contributing to death other than targeted bacterial infections, such as the end-stage diseases, cancer and organ failure [
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
]. From this perspective, the pooled assessment of therapeutical response, defined as an improvement or resolution of signs and symptoms related to infections, would be a great supplement for comparing the clinical efficacy of the treatment, especially when lacking the data of mortality directly attributing to infections [
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
]. Therefore, the merged evaluation of therapeutical response among the included cohorts was newly conducted in our study, with the hope to measure the efficacy of BLBLIs versus carbapenems in BSIs due to ESBL-PE more comprehensively. Besides, unlike the two meta-analysis [
Comparison between carbapenems and β-lactam/β-lactamase inhibitors in the treatment for bloodstream infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis.
Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
], we only included clinical studies where the ESBL-production was checked by phenotypic confirmation test (e.g., clavulanic acid testing) or standard molecular testing for ESBL genes (e.g., whole genome sequencing), according to Clinical and Laboratory Standards Institute criteria [
Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing Enterobacteriaceae.
Risk factors for mortality of patients with ceftriaxone resistant E. coli bacteremia receiving carbapenem versus beta lactam/beta lactamase inhibitor therapy.
]. Although the simplified screening method has made the results of the microbiologic cultures be obtained more quickly and conveniently in the clinic, it is likely to misjudge many isolates resistant to cephalosporins with other mechanisms instead of ESBL-production, such as AmpC and OXA-1 [
]. Once those strains with AmpC were misclassified as ESBL-producers because of resistance to cephalosporins, the clinical outcome would be biased and tend to favor the use of carbapenems in the treatment of infections due to so-called “ESBL-producing” organisms while highlighting the inferiority of BLBLIs [
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Comparison of therapy with β-lactam/β-lactamase inhibitor combinations or carbapenems for bacteraemia of nonurinary source caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae.
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
]. Overall, although the result of mortality was generally the same as before, a more credible and thorough pooled evidence can be expected from the current meta-analysis by adding an efficacy comparison of the therapeutical response, restricting the inclusion criteria of ESBL-production, and including newly updated RCT and cohorts.
Although there was also no statistical difference in all the subgroup analyses, BLBLIs have a numerically higher rate of therapeutical response and lower mortality than carbapenems in the definitive therapy subgroup, whereas the rate of these outcomes was just the opposite in the empirical therapy subgroup. This might be attributed to the different susceptibility of organisms to treatment agents between the two subgroups [
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
]. It meant that patients receiving definitive therapy were more likely to receive the active antibiotics based on the susceptibility testing, no matter if they were BLBLIs or carbapenems [
Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial.
]. By contrast, the sensitivity of the antibiotic prescribed empirically was incontrollable and unknown, which was affected by many factors, such as the previous usage of antibiotics, recent hospital history, the local pathogen epidemiology, and so on [
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
]. In general, the antimicrobial susceptibility of ESBL-PE to BLBLIs, such as PTZ, was always lower than that of carbapenems; although, the exact rate varied according to different regions and species of organisms [
Prevalence and molecular epidemiology of extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli From multiple sectors of the swine industry in Korea: a Korean nationwide monitoring program for a one health approach to combat antimicrobial resistance.
]. Therefore, when patients were treated empirically, the efficacy in BLBLI arms might be potentially attenuated by the relatively higher rate of resistance to ESBL-PE than that in carbapenem arms [
], which might account for the discrepancy that BLBLIs performed better in definitive than empirical therapy for the treatment of ESBL-PE BSIs. In other words, BLBLIs with activity in vitro might be a reasonable alternative to carbapenems for the treatment of such infections to reduce the selection pressure of carbapenem resistance accompanying its widespread use [
Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
]. However, the empirical therapy is always inevitable in clinical scenarios because it usually takes longer than 48 hours to acquire the sensitivity results [
Antipseudomonal monotherapy or combination therapy for older adults with community-onset pneumonia and multidrug-resistant risk factors: a retrospective cohort study.
]. Thus, to carry out the definitive therapy with a proper antibiotic for the treatment of ESBL-PE BSIs as soon as possible, a quicker and more effective molecular diagnostic techniques for reflecting resistance patterns were required [
There are some limitations in the current study. First, only one RCT was included and most of the available data were extracted from retrospective cohorts. Although cohort studies can provide efficacy evidence in a broader range of population and more realistic settings, they were susceptible to selection bias and confounding factors due to the nonrandomized allocation of the treatments. Taking selection bias as an example, the BLBLIs versus carbapenems allocation tended to be influenced by clinical decisions, where the sickest patients were more likely to receive carbapenems therapy (control group with proven efficacy in the clinic), leading to the difference of disease severity between groups and thus relatively lowering the efficacy of the control agents. By contrast, RCT, the gold standard for assessing the causality in medical research, can greatly limit the risk of selection bias and minimize the confounding effect through randomization of groups. Consequently, the scarcity of available RCTs was one of the main limitations in the current study and the noninferiority of BLBLIs versus carbapenems needs to be verified by more RCTs in the future. Second, some of the studies were not especially aimed to evaluate the efficacy of BLBLIs versus carbapenems for the treatment of ESBL-PE BSIs (e.g., risk factors studies [
Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
] with the simple description of mortality). Thus, some of the basic demographic characteristics were not available. Finally, the clinical trials included in this study were not completely homogeneous, with respect to the usage and dosage of BLBLIs or carbapenems, duration of treatment, sources of infections, species of organisms, etc. Overall, these limitations might have a negative influence on the reliability of results, which should be interpreted with great caution.
5. Conclusion
The current meta-analysis revealed that BLBLIs were not inferior to carbapenems, especially in definitive therapy for the treatment of ESBL-PE BSIs, indicating that BLBLIs may be a valid alternative to spare the use of carbapenems. However, due to the limitations of clinical studies included, more RCTs are needed to perform the further assessment.
Funding
This work was supported by the National Natural Science Foundations of China (81770004 and 82073894), Cultivation Project of PLA General Hospital for Distinguished Young Scientists (2020-JQPY-004), and New Medicine Clinical Research Fund (4246Z512).
Ethical approval
Not required.
Author contributions
HZ formulated the original idea, carried out the data extraction, and drafted first version of the manuscript. JX selected the studies and carried out the meta-analysis. QYX performed the database search, reviewed the studies, and extracted the relevant data. YHW engaged in the original idea conception. JW conducted the quality assessment of included studies. MZ revised the draft of manuscript. YC contributed to the definition of the inclusion criteria, data interpretation, and manuscript revision. All authors reviewed and approved the final manuscript and agreed to be accountable for all aspects of the work.
Declarations of competing interest
The authors have no competing interests to declare.
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