Advertisement

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

  • Author Footnotes
    1 Contribute equally to this work.
    Huan Zhang
    Footnotes
    1 Contribute equally to this work.
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 Contribute equally to this work.
    Juan Xu
    Footnotes
    1 Contribute equally to this work.
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Qinyan Xiao
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Yuhang Wang
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Jin Wang
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Man Zhu
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Yun Cai
    Correspondence
    Corresponding authors: Yun Cai, Tel: 86-10-6693-7166; Fax: 86-10-8821-4425
    Affiliations
    Centre of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Centre, Chinese PLA General Hospital, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 Contribute equally to this work.
Open AccessPublished:January 05, 2023DOI:https://doi.org/10.1016/j.ijid.2023.01.001

      Highlights

      • 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.

      Keywords

      1. Introduction

      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 [
      • Benetazzo L
      • Delannoy PY
      • Houard M
      • Wallet F
      • Lambiotte F
      • Vachée A
      • et al.
      Combination therapy with aminoglycoside in Bacteremiasdue to ESBL-producing Enterobacteriaceae in ICU.
      ]. 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 [
      • Tooke CL
      • Hinchliffe P
      • Bragginton EC
      • Colenso CK
      • Hirvonen VHA
      • Takebayashi Y
      • et al.
      β-lactamases and β-lactamase Inhibitors in the 21st Century.
      ]. 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 [
      • Ouchar Mahamat O
      • Lounnas M
      • Hide M
      • Dumont Y
      • Tidjani A
      • Kamougam K
      • et al.
      High prevalence and characterization of extended-spectrum ß-lactamase producing Enterobacteriaceae in Chadian hospitals.
      ], 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 [

      Infectious Diseases Society of America. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 1.0, https://www.idsociety.org/practice-guideline/amr-guidance/; 2022 [accessed 22 December 2022].

      ]. 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 [
      • Karaiskos I
      • Giamarellou H.
      Carbapenem-sparing strategies for ESBL Producers: When and How.
      ]. 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 [
      • Karaiskos I
      • Giamarellou H.
      Carbapenem-sparing strategies for ESBL Producers: When and How.
      ,
      • Corcione S
      • Lupia T
      • Maraolo AE
      • Mornese Pinna S
      • Gentile I
      • De Rosa FG
      Carbapenem-sparing strategy: carbapenemase, treatment, and stewardship.
      ]. Beta-lactamase inhibitors, such as tazobactam, clavulanate, sulbactam, and avibactam, have shown great efficacy for ESBL enzymes in vitro and in vivo [
      • Bassetti M
      • Giacobbe DR
      • Robba C
      • Pelosi P
      • Vena A.
      Treatment of extended-spectrum β-lactamases infections: what is the current role of new β-lactams/β-lactamase inhibitors?.
      ,
      • Gudiol C
      • Cuervo G
      • Carratalà J.
      Optimizing therapy of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae.
      ]. 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 [
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ,
      • Gutiérrez-Gutiérrez B
      • Pérez-Galera S
      • Salamanca E
      • de Cueto M
      • Calbo E
      • Almirante B
      • et al.
      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.
      ,
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ,
      • Gudiol C
      • Royo-Cebrecos C
      • Abdala E
      • Akova M
      • Álvarez R
      • Maestro-de la Calle G
      • et al.
      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.
      ,
      • Cheng WL
      • Hsueh PR
      • Lee CC
      • Li CW
      • Li MJ
      • Chang CM
      • et al.
      Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
      ]. 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) [
      • Harris PNA
      • Tambyah PA
      • Lye DC
      • Mo Y
      • Lee TH
      • Yilmaz M
      • et al.
      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 [
      • Harris PNA
      • Tambyah PA
      • Lye DC
      • Mo Y
      • Lee TH
      • Yilmaz M
      • et al.
      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 [
      • Hayden MK
      • Won SY.
      Carbapenem-sparing therapy for extended-spectrum β-lactamase-producing E coli and Klebsiella pneumoniae bloodstream infection: the search continues.
      ,
      • Bru JP
      • Alfandari S
      • Bleibtreu A
      • Chavanet P
      • Gauzit R
      • Lescure X
      • et al.
      Carbapenems versus beta-lactam/beta-lactamase inhibitors to treat ESBL-producing Enterobacteriaceae infections.
      ]. 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 [
      • Bru JP
      • Alfandari S
      • Bleibtreu A
      • Chavanet P
      • Gauzit R
      • Lescure X
      • et al.
      Carbapenems versus beta-lactam/beta-lactamase inhibitors to treat ESBL-producing Enterobacteriaceae 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 [
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      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) [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ] 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 [
      • Higgins JP
      • Altman DG
      • Gøtzsche PC
      • Jüni P
      • Moher D
      • Oxman AD
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      ], 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 [
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
      ], three prospective cohorts [
      • Rodríguez-Baño J
      • Navarro MD
      • Retamar P
      • Picón E
      • Pascual Á
      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.
      ,
      • Gudiol C
      • Calatayud L
      • Garcia-Vidal C
      • Lora-Tamayo J
      • Cisnal M
      • Duarte R
      • et al.
      Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
      ,
      • Bin C
      • Hui W
      • Renyuan Z
      • Yongzhong N
      • Xiuli X
      • Yingchun X
      • et al.
      Outcome of cephalosporin treatment of bacteremia due to CTX-M–type extended-spectrum β-lactamase–producing Escherichia coli.
      ], and 22 retrospective cohorts [
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ,
      • Gutiérrez-Gutiérrez B
      • Pérez-Galera S
      • Salamanca E
      • de Cueto M
      • Calbo E
      • Almirante B
      • et al.
      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.
      ,
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ,
      • Gudiol C
      • Royo-Cebrecos C
      • Abdala E
      • Akova M
      • Álvarez R
      • Maestro-de la Calle G
      • et al.
      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.
      ,
      • Cheng WL
      • Hsueh PR
      • Lee CC
      • Li CW
      • Li MJ
      • Chang CM
      • et al.
      Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
      ,
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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.
      ,
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Su J
      • Guo Q
      • Li Y
      • Wu S
      • Hu F
      • Xu S
      • et al.
      Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
      ,
      • Namikawa H
      • Yamada K
      • Fujimoto H
      • Oinuma KI
      • Tochino Y
      • Takemoto Y
      • et al.
      Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
      ,
      • Ofer-Friedman H
      • Shefler C
      • Sharma S
      • Tirosh A
      • Tal-Jasper R
      • Kandipalli D
      • Sharma S
      • Bathina P
      • Kaplansky T
      • Maskit M
      • Azouri T
      • Lazarovitch T
      • Zaidenstein R
      • Kaye KS
      • Marchaim D.
      Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
      ,
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ,
      • To KK
      • Lo WU
      • Chan JF
      • Tse H
      • Cheng VC
      • Ho PL.
      Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity.
      ,
      • Peralta G
      • Lamelo M
      • Alvarez-García P
      • Velasco M
      • Delgado A
      • Horcajada JP
      • et al.
      Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
      ,
      • Kang CI
      • Park SY
      • Chung DR
      • Peck KR
      • Song JH.
      Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Chopra T
      • Marchaim D
      • Veltman J
      • Johnson P
      • Zhao JJ
      • Tansek R
      • et al.
      Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
      ,
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      ,
      • De Rosa FG
      • Pagani N
      • Fossati L
      • Raviolo S
      • Cometto C
      • Cavallerio P
      • et al.
      The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.
      ,
      • Lee CC
      • Lee NY
      • Yan JJ
      • Lee HC
      • Chen PL
      • Chang CM
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      ,
      • Chaubey VP
      • Pitout JD
      • Dalton B
      • Ross T
      • Church DL
      • Gregson DB
      • et al.
      Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Apisarnthanarak A
      • Kiratisin P
      • Mundy LM.
      Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Tumbarello M
      • Sanguinetti M
      • Montuori E
      • Trecarichi EM
      • Posteraro B
      • Fiori B
      • et al.
      Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
      ,
      • Endimiani A
      • Luzzaro F
      • Brigante G
      • Perilli M
      • Lombardi G
      • Amicosante G
      • et al.
      Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
      ]) 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 [
      • Cheng WL
      • Hsueh PR
      • Lee CC
      • Li CW
      • Li MJ
      • Chang CM
      • et al.
      Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
      ,
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Su J
      • Guo Q
      • Li Y
      • Wu S
      • Hu F
      • Xu S
      • et al.
      Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
      ,
      • Namikawa H
      • Yamada K
      • Fujimoto H
      • Oinuma KI
      • Tochino Y
      • Takemoto Y
      • et al.
      Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
      ,
      • Peralta G
      • Lamelo M
      • Alvarez-García P
      • Velasco M
      • Delgado A
      • Horcajada JP
      • et al.
      Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
      ,
      • Kang CI
      • Park SY
      • Chung DR
      • Peck KR
      • Song JH.
      Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      ,
      • De Rosa FG
      • Pagani N
      • Fossati L
      • Raviolo S
      • Cometto C
      • Cavallerio P
      • et al.
      The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.
      ,
      • Lee CC
      • Lee NY
      • Yan JJ
      • Lee HC
      • Chen PL
      • Chang CM
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      ,
      • Chaubey VP
      • Pitout JD
      • Dalton B
      • Ross T
      • Church DL
      • Gregson DB
      • et al.
      Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Apisarnthanarak A
      • Kiratisin P
      • Mundy LM.
      Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Tumbarello M
      • Sanguinetti M
      • Montuori E
      • Trecarichi EM
      • Posteraro B
      • Fiori B
      • et al.
      Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
      ] and nine studies were categorized into the definitive therapy group [
      • Gutiérrez-Gutiérrez B
      • Pérez-Galera S
      • Salamanca E
      • de Cueto M
      • Calbo E
      • Almirante B
      • et al.
      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.
      ,
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ,
      • Gudiol C
      • Royo-Cebrecos C
      • Abdala E
      • Akova M
      • Álvarez R
      • Maestro-de la Calle G
      • et al.
      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.
      ,
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
      ,
      • Rodríguez-Baño J
      • Navarro MD
      • Retamar P
      • Picón E
      • Pascual Á
      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.
      ,
      • Gudiol C
      • Calatayud L
      • Garcia-Vidal C
      • Lora-Tamayo J
      • Cisnal M
      • Duarte R
      • et al.
      Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
      ,
      • To KK
      • Lo WU
      • Chan JF
      • Tse H
      • Cheng VC
      • Ho PL.
      Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity.
      ,
      • Chopra T
      • Marchaim D
      • Veltman J
      • Johnson P
      • Zhao JJ
      • Tansek R
      • et al.
      Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
      ,
      • Endimiani A
      • Luzzaro F
      • Brigante G
      • Perilli M
      • Lombardi G
      • Amicosante G
      • et al.
      Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
      ], with one study grouped to both subgroups, which included two mutually exclusive empirical and definitive therapy [
      • Bin C
      • Hui W
      • Renyuan Z
      • Yongzhong N
      • Xiuli X
      • Yingchun X
      • et al.
      Outcome of cephalosporin treatment of bacteremia due to CTX-M–type extended-spectrum β-lactamase–producing Escherichia coli.
      ]. The remaining four studies were categorized into the mixed therapy subgroup for unknown or mixed choice of therapy [
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ,
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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.
      ,
      • Ofer-Friedman H
      • Shefler C
      • Sharma S
      • Tirosh A
      • Tal-Jasper R
      • Kandipalli D
      • Sharma S
      • Bathina P
      • Kaplansky T
      • Maskit M
      • Azouri T
      • Lazarovitch T
      • Zaidenstein R
      • Kaye KS
      • Marchaim D.
      Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
      ,
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ].
      Figure 1
      Figure 1Flow diagram of included studies. BLBLIs, beta-lactam/beta-lactamase inhibitor combinations; BSIs, bloodstream infections; ESBL-PE, extended-spectrum beta-lactamase-producing Enterobacteriaceae; RCT, randomized clinical trial.
      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.
      Table 1Characteristics of the included studies.
      PublicationCountryDesignChoice of therapyOrganisms (%)Source of bloodstream infection (%)SampleAge (years)Outcomes
      βCΒC
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      SpainRetrospectiveMixedEscherichia coli,

      Klebsiella pneumoniae
      Urinary33

      (PTZ,AMC)
      210

      (MEM, ETM, IPM/CLN)
      57.1±13.556.1±14.3b
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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.
      ChinaRetrospectiveMixedE. coli,

      K. pneumoniae
      Nonurinary634358.2±12.355.7±11.9a, b
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
      AustraliaRandomized clinical trialDefinitiveE. coli,

      K. pneumoniae
      NR85

      (PTZ)
      88

      (MEM)
      NRNRa
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ChinaRetrospectiveEmpiricalE. coliAbdominal (49.8)

      Urinary (20.5)

      Lung (19.8)

      Others (9.9)
      95117NRNRa
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ItalyRetrospectiveDefinitiveE. coli,

      Proteus mirabilis
      Urinary (68.5)

      Biliary (10.5)

      Lung (10.5)

      Other (10.5)
      10

      (PTZ)
      19

      (IPM 11, MEM 8)
      NRNRa, b
      • Su J
      • Guo Q
      • Li Y
      • Wu S
      • Hu F
      • Xu S
      • et al.
      Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
      ChinaRetrospectiveEmpiricalE. coli,

      K. pneumoniae
      Urinary

      Nonurinary
      17

      (CSL)
      4665.8±15.059.0±17.3a, b
      • Gudiol C
      • Royo-Cebrecos C
      • Abdala E
      • Akova M
      • Álvarez R
      • Maestro-de la Calle G
      • et al.
      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.
      SpainRetrospectiveDefinitiveE. coli (74.9),

      K. pneumoniae (22.7),

      Enterobacter cloacae (1.2),

      Klebsiella oxytoca (1.2)
      endogenous (52.8)

      catheter (18.1)

      neutropenic enterocolitis (8.1)

      urinary (6.9)

      perianal (6.9)

      Others (7.2)
      17

      (PTZ12, AMC5)
      234

      (MEM130,

      IPM 79,

      ETM 25)
      57 (37–60)52 (36–63)a
      • Namikawa H
      • Yamada K
      • Fujimoto H
      • Oinuma KI
      • Tochino Y
      • Takemoto Y
      • et al.
      Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
      JapanRetrospectiveEmpiricalE. coliUrinary

      Biliary
      4

      (PTZ)
      9

      (MEM, IPM, ETM)
      NRNRa
      • Cheng WL
      • Hsueh PR
      • Lee CC
      • Li CW
      • Li MJ
      • Chang CM
      • et al.
      Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
      ChinaRetrospectiveEmpiricalE. coli,

      K. pneumoniae
      NR439NRNRa
      • Gutiérrez-Gutiérrez B
      • Pérez-Galera S
      • Salamanca E
      • de Cueto M
      • Calbo E
      • Almirante B
      • et al.
      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.
      SpainRetrospectiveDefinitiveE. coli, K. pneumoniae, OthersUrinary (45.3)

      Biliary (11.8)

      Other (42.9)
      92

      (PTZ 60, AMC 32)
      509

      (ETM 205, MEM 185, IPM 118, DPM 1)
      70.5 (56–80)68 (56–78)a, b
      • Ofer-Friedman H
      • Shefler C
      • Sharma S
      • Tirosh A
      • Tal-Jasper R
      • Kandipalli D
      • Sharma S
      • Bathina P
      • Kaplansky T
      • Maskit M
      • Azouri T
      • Lazarovitch T
      • Zaidenstein R
      • Kaye KS
      • Marchaim D.
      Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
      USARetrospectiveMixedE. coli (53.0),

      K. pneumoniae (28.0),

      P. mirabilis (19.0)
      pneumonia (34.0)

      skin (28.0)

      biliary (17.0)

      Other intra-abdominal (9.0)

      primary bacteremia (8.0)

      unknown (5.0)
      10

      (PTZ)
      64

      (ETM, IPM, MEM, DPM)
      70.2 ±16a
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ChinaRetrospectiveMixedP. mirabilisurosepsis (50.0)

      catheter (8.8)

      pneumonia (17.6)

      primary bacteremia (5.9)

      Other/unknown (17.6)
      13

      (PTZ)
      21

      (MEM, IPM, ETM)
      76.771.6a
      • To KK
      • Lo WU
      • Chan JF
      • Tse H
      • Cheng VC
      • Ho PL.
      Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity.
      ChinaRetrospectiveDefinitiveE. coliUrinary

      Biliary

      Liver

      Intra-abdominala

      Pneumonia

      Other
      21144NRNRa
      • Rodríguez-Baño J
      • Navarro MD
      • Retamar P
      • Picón E
      • Pascual Á
      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.
      SpainProspective, post hoc analysis of six cohortsDefinitiveE. coliUrinary

      Biliary

      Unknown
      54

      (AMC 36, PTZ 18)
      120

      (IPM 84, ETM 20, MEM 16)
      67 (56–83)70 (55–78)a
      • Kang CI
      • Park SY
      • Chung DR
      • Peck KR
      • Song JH.
      Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      KoreaRetrospectiveEmpiricalE. coli,

      K. pneumoniae
      NR36

      (PTZ)
      78NRNRa, b
      • Peralta G
      • Lamelo M
      • Alvarez-García P
      • Velasco M
      • Delgado A
      • Horcajada JP
      • et al.
      Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
      SpainRetrospectiveEmpiricalEnterobacteriaceaeUrinary

      Biliary

      Intra-abdominal

      Pneumonia

      Catheter

      Unknown
      117

      (AMC, PTZ)
      70NRNRa
      • Chopra T
      • Marchaim D
      • Veltman J
      • Johnson P
      • Zhao JJ
      • Tansek R
      • et al.
      Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
      USARetrospectiveDefinitiveK. pneumoniae,

      E. coli
      NR18

      (PTZ)
      33NRNRa
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      USARetrospectiveEmpiricalE. cloacaeNR4 (PTZ)8

      (IPM 3, MEM 3, ETM 2)
      NR58.25±8.36a, b
      • De Rosa FG
      • Pagani N
      • Fossati L
      • Raviolo S
      • Cometto C
      • Cavallerio P
      • et al.
      The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.
      ItalyRetrospectiveEmpiricalE. coli,

      K. pneumoniae,P. mirabilis
      NR8

      (PTZ 6, AMC 2)
      57

      (IPM, MEM)
      NRNRa
      • Chaubey VP
      • Pitout JD
      • Dalton B
      • Ross T
      • Church DL
      • Gregson DB
      • et al.
      Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
      CanadaRetrospectiveEmpiricalE. coli (91.0),

      K. pneumoniae (9.0)
      NR1610NRNRa
      • Lee CC
      • Lee NY
      • Yan JJ
      • Lee HC
      • Chen PL
      • Chang CM
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      ChinaRetrospectiveEmpiricalE. cloacaeNR13

      (PTZ)
      24NRNRa
      • Gudiol C
      • Calatayud L
      • Garcia-Vidal C
      • Lora-Tamayo J
      • Cisnal M
      • Duarte R
      • et al.
      Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
      SpainProspectiveDefinitiveE. coliNR214NRNRa
      • Apisarnthanarak A
      • Kiratisin P
      • Mundy LM.
      Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ThailandRetrospectiveEmpiricalE. coli (86.7),

      K. pneumoniae (13.3)
      Urinary (56.0)

      Respiratory (17.0)

      Biliary (11.0)

      Primary bacteremia (11.0)

      Intra-abdominal (6.0)
      10

      (AMC, SAM, PTZ)
      5

      (ETM, IPM, MEM)
      NRNRa
      • Tumbarello M
      • Sanguinetti M
      • Montuori E
      • Trecarichi EM
      • Posteraro B
      • Fiori B
      • et al.
      Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
      ItalyRetrospectiveEmpiricalE. coli,

      K. pneumoniae,

      P. mirabilis
      Urinary (28.4)

      Pancreatico-biliary (12.9)

      Surgical wound (10.7)

      Lower respiratory (3.2)

      Central venous catheter (2.7)

      Unknown (46.2)
      33

      (AMC, PTZ)
      28

      (IPM, MEM)
      NRNRa
      • Bin C
      • Hui W
      • Renyuan Z
      • Yongzhong N
      • Xiuli X
      • Yingchun X
      • et al.
      Outcome of cephalosporin treatment of bacteremia due to CTX-M–type extended-spectrum β-lactamase–producing Escherichia coli.
      ChinaProspectiveEmpiricalE. coliBiliary 5

      Abdominal 2

      Urinary 1

      unknown 1
      6

      (CSL)
      3

      (IPM/CLN)
      NRNRa, b
      DefinitiveBiliary 2

      Urinary 1

      pneumonia 1

      unknown 2
      1

      (CSL)
      5

      (IPM/CLN)
      • Endimiani A
      • Luzzaro F
      • Brigante G
      • Perilli M
      • Lombardi G
      • Amicosante G
      • et al.
      Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
      ItalyRetrospectiveDefinitiveP. mirabilisUrinary

      Primary bacteremia
      4

      (SAM 2,

      AMC 1, PTZ 1)
      2

      (MEM 1, IPM 1)
      58.5±18.080.5a, b
      Note: Outcomes were as follows: a, mortality; b, therapeutic response.
      Abbreviations: AMC, amoxicillin/clavulanate; CSL, cefoperazone/sulbactam; DPM, doripenem; ETM, ertapenem; IPM, imipenem; IPM/CLN, imipenem/cilastatin; MEM, meropenem; NR, not reported; PTZ, piperacillin-tazobactam; SAM, ampicillin-sulbactam; TCC, ticarcillin/clavulanate.

      3.2 Study quality

      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.
      StudySelectionComparabilityOutcomeScores
      Representativeness of the exposed cohortSelection of the non-exposed cohortAscertainment of exposureDemonstration that outcome of interest was not present at the start of studyComparability of cohorts based on the design or analysisAssessment of outcomesWas follow-up long enough for outcomes to occurAdequacy of follow-up of cohorts
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ★☆8
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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.
      ★☆8
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ★☆8
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ★☆8
      • Su J
      • Guo Q
      • Li Y
      • Wu S
      • Hu F
      • Xu S
      • et al.
      Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
      ★☆7
      • Gudiol C
      • Royo-Cebrecos C
      • Abdala E
      • Akova M
      • Álvarez R
      • Maestro-de la Calle G
      • et al.
      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.
      ★☆8
      • Namikawa H
      • Yamada K
      • Fujimoto H
      • Oinuma KI
      • Tochino Y
      • Takemoto Y
      • et al.
      Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
      ★☆7
      • Cheng WL
      • Hsueh PR
      • Lee CC
      • Li CW
      • Li MJ
      • Chang CM
      • et al.
      Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
      ★☆8
      • Gutiérrez-Gutiérrez B
      • Pérez-Galera S
      • Salamanca E
      • de Cueto M
      • Calbo E
      • Almirante B
      • et al.
      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.
      ★☆8
      • Ofer-Friedman H
      • Shefler C
      • Sharma S
      • Tirosh A
      • Tal-Jasper R
      • Kandipalli D
      • Sharma S
      • Bathina P
      • Kaplansky T
      • Maskit M
      • Azouri T
      • Lazarovitch T
      • Zaidenstein R
      • Kaye KS
      • Marchaim D.
      Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
      ★☆8
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ★☆8
      • To KK
      • Lo WU
      • Chan JF
      • Tse H
      • Cheng VC
      • Ho PL.
      Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity.
      ★☆7
      • Rodríguez-Baño J
      • Navarro MD
      • Retamar P
      • Picón E
      • Pascual Á
      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.
      ★☆8
      • Kang CI
      • Park SY
      • Chung DR
      • Peck KR
      • Song JH.
      Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ★☆7
      • Peralta G
      • Lamelo M
      • Alvarez-García P
      • Velasco M
      • Delgado A
      • Horcajada JP
      • et al.
      Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
      ★☆7
      • Chopra T
      • Marchaim D
      • Veltman J
      • Johnson P
      • Zhao JJ
      • Tansek R
      • et al.
      Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
      ★☆8
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      ★☆7
      • De Rosa FG
      • Pagani N
      • Fossati L
      • Raviolo S
      • Cometto C
      • Cavallerio P
      • et al.
      The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.
      ★☆7
      • Chaubey VP
      • Pitout JD
      • Dalton B
      • Ross T
      • Church DL
      • Gregson DB
      • et al.
      Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
      ★☆7
      • Lee CC
      • Lee NY
      • Yan JJ
      • Lee HC
      • Chen PL
      • Chang CM
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      ★☆8
      • Gudiol C
      • Calatayud L
      • Garcia-Vidal C
      • Lora-Tamayo J
      • Cisnal M
      • Duarte R
      • et al.
      Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
      ★☆8
      • Apisarnthanarak A
      • Kiratisin P
      • Mundy LM.
      Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ★☆7
      • Tumbarello M
      • Sanguinetti M
      • Montuori E
      • Trecarichi EM
      • Posteraro B
      • Fiori B
      • et al.
      Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
      ★☆8
      • Bin C
      • Hui W
      • Renyuan Z
      • Yongzhong N
      • Xiuli X
      • Yingchun X
      • et al.
      Outcome of cephalosporin treatment of bacteremia due to CTX-M–type extended-spectrum β-lactamase–producing Escherichia coli.
      ★☆8
      • Endimiani A
      • Luzzaro F
      • Brigante G
      • Perilli M
      • Lombardi G
      • Amicosante G
      • et al.
      Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
      ★☆7
      NOS, Newcastle-Ottawa Scale.
      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.

      3.3 Therapeutic response

      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 2
      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.

      3.4 Mortality

      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 3
      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 4
      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.

      4. Discussion

      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 [
      • Muhammed M
      • Flokas ME
      • Detsis M
      • Alevizakos M
      • Mylonakis E.
      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.
      ] and 2018 [
      • Sfeir MM
      • Askin G
      • Christos P
      Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
      ], we additionally evaluated the efficacy of therapeutical response between BLBLIs and carbapenems compared with the two studies [
      • Muhammed M
      • Flokas ME
      • Detsis M
      • Alevizakos M
      • Mylonakis E.
      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.
      ,
      • Sfeir MM
      • Askin G
      • Christos P
      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 [
      • Muhammed M
      • Flokas ME
      • Detsis M
      • Alevizakos M
      • Mylonakis E.
      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.
      ,
      • Sfeir MM
      • Askin G
      • Christos P
      Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
      ] because of the scarcity of infection-related mortality. Although all-cause mortality is an important and crucial measure of the treatment [
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      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 [
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Lichtner G
      • Balzer F
      • Haufe S
      • Giesa N
      • Schiefenhövel F
      • Schmieding M
      • et al.
      Predicting lethal courses in critically ill COVID-19 patients using a machine learning model trained on patients with non-COVID-19 viral pneumonia.
      ]. 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 [
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ,
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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 [
      • Muhammed M
      • Flokas ME
      • Detsis M
      • Alevizakos M
      • Mylonakis E.
      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.
      ,
      • Sfeir MM
      • Askin G
      • Christos P
      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 [

      Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 32nd ed., https://clsi.org/standards/products/microbiology/documents/m100/; 2022 [accessed 22 December 2022].

      ] and thus excluded these studies merely depending on the ESBL screening test represented by the third-generation cephalosporins resistance [
      • Xie O
      • Cisera K
      • Taylor L
      • Hughes C
      • Rogers B.
      Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection.
      ,
      • Ng TM
      • Khong WX
      • Harris PN
      • De PP
      • Chow A
      • Tambyah PA
      • et al.
      Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing Enterobacteriaceae.
      ,
      • Metan G
      • Altinbas A
      • Zarakolu P
      • Yildiz O
      • Cetinkaya Sardan Y
      • Sumerkan B
      • et al.
      Predictors of mortality in patients with bacteremia of unknown source due to extended spectrum beta-lactamase producing Escherichia coli.
      ,
      • Nasir N
      • Ahmed S
      • Razi S
      • Awan S
      • Mahmood SF.
      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 [

      Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 32nd ed., https://clsi.org/standards/products/microbiology/documents/m100/; 2022 [accessed 22 December 2022].

      ]. Taking AmpC as an example, it is capable of hydrolyzing third-generation cephalosporins but not carbapenems [
      • Drieux L
      • Brossier F
      • Sougakoff W
      • Jarlier V.
      Phenotypic detection of extended-spectrum beta-lactamase production in Enterobacteriaceae: review and bench guide.
      ] and cannot be inhibited by beta-lactamase inhibitors (e.g., clavulanic acid, sulbactam, and tazobactam) [

      Infectious Diseases Society of America. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 1.0, https://www.idsociety.org/practice-guideline/amr-guidance/; 2022 [accessed 22 December 2022].

      ]. 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 [
      • Mathers AJ
      • Lewis JS
      2nd. CON: testing for ESBL production is unnecessary for ceftriaxone-resistant Enterobacterales.
      ,
      • Tamma PD
      • Humphries RM.
      PRO: testing for ESBL production is necessary for ceftriaxone-non-susceptible Enterobacterales: perfect should not be the enemy of progress.
      ]. Moreover, we enrolled the most recently published six cohorts since 2018 [
      • Pierrotti LC
      • Pérez-Nadales E
      • Fernández-Ruiz M
      • Gutiérrez-Gutiérrez B
      • Tan BH
      • Carratalà J
      • et al.
      Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
      ,
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ,
      • Luo H
      • Xiao Y
      • Hang Y
      • Chen Y
      • Zhu H
      • Fang X
      • et al.
      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.
      ,
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Su J
      • Guo Q
      • Li Y
      • Wu S
      • Hu F
      • Xu S
      • et al.
      Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
      ,
      • Namikawa H
      • Yamada K
      • Fujimoto H
      • Oinuma KI
      • Tochino Y
      • Takemoto Y
      • et al.
      Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
      ] and the only RCT by now, to get more available and comprehensive data regarding this topic [
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      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 [
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ]. The empirical therapy referred to antibiotics administrated before the susceptibility testing results were reported [
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ], whereas the others, thereafter, were divided into definitive group [
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      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 [
      • Harris PNA
      • Tambyah PA
      • Lye DC
      • Mo Y
      • Lee TH
      • Yilmaz M
      • et al.
      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 [
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      ,
      • Al-Garni SM
      • Ghonaim MM
      • Ahmed MMM
      • Al-Ghamdi AS
      • Ganai FA.
      Risk factors and molecular features of extended-spectrum beta-lactamase producing bacteria at southwest of Saudi Arabia.
      ]. 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 [
      • Al-Garni SM
      • Ghonaim MM
      • Ahmed MMM
      • Al-Ghamdi AS
      • Ganai FA.
      Risk factors and molecular features of extended-spectrum beta-lactamase producing bacteria at southwest of Saudi Arabia.
      ,
      • Zhang F
      • Li Y
      • Lv Y
      • Zheng B
      • Xue F.
      Bacterial susceptibility in bloodstream infections: results from China Antimicrobial Resistance Surveillance Trial (CARST) Program, 2015–2016.
      ,
      • Kim YA
      • Kim H
      • Seo YH
      • Park GE
      • Lee H
      • Lee K.
      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 [
      • Tsai HY
      • Chen YH
      • Tang HJ
      • Huang CC
      • Liao CH
      • Chu FY
      • et al.
      Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
      ], 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 [
      • Meini S
      • Laureano R
      • Tascini C
      • Arena F
      • Fani L
      • Frullini A
      • et al.
      Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
      ,
      • Henderson A
      • Paterson DL
      • Chatfield MD
      • Tambyah PA
      • Lye DC
      • De PP
      • et al.
      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 [
      • Obodozie-Ofoegbu OO
      • Teng C
      • Mortensen EM
      • Frei CR.
      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 [
      • Tamma PD
      • Humphries RM.
      PRO: testing for ESBL production is necessary for ceftriaxone-non-susceptible Enterobacterales: perfect should not be the enemy of progress.
      ].
      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 [
      • Gudiol C
      • Calatayud L
      • Garcia-Vidal C
      • Lora-Tamayo J
      • Cisnal M
      • Duarte R
      • et al.
      Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
      ,
      • Xiao T
      • Yang K
      • Zhou Y
      • Zhang S
      • Ji J
      • Ying C
      • et al.
      Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
      ,
      • Qureshi ZA
      • Paterson DL
      • Pakstis DL
      • Adams-Haduch JM
      • Sandkovsky G
      • Sordillo E
      • et al.
      Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
      ,
      • Apisarnthanarak A
      • Kiratisin P
      • Mundy LM.
      Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      ,
      • Tumbarello M
      • Sanguinetti M
      • Montuori E
      • Trecarichi EM
      • Posteraro B
      • Fiori B
      • et al.
      Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
      ,
      • Endimiani A
      • Luzzaro F
      • Brigante G
      • Perilli M
      • Lombardi G
      • Amicosante G
      • et al.
      Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
      ] 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.

      References

        • Benetazzo L
        • Delannoy PY
        • Houard M
        • Wallet F
        • Lambiotte F
        • Vachée A
        • et al.
        Combination therapy with aminoglycoside in Bacteremiasdue to ESBL-producing Enterobacteriaceae in ICU.
        Antibiotics (Basel). 2020; 9: 777https://doi.org/10.3390/antibiotics9110777
        • Tooke CL
        • Hinchliffe P
        • Bragginton EC
        • Colenso CK
        • Hirvonen VHA
        • Takebayashi Y
        • et al.
        β-lactamases and β-lactamase Inhibitors in the 21st Century.
        J Mol Biol. 2019; 431: 3472-3500https://doi.org/10.1016/j.jmb.2019.04.002
        • Ouchar Mahamat O
        • Lounnas M
        • Hide M
        • Dumont Y
        • Tidjani A
        • Kamougam K
        • et al.
        High prevalence and characterization of extended-spectrum ß-lactamase producing Enterobacteriaceae in Chadian hospitals.
        BMC Infect Dis. 2019; 19: 205https://doi.org/10.1186/s12879-019-3838-1
      1. Infectious Diseases Society of America. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections: Version 1.0, https://www.idsociety.org/practice-guideline/amr-guidance/; 2022 [accessed 22 December 2022].

        • Karaiskos I
        • Giamarellou H.
        Carbapenem-sparing strategies for ESBL Producers: When and How.
        Antibiotics (Basel). 2020; 9: 61https://doi.org/10.3390/antibiotics9020061
        • Corcione S
        • Lupia T
        • Maraolo AE
        • Mornese Pinna S
        • Gentile I
        • De Rosa FG
        Carbapenem-sparing strategy: carbapenemase, treatment, and stewardship.
        Curr Opin Infect Dis. 2019; 32: 663-673https://doi.org/10.1097/QCO.0000000000000598
        • Bassetti M
        • Giacobbe DR
        • Robba C
        • Pelosi P
        • Vena A.
        Treatment of extended-spectrum β-lactamases infections: what is the current role of new β-lactams/β-lactamase inhibitors?.
        Curr Opin Infect Dis. 2020; 33: 474-481https://doi.org/10.1097/QCO.0000000000000685
        • Gudiol C
        • Cuervo G
        • Carratalà J.
        Optimizing therapy of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae.
        Curr Opin Crit Care. 2019; 25: 438-448https://doi.org/10.1097/MCC.0000000000000646
        • Pierrotti LC
        • Pérez-Nadales E
        • Fernández-Ruiz M
        • Gutiérrez-Gutiérrez B
        • Tan BH
        • Carratalà J
        • et al.
        Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).
        Transpl Infect Dis. 2021; 23: e13520https://doi.org/10.1111/tid.13520
        • Gutiérrez-Gutiérrez B
        • Pérez-Galera S
        • Salamanca E
        • de Cueto M
        • Calbo E
        • Almirante B
        • et al.
        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.
        Antimicrob Agents Chemother. 2016; 60: 4159-4169https://doi.org/10.1128/AAC.00365-16
        • Meini S
        • Laureano R
        • Tascini C
        • Arena F
        • Fani L
        • Frullini A
        • et al.
        Clinical outcomes of elderly patients with bloodstream infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward.
        Eur J Intern Med. 2018; 48: 50-56https://doi.org/10.1016/j.ejim.2017.10.014
        • Gudiol C
        • Royo-Cebrecos C
        • Abdala E
        • Akova M
        • Álvarez R
        • Maestro-de la Calle G
        • et al.
        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.
        Antimicrob Agents Chemother. 2017; 61 (e00164–17)https://doi.org/10.1128/AAC.00164-17
        • Cheng WL
        • Hsueh PR
        • Lee CC
        • Li CW
        • Li MJ
        • Chang CM
        • et al.
        Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.
        J Microbiol Immunol Infect. 2016; 49: 208-215https://doi.org/10.1016/j.jmii.2014.05.003
        • Harris PNA
        • Tambyah PA
        • Lye DC
        • Mo Y
        • Lee TH
        • Yilmaz M
        • et al.
        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.
        JAMA. 2018; 320: 984-994https://doi.org/10.1001/jama.2018.12163
        • Hayden MK
        • Won SY.
        Carbapenem-sparing therapy for extended-spectrum β-lactamase-producing E coli and Klebsiella pneumoniae bloodstream infection: the search continues.
        JAMA. 2018; 320: 979-981https://doi.org/10.1001/jama.2018.12565
        • Bru JP
        • Alfandari S
        • Bleibtreu A
        • Chavanet P
        • Gauzit R
        • Lescure X
        • et al.
        Carbapenems versus beta-lactam/beta-lactamase inhibitors to treat ESBL-producing Enterobacteriaceae infections.
        Med Mal Infect. 2020; 50: 313-315https://doi.org/10.1016/j.medmal.2019.09.010
        • Henderson A
        • Paterson DL
        • Chatfield MD
        • Tambyah PA
        • Lye DC
        • De PP
        • et al.
        Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the Merino study.
        Clin Infect Dis. 2021; 73: e3842-e3850https://doi.org/10.1093/cid/ciaa1479
        • Stang A.
        Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
        Eur J Epidemiol. 2010; 25: 603-605https://doi.org/10.1007/s10654-010-9491-z
        • Higgins JP
        • Altman DG
        • Gøtzsche PC
        • Jüni P
        • Moher D
        • Oxman AD
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928https://doi.org/10.1136/bmj.d5928
        • Rodríguez-Baño J
        • Navarro MD
        • Retamar P
        • Picón E
        • Pascual Á
        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.
        Clin Infect Dis. 2012; 54: 167-174https://doi.org/10.1093/cid/cir790
        • Gudiol C
        • Calatayud L
        • Garcia-Vidal C
        • Lora-Tamayo J
        • Cisnal M
        • Duarte R
        • et al.
        Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome.
        J Antimicrob Chemother. 2010; 65: 333-341https://doi.org/10.1093/jac/dkp411
        • Bin C
        • Hui W
        • Renyuan Z
        • Yongzhong N
        • Xiuli X
        • Yingchun X
        • et al.
        Outcome of cephalosporin treatment of bacteremia due to CTX-M–type extended-spectrum β-lactamase–producing Escherichia coli.
        Diagn Microbiol Infect Dis. 2006; 56: 351-357https://doi.org/10.1016/j.diagmicrobio.2006.06.015
        • Luo H
        • Xiao Y
        • Hang Y
        • Chen Y
        • Zhu H
        • Fang X
        • et al.
        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.
        Ann Clin Microbiol Antimicrob. 2021; 20: 63https://doi.org/10.1186/s12941-021-00471-6
        • Xiao T
        • Yang K
        • Zhou Y
        • Zhang S
        • Ji J
        • Ying C
        • et al.
        Risk factors and outcomes in non-transplant patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia: a retrospective study from 2013 to 2016.
        Antimicrob Resist Infect Control. 2019; 8: 144https://doi.org/10.1186/s13756-019-0599-y
        • Su J
        • Guo Q
        • Li Y
        • Wu S
        • Hu F
        • Xu S
        • et al.
        Comparison of empirical therapy with cefoperazone/sulbactam or a carbapenem for bloodstream infections due to ESBL-producing Enterobacteriaceae.
        J Antimicrob Chemother. 2018; 73: 3176-3180https://doi.org/10.1093/jac/dky323
        • Namikawa H
        • Yamada K
        • Fujimoto H
        • Oinuma KI
        • Tochino Y
        • Takemoto Y
        • et al.
        Clinical characteristics of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli at a tertiary hospital.
        Intern Med. 2017; 56: 1807-1815https://doi.org/10.2169/internalmedicine.56.7702
        • Ofer-Friedman H
        • Shefler C
        • Sharma S
        • Tirosh A
        • Tal-Jasper R
        • Kandipalli D
        • Sharma S
        • Bathina P
        • Kaplansky T
        • Maskit M
        • Azouri T
        • Lazarovitch T
        • Zaidenstein R
        • Kaye KS
        • Marchaim D.
        Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
        Infect Control Hosp Epidemiol. 2015; 36: 981-985https://doi.org/10.1017/ice.2015.101
        • Tsai HY
        • Chen YH
        • Tang HJ
        • Huang CC
        • Liao CH
        • Chu FY
        • et al.
        Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum β-lactamase-producing Proteus mirabilis.
        Diagn Microbiol Infect Dis. 2014; 80: 222-226https://doi.org/10.1016/j.diagmicrobio.2014.07.006
        • To KK
        • Lo WU
        • Chan JF
        • Tse H
        • Cheng VC
        • Ho PL.
        Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity.
        Int J Infect Dis. 2013; 17: e120-e124https://doi.org/10.1016/j.ijid.2012.09.008
        • Peralta G
        • Lamelo M
        • Alvarez-García P
        • Velasco M
        • Delgado A
        • Horcajada JP
        • et al.
        Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study.
        BMC Infect Dis. 2012; 12: 245https://doi.org/10.1186/1471-2334-12-245
        • Kang CI
        • Park SY
        • Chung DR
        • Peck KR
        • Song JH.
        Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
        J Infect. 2012; 64: 533-534https://doi.org/10.1016/j.jinf.2012.01.008
        • Chopra T
        • Marchaim D
        • Veltman J
        • Johnson P
        • Zhao JJ
        • Tansek R
        • et al.
        Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and Escherichia coli.
        Antimicrob Agents Chemother. 2012; 56: 3936-3942https://doi.org/10.1128/AAC.05419-11
        • Qureshi ZA
        • Paterson DL
        • Pakstis DL
        • Adams-Haduch JM
        • Sandkovsky G
        • Sordillo E
        • et al.
        Risk factors and outcome of extended-spectrum β-lactamase-producing Enterobacter cloacae bloodstream infections.
        Int J Antimicrob Agents. 2011; 37: 26-32https://doi.org/10.1016/j.ijantimicag.2010.09.009
        • De Rosa FG
        • Pagani N
        • Fossati L
        • Raviolo S
        • Cometto C
        • Cavallerio P
        • et al.
        The effect of inappropriate therapy on bacteremia by ESBL-producing bacteria.
        Infection. 2011; 39: 555-561https://doi.org/10.1007/s15010-011-0201-x
        • Lee CC
        • Lee NY
        • Yan JJ
        • Lee HC
        • Chen PL
        • Chang CM
        • et al.
        Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
        Antimicrob Agents Chemother. 2010; 54: 3551-3556https://doi.org/10.1128/AAC.00055-10
        • Chaubey VP
        • Pitout JD
        • Dalton B
        • Ross T
        • Church DL
        • Gregson DB
        • et al.
        Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae.
        BMC Res Notes. 2010; 3: 116https://doi.org/10.1186/1756-0500-3-116
        • Apisarnthanarak A
        • Kiratisin P
        • Mundy LM.
        Predictors of mortality from community-onset bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
        Infect Control Hosp Epidemiol. 2008; 29: 671-674https://doi.org/10.1086/588082
        • Tumbarello M
        • Sanguinetti M
        • Montuori E
        • Trecarichi EM
        • Posteraro B
        • Fiori B
        • et al.
        Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.
        Antimicrob Agents Chemother. 2007; 51: 1987-1994https://doi.org/10.1128/AAC.01509-06
        • Endimiani A
        • Luzzaro F
        • Brigante G
        • Perilli M
        • Lombardi G
        • Amicosante G
        • et al.
        Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases.
        Antimicrob Agents Chemother. 2005; 49: 2598-2605https://doi.org/10.1128/AAC.49.7.2598-2605.2005
        • Muhammed M
        • Flokas ME
        • Detsis M
        • Alevizakos M
        • Mylonakis E.
        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.
        Open Forum Infect Dis. 2017; 4 (ofx099)https://doi.org/10.1093/ofid/ofx099
        • Sfeir MM
        • Askin G
        • Christos P
        Beta-lactam/beta-lactamase inhibitors versus carbapenem for bloodstream infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae: systematic review and meta-analysis.
        Int J Antimicrob Agents. 2018; 52: 554-570https://doi.org/10.1016/j.ijantimicag.2018.07.021
        • Lichtner G
        • Balzer F
        • Haufe S
        • Giesa N
        • Schiefenhövel F
        • Schmieding M
        • et al.
        Predicting lethal courses in critically ill COVID-19 patients using a machine learning model trained on patients with non-COVID-19 viral pneumonia.
        Sci Rep. 2021; 11: 13205https://doi.org/10.1038/s41598-021-92475-7
      2. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 32nd ed., https://clsi.org/standards/products/microbiology/documents/m100/; 2022 [accessed 22 December 2022].

        • Xie O
        • Cisera K
        • Taylor L
        • Hughes C
        • Rogers B.
        Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection.
        Ann Clin Microbiol Antimicrob. 2020; 19: 57https://doi.org/10.1186/s12941-020-00400-z
        • Ng TM
        • Khong WX
        • Harris PN
        • De PP
        • Chow A
        • Tambyah PA
        • et al.
        Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing Enterobacteriaceae.
        PLoS One. 2016; 11e0153696https://doi.org/10.1371/journal.pone.0153696
        • Metan G
        • Altinbas A
        • Zarakolu P
        • Yildiz O
        • Cetinkaya Sardan Y
        • Sumerkan B
        • et al.
        Predictors of mortality in patients with bacteremia of unknown source due to extended spectrum beta-lactamase producing Escherichia coli.
        J Chemother. 2009; 21: 448-451https://doi.org/10.1179/joc.2009.21.4.448
        • Nasir N
        • Ahmed S
        • Razi S
        • Awan S
        • Mahmood SF.
        Risk factors for mortality of patients with ceftriaxone resistant E. coli bacteremia receiving carbapenem versus beta lactam/beta lactamase inhibitor therapy.
        BMC Res Notes. 2019; 12: 611https://doi.org/10.1186/s13104-019-4648-7
        • Drieux L
        • Brossier F
        • Sougakoff W
        • Jarlier V.
        Phenotypic detection of extended-spectrum beta-lactamase production in Enterobacteriaceae: review and bench guide.
        Clin Microbiol Infect. 2008; 14: 90-103https://doi.org/10.1111/j.1469-0691.2007.01846.x
        • Mathers AJ
        • Lewis JS
        2nd. CON: testing for ESBL production is unnecessary for ceftriaxone-resistant Enterobacterales.
        JAC Antimicrob Resist. 2021; 3 (dlab020)https://doi.org/10.1093/jacamr/dlab020
        • Tamma PD
        • Humphries RM.
        PRO: testing for ESBL production is necessary for ceftriaxone-non-susceptible Enterobacterales: perfect should not be the enemy of progress.
        JAC Antimicrob Resist. 2021; 3 (dlab019)https://doi.org/10.1093/jacamr/dlab019
        • Al-Garni SM
        • Ghonaim MM
        • Ahmed MMM
        • Al-Ghamdi AS
        • Ganai FA.
        Risk factors and molecular features of extended-spectrum beta-lactamase producing bacteria at southwest of Saudi Arabia.
        Saudi Med J. 2018; 39: 1186-1194https://doi.org/10.15537/smj.2018.12.23273
        • Zhang F
        • Li Y
        • Lv Y
        • Zheng B
        • Xue F.
        Bacterial susceptibility in bloodstream infections: results from China Antimicrobial Resistance Surveillance Trial (CARST) Program, 2015–2016.
        J Glob Antimicrob Resist. 2019; 17: 276-282https://doi.org/10.1016/j.jgar.2018.12.016
        • Kim YA
        • Kim H
        • Seo YH
        • Park GE
        • Lee H
        • Lee K.
        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.
        Ann Lab Med. 2021; 41: 285-292https://doi.org/10.3343/alm.2021.41.3.285
        • Obodozie-Ofoegbu OO
        • Teng C
        • Mortensen EM
        • Frei CR.
        Antipseudomonal monotherapy or combination therapy for older adults with community-onset pneumonia and multidrug-resistant risk factors: a retrospective cohort study.
        Am J Infect Control. 2019; 47: 1053-1058https://doi.org/10.1016/j.ajic.2019.02.018