European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine)

Guidelines European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine) Mical Paul 1 , 2 , x , Elena Carrara 3 , x , Pilar Retamar 4 , 5 , Thomas T€ angd en 6 , Roni Bitterman 1 , 2 , Robert A. Bonomo 7 , 8 , 9 , Jan de Waele 10 , George L. Daikos 11 , Murat Akova 12 , Stephan Harbarth 13 , Celine Pulcini 14 , 15 , Jos e Garnacho-Montero 16 , Katja Seme 17 , Mario Tumbarello 18 , Paul Christoffer Lindemann 19 , Sumanth Gandra 20 , Yunsong Yu 21 , 22 , 23 , Matteo Bassetti 24 , 25 , Johan W. Mouton 26 , y , Evelina Tacconelli 3 , 27 , 28 , * , x , Jesús Rodríguez-Ba~ no 4 , 5 , x 1) Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel 2) Faculty of Medicine, Technion eIsrael Institute of Technology, Haifa, Israel 3) Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, Verona, Italy 4) Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain 5) Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena/Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain 6) Department of Medical Sciences, Uppsala University, Uppsala, Sweden 7) Department of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA 8) Medical Service, Research Service, and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA 9) VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH, USA 10) Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium 11) First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece 12) Hacettepe University School of Medicine, Department of Infectious Diseases, Ankara, Turkey 13) Infection Control Programme, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland 14) Universit e de Lorraine, APEMAC, Nancy, France 15) Universit e de Lorraine, CHRU-Nancy, Infectious Diseases Department, Nancy, France 16) Intensive Care Unit. Virgen Macarena University Hospital, Seville, Spain 17) Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia 18) Department of Medical Biotechnologies, University of Siena, Italy 19) Haukeland University Hospital, Department of Microbiology, Bergen, Norway 20) Division of Infectious Diseases, Washington University School of Medicine in St Louis, St Louis, MO, USA 21) Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 22) Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China 23) Regional Medical Centre for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China 24) Department of Health Sciences, University of Genoa, Genoa, Italy 25) Clinica Malattie Infettive, San Martino Policlinico Hospital, Genoa, Italy 26) Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands 27) Division of Infectious Diseases, Department of Internal Medicine I, German Centre for Infection Research, University of Tübingen, Tübingen, Germany 28) German Centre for Infection Research (DZIF), Clinical Research Unit for Healthcare Associated Infections, Tübingen, Germany *Corresponding author. Evelina Tacconelli, Infectious Diseases Division, Diagnostics and Public Health Department, University of Verona, P.le L.A. Scuro 10, 37134, Verona, Italy. E-mail address: [email protected] (E. Tacconelli). y Deceased. x Mical Paul and Elena Carrara made equal contributions to these guidelines; Evelina Tacconelli and Jesús Rodríguez-Ba~ no made equal contributions to these guidelines. Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com https://doi.org/10.1016/j.cmi.2021.11.025 1198-743X/©2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Clinical Microbiology and Infection 28 (2022) 521e547 article info Article history: Received 7 August 2021 Received in revised form 28 November 2021 Accepted 29 November 2021 Available online 16 December 2021 Editor: L. Leibovici Keywords: Acinetobacter baumannii Carbapenem-resistant bacteria ESCMID GRADE Multidrug resistant bacteria abstract Scope: These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy. Methods: An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/ recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak). Recommendations: The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, b -lactam/ b -lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed. Mical Paul, Clin Microbiol Infect 2022;28:521 ©2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Scope and context According to estimates from the European Center of Disease and Control (ECDC), antibiotic-resistant bacteria caused 600 000 infections and 27 000 attributable deaths in 2015 in Europe [2]. Almost 70% of this disease burden, in terms of both number of cases and attributable deaths, is caused by multi-drug-resistant Gram-negative bacteria (MDR-GNB). Ratios of attributable deaths compared with the non-infected population or with a population infected with susceptible isolates of the same bacteria are positive, with a factor-increase ranging from 1.5 for MDR Pseudomonas aeruginosa to 6.2 for carbapenem-resistant (CR) Klebsiella pneumoniae from 2007 to 2015 [2]. The substantial burden of disease, together with the paucity of available treatments and slowly progressing antibiotic pipeline have led the World Health Organization to prioritize four MDR-GNB phenotypes as of critical priority for future research and development investments: CR-Acinetobacter baumannii,CR- P. aeruginosa and CR- and third-generation cephalosporin-resis- tant Enterobacterales [3]. Since the issuing of the priority list in 2017, five new antibiotics with activity against MDR-GNB were approved by the European Medicines Agency (EMA) and and the US Food and Drug Administration (FDA), none of which has a new mode of action and all followed a fast-track development pathway that is granted to drugs potentially addressing unmet medical needs [4]. In parallel with huge efforts by pharmaceutical companies, and profit and non-profit organizations to promote research and development of new antibiotics, the scientific community and public health agencies are strongly calling for an increasingly parsimonious use of available antibiotics in order to prevent further development of resistance. In this paradoxical scenario prescribing antibiotics for MDR-GNB infections has become a significant challenge for clinicians worldwide, stretched between the well-known limitations of the old drugs, fear of promoting resistance by using the new antibiotics, the paucity of data on the effects of newly developed antibiotics against MDRGNB and the costs of the new antibiotics [5]. The objective of these evidence-based guidelines is to provide recommendations for treatment of infections caused by MDR-GNB in hospitalized patients. Questions addressed by the guideline Target MDR-GNB and the questions addressed were selected by consensus in the first panel meeting. The guidelines address the targeted treatment of infections caused by third-generation cephalosporin-resistant Enterobacterales (3GCephRE), CR Enterobacterales (CRE), CR P. aeruginosa (CRPA) and CR A. baumannii (CRAB). The following questions were addressed. (a) What is the antibiotic of choice for patients infected with the target MDR-GNB? (b) Should combination antibiotic therapy be used for patients infected with the target CR-GNB? The recommendations are summarized in Table 1. The potential in vitro activity of antibiotics reviewed against the target MDR-GNB is provided in Table 2.In vitro data point to specific antibiotic combinations that are synergistic against specific CR-GNB or prevent resistance emergence. Yet for patient management, evidence from clinical studies is necessary to select the optimal treatment, including both single and combination therapies [6,7] Therefore, the guidelines are based on a systematic review of clinical evidence. Expected users of these guidelines include both policy-makers and in-hospital antibiotic prescribers, especially infectious disease, clinical microbiology and intensive care specialists. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547522 Table 1 Summary of recommendations Recommendation Strength of recommendation Level of evidence Third-generation cephalosporin-resistant Enterobacterales (3GCephRE) Recommendations on the choice of antibiotic treatment for 3GCephRE For patients with BSI and severe infection due to 3GCephRE, we recommend a carbapenem (imipenem or meropenem) as targeted therapy Strong Moderate For patients with BSI due to 3GCephRE without septic shock, ertapenem instead of imipenem or meropenem may be used. Conditional Moderate For patients with low-risk, non-severe infections due to 3GCephRE, under the consideration of antibiotic stewardship, we suggest piperacillin-tazobactam, amoxicillin/clavulanic acid or quinolones. It may be good practice to consider cotrimoxazole for non-severe cUTI. Conditional/good practice statement Moderate/expert opinion For cUTI in patients without septic shock, we conditionally recommend aminoglycosides when active in vitro for short durations of therapy, or IV fosfomycin. Conditional/strong Moderate/high Among all patients with 3GCephRE infections, stepdown targeted therapy following carbapenems once patients are stabilized, using old BLBLI, quinolones, cotrimoxazole or other antibiotics based on the susceptibility pattern of the isolate, is good clinical practice. Good practice statement Expert opinion We do not recommend tigecycline for infections caused by 3GCephRE. Strong Very low Among all patients with 3GCephRE infections the new BLBLI are reserved antibiotics for extensively resistant bacteria and therefore, we consider it good clinical practice to avoid their use for infections caused by 3GCephRE, due to antibiotic stewardship considerations. Good practice statement Expert opinion We suggest that cephamycins (e.g. cefoxitin, cefmetazole, flomoxef) and cefepime not be used for 3GCephRE infections. Conditional Very low For cefoperazone-sulbactam, ampicillin-sulbactam, ticarcillin-clavulanic acid, temocillin and mecillinam there is insufficient evidence for the management of patients with 3GCephRE infections at the time of writing and therefore no recommendation can be issued. No recommendation Carbapenem-resistant Enterobacterales (CRE) Recommendations on the choice of antibiotic treatment for CRE For patients with severe infections due to CRE, we suggest meropenem-vaborbactam or ceftazidime-avibactam if active in vitro. Conditional Moderate/low For patients with severe infections due to CRE carrying metallob -lactamases and/or resistant to all other antibiotics, including ceftazidime-avibactam and meropenem-vaborbactam, we conditionally recommend treatment with cefiderocol. Conditional Low For patients with non-severe infections due to CRE, under the consideration of antibiotic stewardship, we consider the use of an old antibiotic, chosen from among the in vitro active on an individual basis and according to the source of infection, as good clinical practice. For patients with cUTI, we suggest aminoglycosides, including plazomicin, over tigecycline. Good practice statement/conditional Expert opinion/low We suggest that tigecycline not be used for BSI and HAP/VAP; if necessary, in patients with pneumonia, clinicians may use high-dose tigecycline. Conditional Low There is no evidence to recommend for or against the use of imipenem-relebactam and fosfomycin monotherapies for CRE at the time of writing. No recommendation Recommendations on combination therapy for CRE For patients with CRE infections susceptible to and treated with ceftazidime-avibactam, meropenem-vaborbactam or cefiderocol, we do not recommend combination therapy. Strong Low For patients with severe infections caused by CRE carrying metallob -lactamases and/or resistant to new antibiotic monotherapies, we suggest aztreonam and ceftazidime-avibactam combination therapy. Conditional Moderate For patients with severe infections caused by CRE susceptible in vitro only to polymyxins, aminoglycosides, tigecycline or fosfomycin, or in the case of non-availability of new BLBLI, we suggest treatment with more than one drug active in vitro. No recommendation for or against specific combinations can be provided. Conditional Moderate We suggest that clinicians avoid carbapenem-based combination therapy for CRE infections, unless the meropenem MIC is 8 mg/L, where high-dose extended-infusion meropenem may be used as part of combination therapy if the new BLBLI are not used. Conditional Low In patients with non-severe infections or among patients with low-risk infections, under the consideration of antibiotic stewardship, we consider the use of monotherapy chosen from among the in vitro active old drugs, on an individual basis and according to the source of infection as good clinical practice Good practice statement Expert opinion Carbapenem-resistant Pseudomonas aeruginosa (CRPA) Recommendations on the choice of antibiotic treatment for CRPA In patients with severe infections due to difficult to treat CRPA, we suggest therapy with ceftolozane-tazobactam if active in vitro. Insufficient evidence is available for imipenemrelebactam, cefiderocol and ceftazidime-avibactam at this time. Conditional Very low In patients with non-severe or low-risk CRPA infections, under the consideration of antibiotic stewardship, we consider it good clinical practice to use the old antibiotics, chosen from among the in vitro active antibiotics on an individual basis and according to the source of infection. Good practice statement Expert opinion Recommendations on combination therapy for CRPA Lacking evidence, we cannot recommend for or against the use of combination therapy with the new BLBLI (ceftazidime-avibactam and ceftolozane-tazobactam) or cefiderocol for CRPA infections. No recommendation When treating severe infections caused by CRPA with polymyxins, aminoglycosides, or fosfomycin, we suggest treatment with two in vitro active drugs. No recommendation for or against specific combinations can be provided. Conditional Very low In patients with non-severe or low-risk CRPA infections, under the consideration of antibiotic stewardship, we consider it good clinical practice to use monotherapy chosen from among the drugs active in vitro, on an individual basis and according to the source of infection. Good practice statement Expert opinion (continued on next page) M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 523 Table 1 (continued ) Recommendation Strength of recommendation Level of evidence Carbapenem-resistant Acinetobacter baumannii (CRAB) Recommendations on the choice of antibiotic treatment for CRAB For patients with CRAB susceptible to sulbactam and HAP/VAP, we suggest ampicillinsulbactam. Conditional Low For patients with CRAB resistant to sulbactam, a polymyxin or high-dose tigecycline can be used if active in vitro. Lacking evidence, we cannot recommend on the preferred antibiotic. No recommendation We conditionally recommend against cefiderocol for the treatment of infections caused by CRAB. Conditional Low Recommendations on combination therapy for CRAB For all patients with CRAB infections, we do not recommend polymyxin-meropenem combination therapy or polymyxin-rifampin combination therapy. Strong High/moderate For patients with severe and high-risk CRAB infections, we suggest combination therapy including two in vitro active antibiotics among the available antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam combinations). Conditional Very low For patients with CRAB infections with a meropenem MIC 8 mg/L, we consider carbapenem combination therapy, using high-dose extended-infusion carbapenem dosing, as good clinical practice. Good practice statement Expert opinion All carbapenem-resistant Gram-negative bacteria For pan-resistant CR-GNB (resistant also to polymyxins), treatment with the least resistant antibiotic/s based on MICs relative to the breakpoints is considered as good clinical practice. Good practice statement Expert opinion Abbreviations: BLBLI, b -lactamase/ b -lactamase inhibitors; BSI, bloodstream infections; cUTI, complicated urinary tract infections; HAP, hospital-acquired pneumonia; IV, intravenous; VAP, ventilator-associated pneumonia. Table 2 Potential in vitro activity of antibiotics against target carbapenem-resistant Gram-negative bacteria and approved indications CRAB ESBLs CRPA non-MBL CRE non-CP CRE-KPC CRE-OXA-48 CRE-MBL Current clinical indications/approval New antibiotics Ceftolozane-tazobactam No Yes Yes No No No No FDA and EMA approved for cUTI, cIAI, HAP and VAP Ceftazidime-avibactam No Yes Yes þ/eYes Yes No FDA and EMA approved for cIAI and cUTI, HAP and VAP, and (in EMA only) for the treatment Gramnegative infections in patients with limited treatment options Meropenem-vaborbactam No Yes No þ/eYes No No FDA approved for cUTI, EMA approved for cUTI, HAP and VAP, and for the treatment Gram-negative infections in patients with limited treatment options Imipenem-cilastatin/ relebactam No Yes Yes þ/eYes No No FDA approved for cUTI and cIAI; EMA approved for HAP and VAP and for BSI with a suspected respiratory source, and for the treatment Gram-negative infections in patients with limited treatment options Plazomicin No Yes þ/eYes Yes Yes þ/eFDA approval cUTI, EMA application withdrawn Eravacycline Yes Yes No Yes Yes Yes Yes FDA and EMA approved for cIAI Cefiderocol Yes Yes Yes Yes Yes Yes Yes FDA cUTI, HAP and VAP; EMA for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options Old antibiotics Polymyxins Yes Yes Yes Yes Yes Yes Yes FDA: serious infections caused by susceptible strains, when less potentially toxic drugs are ineffective or contraindicated. EMA: treatment of serious infections due to aerobic Gram-negative pathogens in patients with limited treatment options Aminoglycosides þ/eþ/eþ/eþ/eþ/eþ/eþ/eEMA and FDA: for the treatment of a variety of bacterial infections Fosfomycin iv No Yes þ/eþ/eþ/eþ/eþ/eEMA: to treat serious infections when other antibiotic treatments are not suitable. FDA: under review Aztreonam No No þ/eNo No No þ/eEMA and FDA: for the treatment of infections caused by susceptible Gram-negative microorganisms Tigecycline Yes Yes No Yes Yes Yes Yes EMA and FDA: complicated SSTI and IAI (FDA also CAP) Temocillin No Yes No No þ/eNo No EMA and FDA: orphan drug status for the treatment of infections caused by Burkholderia cepacia in patients with cystic fibrosis The table presents the spectrum of potential in vitro activity of the listed antibiotics; resistance can develop and treatment should be directed by susceptibility testing. Abbreviations: BSI, bloodstream infection; CAP, community-acquired pneumonia; cIAI, complicated intra-abdominal infections; CRAB, carbapenem-resistant Acinetobacter baumannii; CRE non-CP, non-carbapenemase-producing carbapenem-resistant Enterobacterales; CRPA non-MBL, carbapenem-resistant Pseudomonas aeruginosa non-met- allob -lactamase-producing; cUTI, complicated urinary tract infections; EMA, European Medicines Agency; ESBLs, extended-spectrum b -lactmases; FDA, US Food and Drug Administration; HAP, hospital-acquired pneumonia; MBL, metallob -lactamase; SSTI, skin and soft-tissue infections; VAP, ventilator-associated pneumonia. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547524 Methods First, a systematic review was performed to support the recommendations. The certainty of the evidence was classified using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Second, an expert panel translated the evidence to recommendations and the strength of recommendations was adjudicated. Finally, the recommendations were discussed and revised until consensus was achieved and the final list of recommendations was formally approved by the whole panel. The review protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [8] and foresaw the inclusion of all studies evaluating the efficacy of any antibiotic regimen on clinical outcomes in hospitalized patients with infections caused by MDR-GNB. Description of the developing group A guideline panel was convened by the ESCMID Executive Committee in 2018. Experts on the management of MDR-GNB infections, bacteriology and mechanisms of resistance were selected from the fields of infectious diseases, clinical microbiology, intensive care and pharmacokinetics-pharmacodynamics, targeting multinational representation. Conflict of interest statements were collected from all panel members before starting and after completion of the guideline development. The guideline development process is further detailed in the Supplementary material (Appendix S1). Literature search Relevant clinical studies were identified through computerized literature searches using PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, FDA drug approval documents and the panel experts' own studies. Three separate search strategies for each target organism (Acinetobacter, Enterobacterales and P. aeruginosa) were developed through the combination of Medical Subject Headings and equivalent terms and adapted for the different databases (Appendix 1). The last systematic search was conducted in December 2019. After the final search date, studies (including randomized controlled trials from international conferences) having a significant impact on the recommendations were identified by the authors and added, until 12 July (ECCMID) 2021. Inclusion criteria We included comparative randomized controlled trials (RCT) or observational studies (both retrospective or prospective), examining different antibiotic treatment regimens for infections caused by the designated MDR-GNB. Only studies reporting on the defined clinical and/or microbiological outcomes were included. We did not include conference proceedings and excluded case reports, small case series with fewer than ten patients, in vitro and animal studies and studies on prophylaxis or decolonization. The guidelines address two main questions on selection of the optimal monotherapy and on monotherapy versus combination therapy for the different MDR-GNB. The questions were posed in the PICO framework (Population/participant, Intervention, Comparator/control, Outcome). The full PICO questions are detailed in the Supplementary material (Appendix S1). In brief, the research questions were formulated as follow: Population: Hospitalized patients with infections requiring systemic treatment due to the selected microorganisms (3GCephRE, CRE, CRPA and CRAB). We excluded studies assessing patients with uncomplicated urinary tract infections (UTI) and tracheobronchitis. Intervention: Targeted treatment (following pathogen and susceptibility identification) with systemic antibiotics, preferably defined in terms of dosage and duration. We included EMA- or FDA- approved antibiotics, approved for any indication. Comparator: Patients receiving another antibiotic/antibiotic scheme. The two comparisons assessed any antibiotic versus different antibiotic/s and monotherapy versus combination therapy. Outcomes: The primary outcome considered for all analyses was all-cause mortality, preferably at 30 days. If 30-day data were unavailable, we used the closest defined time-point and if unavailable in-hospital all-cause mortality. Secondary outcomes included clinical failure (or cure), microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. All outcomes reported in the studies, of the defined outcomes, were extracted. Definitions Sepsis: We adopted the sepsis-3 definition for sepsis, as severe presentation of infection with life-threatening organ dysfunction caused by a dysregulated host response to infection [9]. Septic shock: We similarly accept the sepsis-3 definitions for septic shock when the underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality [9]. Severe infections: sepsis or septic shock. Low and high-risk infections: Based on the INCREMENT score, we defined infections (including bloodstream infections (BSI)) originating from a urinary tract source of infection or biliary infections after source control as infections at low risk for mortality and other infections as high-risk infections [10,11]. New antibiotics: Antibiotics approved after 2010. Uncomplicated UTI: Infection causing local bladder signs and symptoms, without fever, other signs of systemic infection, or findings suggestive of kidney involvement. Difficult to treat resistance (DTR): Resistance to all b -lactams, including carbapenems, b -lactamase inhibitor combinations and fluoroquinolones [12]. Risk of bias assessment Risk of bias assessment was performed for each study by two reviewers independently using adapted versions of the Effective Practice and Organization of Care guidelines for RCT and the NewcastleeOttawa Scale for non-randomized studies [13,14] Individual studies were classified overall as providing low, moderate or high risk of bias evidence. Review procedures and data extraction All articles identified by the search were screened on the basis of the abstract against eligibility criteria and non-relevant documents or duplicates were excluded. Full texts of potentially eligible articles were then assessed by two reviewers independently who applied eligibility criteria. Relevant data were extracted into a pre-defined database. Data extraction and risk of bias assessment were performed independently by two reviewers among the guideline expert panel and discrepancies were resolved through discussion between the two reviewers and, if necessary, with the guideline expert panel. All and only panel members participated in the eligibility assessment and data extraction. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 525 Data synthesis and development of recommendations Because of the large, expected heterogeneity of study designs, treatment schemes, patient populations and resistance definitions the expert panel agreed not to perform quantitative synthesis of the data using meta-analysis and results were summarized qualitatively. When possible, recommendations tried to address severe infections versus others, at-risk infection sources versus others and different mechanisms of resistance. Available evidence for each treatment comparison was classified by the panel following the GRADE system [15]. Certainty of the evidence was classified as high, moderate, low or very low. Recommendations were classified as strong or conditional (weak). When no evidence was available, good practice statements were designated based on expert opinion. All recommendations are conditional on the in vitro activity of the recommended antibiotics. 1. Third-generation cephalosporin-resistant Enterobacterales Question 1.1: What is the antibiotic of choice for 3GCephRE Recommendations For patients with BSI and severe infection due to 3GCephRE, we recommend a carbapenem (imipenem or meropenem) as targeted therapy (strong recommendation for use, moderate certainty of evidence). For patients with BSI due to 3GCephRE without septic shock, ertapenem instead of imipenem or meropenem may be used (conditional recommendation for use, moderate certainty of evidence). For patients with low-risk, non-severe infections due to 3GCephRE, under the consideration of antibiotic stewardship, we suggest piperacillin-tazobactam, amoxicillin/clavulanic acid or quinolones (conditional recommendation for use, moderate certainty of evidence/good practice statement). It may be good practice to consider cotrimoxazole for non-severe complicated UTI (cUTI) (good practice statement). For cUTI in patients without septic shock, we conditionally recommend aminoglycosides when active in vitro, for short durations of therapy (conditional recommendation for use, moderate certainty of evidence), or intravenous fosfomycin (strong recommendation for use, high certainty of evidence) Among all patients with 3GCephRE infections, stepdown targeted therapy following carbapenems once patients are stabilized, using old b -lactam/ b -lactamase inhibitors (BLBLI), quinolones, cotrimoxazole or other antibiotics based on the susceptibility pattern of the isolate, is good clinical practice (good practice statement). We do not recommend tigecycline for infections caused by 3GCephRE (strong recommendation against use, very low certainty of evidence). Among all patients with 3GCephRE infections, the new BLBLI are reserve antibiotics for extensively resistant bacteria and therefore, we consider it good clinical practice to avoid their use for infections caused by 3GCephRE, due to antibiotic stewardship considerations (good practice statement). We suggest that cephamycins (e.g. cefoxitin, cefmetazole, flomoxef) and cefepime not be used for 3GCephRE infections (conditional recommendation against use, very low certainty of evidence). For cefoperazone-sulbactam, ampicillin-sulbactam, ticarcillinclavulanic acid, temocillin and mecillinam there is insufficient evidence for the management of patients with 3GCephRE infections at the time of writing and therefore no recommendation can be issued. Review of the evidence The data available on 3GCephRE are derived mainly from observational studies in the hospital setting including patients with BSI and urinary source of infection. In many studies there was a lack of information on the bacterial species and mechanisms of resistance. Extended-spectrum b -lactamase (ESBL) production was the most commonly reported resistance mechanism, mostly without specifying the type of b -lactamases conferring the ESBL phenotype. The main comparison is between the older BLBLI (amoxicillinclavulanate and piperacillin-tazobactam) and carbapenems and discusses the conflict between the MERINO RCT [16] and the observational data [17,18]. An underlying stewardship consideration for this comparison was the association between carbapenem use and CRE [19]. Data on new antibiotics are sparse because most new antibiotic approval RCT were syndrome-based and the subgroups of patients with 3GCephRE infections were small. For 3GcephRE, only PICO 1 on the choice of antibiotic treatment was addressed. The evidence on treatment of infections caused by 3GCephRE is provided by clinical syndrome: BSI, UTI, pneumonia and intraabdominal infection (IAI). All studies referred to in the text are described in Table 3. Bloodstream infections BLBLI versus carbapenems. The MERINO trial compared piperacillin-tazobactam with meropenem among patients with BSI caused by third-generation cephalosporin-resistant Escherichia coli and K. pneumoniae [16]. The primary outcome was 30-day mortality and the study did not prove the non-inferiority of piperacillintazobactam, with 30-day mortality rates of 23/187 (12.3%) with piperacillin-tazobactam versus 7/191 (3.7%) with meropenem (risk difference (RD) 8.6%, one-sided 97.5% CI e∞to 14.5%). The risk difference was lower in the subgroup of patients with UTI (RD 3.7%, e∞to 10.7%) than among patients with other sources of BSI (RD 14.1%, e∞to 24.5%). Following the trial, the authors found a high rate of false susceptibility to piperacillin-tazobactam among OXA-1 producers with automatic methods or strip-gradient tests performed in the trial sites. A further analysis of the trial excluded patients with BSI caused by non-susceptible strains (piperacillintazobactam MIC >16 mg/L; meropenem MIC >1 mg/L CLSI, or MIC >2 mg/L EUCAST), as assessed by broth microdilution in a reference laboratory [20] The difference between groups decreased and was non-significant with a smaller sample size, mortality 13/134 (9.7%) with piperacillin-tazobactam versus 6/149 (4%) with meropenem, risk difference 5.7% (95% CI e1% to 11%). The certainty from this trial showing advantage of meropenem compared with piperacillintazobactam was classified as moderate, due to indirectness related to the high rate of OXA-1-producers with high MICs to piperacillintazobactam and to the small sample size of the further subgroup analyses. The MERINO-2 was a pilot RCT comparing piperacillintazobactam and meropenem among patients with BSI caused by presumed Amp-C b -lactamase-producing but third-generation cephalosporin-susceptible Enterobacter spp., Citrobacter freundii, Morganella morganii,Providencia spp., Klebsiella aerogenes or Serratia marcescens [21]. Among 70 included patients, mortality was very low (two patients in the meropenem arm) and there was no significant difference in clinical failure (8/38, 21% with piperacillintazobactam versus 4/34, 12% with meropenem). A large number of observational studies compared carbapenem therapy with old BLBLI for the therapy of 3GCephRE BSI (20 studies, Table 3)[22e41]. Empirical and targeted therapies were assessed in about half of the studies each, and all reported on mortality, M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547526 Table 3 Studies evaluating the treatment of third-generation cephalosporin-resistant Enterobacterales infections Author year Design Infection/s included Pathogen % ICU % UTI % BSI Treatment phase Group 1 Group 2 Outcome measured Statistic used Effect estimate CI low CI high Risk of bias Zanetti 2003 [88] Subgroup analysis of RCT HAP Any GNB 100 0 Any Cefepime, n¼13 Imipenem, n¼10 Clinical cure Crude 9/13 vs. 10/10 H Endimiani 2004 [66] Cohort retrospective BSI Klebsiella 62 100 Targeted FQ, n¼7 Carbapenem, n¼10 Clinical cure Crude unadjusted 2/7 vs. 8/10, p 0.03 H Paterson 2004 [254] Cohort prospective BSI Klebsiella 39.4 14.1 100 Targeted Carbapenem, n¼42 Other than carbapenem, n¼29 Mortality OR adjusted 0.28 0.08 1 H Goethaert 2006 [91] Cohort retrospective Any, mainly pneumonia Enterobacter 100 5 15.9 Targeted Cefepime, n¼21 Imipenem or meropenem, n¼23 Mortality Crude unadjusted 11/21 vs. 8/23, NS H Goethaert 2006 [91] Cohort retrospective Any, mainly pneumonia Enterobacter 100 5 15.9 Targeted Cefepime, n¼21 Imipenem or meropenem, n¼23 Clinical improvement Crude unadjusted 13/21 vs. 16/23, p 0.59 H Goethaert 2006 [91] Cohort retrospective Any, mainly pneumonia Enterobacter 100 5 15.9 Targeted Cefepime, n¼21 Imipenem or meropenem, n¼23 Microbiological cure Crude unadjusted 5/21 vs. 2/23, p 0.76 H Huang 2006 [45] Cohort retrospective BSI Enterobacterales 33.3 20.4 100 Targeted Non-carbapenems, n¼32 Imipenem or meropenem, n¼22 Mortality Crude unadjusted 9/32 vs. 2/22, p 0.09 H Lee 2006 [55] Cohort retrospective BSI Klebsiella 48.1 11.1 100 Targeted Flomoxef, n¼7 Imipenem or meropenem, n¼20 Mortality Crude unadjusted 2/7 vs. 5/20, p 0.86 H Chaubey 2010 [42] Cohort retrospective BSI E. coli and Klebsiella 48 100 Any BLBLI, n¼28 Other than BLBLI, n¼51 Mortality RR unadjusted 1.09 0.44 2.69 H Chaubey 2010 [42] Cohort retrospective BSI E. coli and Klebsiella 48 100 Any Carbapenem, n¼30 Other than carbapenem, n¼49 Mortality RR unadjusted 0.54 0.19 1.53 H Chaubey 2010 [42] Cohort retrospective BSI E. coli and Klebsiella 48 100 Any FQ, n¼4 Other than FQ, n¼75 Mortality RR unadjusted 1.25 0.22 7.24 H Chaubey 2010 [42] Cohort retrospective BSI E. coli and Klebsiella 48 100 Any Aminoglycosides, n¼10 Other than aminoglycosides, n¼69 Mortality RR unadjusted 0.46 0.07 3.11 H Chaubey 2010 [42] Cohort retrospective BSI E. coli and Klebsiella 48 100 Any Sulfamethoxazole, n¼3 Other than sulfametoxazole, n¼76 Mortality RR unadjusted 1.69 0.32 8.91 H Freire 2010 [87] Subgroup analysis of RCT HAP/VAP E. coli and Klebsiella 0 15.4 Any Tigecycline, n¼21 Imipenem, n¼20 Clinical cure Crude 14/21 vs. 19/20, NS M Lee 2010 [30] Cohort retrospective BSI Enterobacter 64.4 7.4 100 Targeted Non carbapenems, n¼61 Carbapenem, n¼53 Infectionrelated mortality Adjusted Reported as NS, p 0.15 H Lee 2011 [53] Cohort retrospective BSI E. coli and Klebsiella 100 Any Ertapenem, n¼73 Imipenemmeropenem, n¼171 Mortality Crude unadjusted 12/73 vs. 30/171, p 1.0 H Chopra 2012 [43] Cohort retrospective BSI Enterobacterales 25.5 100 Targeted Cefepime, n¼31 Other than cefepime, n¼79 Mortality OR adjusted 0.8 0.34 2.29 M Chopra 2012 [43] Cohort retrospective BSI Enterobacterales 25.5 100 Targeted Carbapenem, n¼78 Other than carbapenem, n¼32 Mortality OR adjusted 0.5 0.25 1.21 M Collins 2012 [50] Cohort retrospective BSI Enterobacterales 41.4 100 Empirical Ertapenem, n¼24 Imipenem or meropenem, n¼103 Mortality OR adjusted 0.82 0.17 3.81 M Collins 2012 [50] Cohort retrospective BSI Enterobacterales 41.4 100 Targeted Ertapenem, n¼72 Imipenem OR meropenem, n¼132 Mortality OR adjusted 0.5 0.12 2.1 M Rodríguez-Ba~ no 2012 [31] Cohort prospective BSI E. coli 12.6 41.9 100 Empirical BLBLI, n¼72 Carbapenem, n¼31 Mortality HR adjusted 0.93 0.25 3.51 M Rodríguez-Ba~ no 2012 [31] Cohort prospective BSI E. coli 8.7 41.9 100 Targeted BLBLI, n¼54 Carbapenem, n¼120 Mortality HR adjusted 0.76 0.28 2.07 M Vazquez 2012 [83] Subgroup analysis of RCT UTI Enterobacterales 100 7.3 Targeted Ceftazidime-avibactam, n¼7 Imipenem, n¼11 Microbiological cure Crude 6/7 vs. 9/11, NS L Wu 2012 [51] Cohort prospective BSI E. coli 16.3 38.8 100 Targeted Ertapenem, n¼27 Imipenemmeropenem, n¼22 Mortality HR adjusted 0.02 0.001 1.1 H Yang 2012 [56] Cohort retrospective BSI Klebsiella 50.9 0 100 Targeted Flomoxef, n¼19 Carbapenem, n¼23 Mortality OR adjusted 3.52 1.19 58.17 H (continued on next page) M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 527 Table 3 (continued ) Author year Design Infection/s included Pathogen % ICU % UTI % BSI Treatment phase Group 1 Group 2 Outcome measured Statistic used Effect estimate CI low CI high Risk of bias Doi 2013 [76] Cohort retrospective UTI Enterobacterales 100 36.3 Targeted Cefmetazole, n¼10 Carbapenem, n¼12 Clinical cure Crude unadjusted 9/10 vs. 12/12, p 0.46 H Kang 2013 [70] Cohort retrospective BSI E. coli 39.1 100 Targeted Aminoglycoside, n¼5 Carbapenem, n¼61 Mortality Crude unadjusted 0/5 vs. 6/61 H Lee 2013 [81] Cohort retrospective BSI Enterobacterales 78 100 Targeted Cefepime, n¼17 Carbapenem, n¼161 Mortality OR adjusted 9.93 2.77 31.91 M Lee 2013 [81] Cohort retrospective UTI Enterobacterales 100 4 Any Non-carbapenems, n¼23 Carbapenem, n¼4 Clinical cure Crude unadjusted 23/23 vs. 4/4 H Lee 2013 [81] Cohort retrospective UTI Enterobacterales 100 4 Any Non-carbapenems, n¼23 Carbapenem, n¼4 Relapse Crude unadjusted 1/23 vs. 0/4 H Tamma 2013 [61] Cohort retrospective Any Enterobacterales 57.8 48.7 Targeted Cefepime, n¼46 Meropenem, n¼32 Mortality OR adjusted 0.63 0.23 2.11 H To 2013 [46] Cohort retrospective BSI E. coli 3.9 43.6 100 Targeted Non-carbapenem, n¼52 Carbapenem, n¼91 Mortality Crude unadjusted 6/52 vs. 10/91, p 1.0 H To 2013 [46] Cohort retrospective BSI E. coli 3.9 43.6 100 Targeted Non-BLBLI, n¼122 BLBLI, n¼21 Crude unadjusted 13/122 vs. 3/21, p 0.626 H Blanchette 2014 [62] Case-control, matched Any Enterobacterales 18.7 31.2 20.8 Targeted Cefepime, n¼32 Ertapenem, n¼16 Clinical cure Matched 88% vs. 69%, p 0.138 H Falcone 2014 [44] Cohort retrospective BSI Enterobacterales 37.2 12.8 100 Targeted Non-carbapenem Carbapenem Mortality Crude unadjusted 54.3% vs. 28.5%, p 0.02 H Falcone 2014 [44] Cohort retrospective BSI Enterobacterales 37.2 12.8 100 Empirical Non-carbapenem, n¼52 Carbapenem, n¼42 Mortality Crude unadjusted 15/52 vs. 20/42, p 0.08 H Park 2014 [82] Cohort retrospective UTI E. coli 13.8 100 34.2 Targeted Non-carbapenem containing regimen, n¼67 Carbapenems, n¼85 Microbiological failure HR adjusted 0.99 0.31 3.19 M Park 2014 [82] Cohort retrospective UTI E. coli 13.8 100 34.2 Targeted Non-carbapenem containing regimen, n¼67 Carbapenems, n¼85 Clinical failure HR adjusted 1.05 0.24 4.62 M Pilmis 2014 [77] Cohort retrospective Any Enterobacterales 75.5 24.5 Targeted Non-carbapenem, n¼22 Carbapenem, n¼31 Clinical cure Crude unadjusted 22/22 vs. 30/31, NS H Pilmis 2014 [77] Cohort retrospective Any Enterobacterales 75.5 24.5 Targeted Non-carbapenem, n¼22 Carbapenem, n¼31 Relapse Crude unadjusted 3/22 vs. 7/31, NS H Siedner 2014 [64] Cohort retrospective BSI Enterobacter 24 7 100 Empirical Cefepime, n¼28 Carbapenem, n¼32 Microbiological cure Crude unadjusted 5/28 vs. 6/32 H Tsai 2014 [26] Cohort retrospective BSI Proteus 51.1 100 Not specified Piperacillin-tazobactam, n¼13 Carbapenem, n¼21 Mortality OR adjusted 4.38 0.35 54.9 H Harris 2015 [23] Cohort retrospective BSI E. coli and Klebsiella 14.9 46.8 100 Targeted BLBLI, n¼24 Carbapenem, n¼23 Mortality HR adjusted 0.91 0.13 6.28 H Lee 2015 [63] Cohort retrospective BSI Enterobacter 21.9 100 Targeted Cefepime, n¼72 Carbapenem, n¼72 Mortality Crude unadjusted 19/72 vs. 16/72, p 0.7 H Lee 2015 [57] Cohort retrospective BSI E. coli and Klebsiella 22.6 100 Targeted Flomoxef, n¼132 Carbapenem, n¼257 Mortality OR adjusted 1.4 0.5 4.2 M Matsumura 2015 [58] Cohort retrospective BSI E. coli 52.8 100 Empirical Cefmetazole or flomoxef, n¼26 Carbapenem, n¼45 Mortality HR adjusted 0.87 0.11 6.52 H Matsumura 2015 [58] Cohort retrospective BSI E. coli 52.8 100 Targeted Cefmetazole or flomoxef, n¼59 Carbapenem, n¼54 Mortality HR adjusted 1.04 0.24 4.49 H Ofer-Friedman 2015 [41] Cohort retrospective BSI Enterobacterales 0 100 Targeted Piperacillin-tazobactam, n¼10 Carbapenem, n¼69 Mortality OR adjusted 7.9 1.2 53 H Solomkin 2015 [255] Subgroup analysis of RCT IAI Enterobacterales 0 2.5 Targeted Ceftolozane-tazobactam þmetronidazole, n¼24 Meropenem, n¼26 Clinical cure Crude 23/24 (95.8%) vs. 23/26 (88.5%), NS L Tamma 2015 [25] Cohort retrospective BSI Enterobacterales 13.8 20.6 100 Empirical Piperacillin-tazobactam, n¼103 Carbapenem, n¼110 Mortality OR adjusted 1.92 1.07 3.45 M Wagenlehner 2015 [86] Subgroup analysis of RCT UTI Enterobacterales 100 7.7 Any Ceftolozane-tazobactam, n¼61 Levofloxacin, n¼57 Clinical cure Crude absolute difference 55/61 (90.2%) vs. 42/57 (73.7%), difference 16.5% (95% CI 2.6e30.2) H Carmeli 2016 [84] Subgroup analysis of RCT UTI Enterobacterales 100 3.5 Targeted Ceftazidime-avibactam, n¼130 Best available treatment, n¼132 Microbiological cure Crude 107/130 (82.3%) vs. 85/ 132 (64.4%), p 0.002 L Carmeli 2016 [84] Subgroup analysis of RCT UTI Enterobacterales 100 3.5 Targeted Ceftazidime-avibactam, n¼130 Best available treatment, n¼132 Clinical cure Crude 120/130 (92.3%) vs. 124/ 132 (93.9%), NS L Carmeli 2016 [84] Subgroup analysis of RCT IAI Enterobacterales 0 0 Targeted Ceftazidime-avibactam (þmetronidazole), n¼9 Best available treatment, n¼10 Microbiological cure Crude 7/9 vs. 5/10, NS M Dizbay 2016 [28] Cohort retrospective UTI E. coli and Klebsiella 100 Targeted Piperacillin-tazobactam, n¼60 Ertapenem, n¼170 Microbiological cure Crude unadjusted 60/60 vs. 170/170, NS H Fukuchi 2016 [59] Cohort retrospective BSI Enterobacterales 31.8 50.7 100 Targeted Cefmetazole, n¼26 Carbapenem, n¼43 Mortality Crude unadjusted 1/26 vs. 5/43 H M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547528 Guti errez-Guti errez 2016 [22] Cohort retrospective BSI Enterobacterales 10.7 46 100 Empirical BLBLI, n¼170 Carbapenem, n¼195 Mortality OR adjusted 0.55 0.25 1.18 M Guti errez-Guti errez 2016 [22] Cohort retrospective BSI Enterobacterales 10.7 46 100 Empirical BLBLI, n¼170 Carbapenem, n¼195 Clinical cure OR adjusted 1.37 0.69 2.76 M Guti errez-Guti errez 2016 [22] Cohort retrospective BSI Enterobacterales 11 45 100 Targeted BLBLI, n¼92 Carbapenem, n¼509 Mortality OR adjusted 0.59 0.19 1.71 M Guti errez-Guti errez 2016 Cohort retrospective BSI Enterobacterales 11 45 100 Targeted BLBLI, n¼92 Carbapenem, n¼509 Clinical cure OR adjusted 1.61 0.58 4.86 M Guti errez-Guti errez 2016b [52] Cohort retrospective BSI Enterobacterales 13.8 47.2 100 Empirical Ertapenem, n¼32 Meropenemimipenem, n¼163 Clinical cure OR adjusted 1.87 0.24 20.08 M Guti errez-Guti errez 2016b [52] Cohort retrospective BSI Enterobacterales 12.6 45.8 100 Targeted Ertapenem, n¼205 Meropenemimipenem, n¼304 Mortality OR adjusted 0.93 0.43 2.03 M Guti errez-Guti errez 2016b [52] Cohort retrospective BSI Enterobacterales 12.6 45.8 100 Targeted Ertapenem, n¼205 Meropenemimipenem, n¼304 Clinical cure OR adjusted 1.04 0.44 2.5 M Mazuski 2016 [93] Subgroup analysis of RCT IAI Enterobacterales 0 Targeted Ceftazidime-avibactam þmetronidazole, n¼44 Meropenem, n¼62 Clinical cure Crude absolute difference e3.7 e19.31 10.44 L Ng 2016 [24] Cohort retrospective BSI E. coli and Klebsiella 8.6 59 100 Empirical Piperacillin-tazobactam, n¼94 Carbapenem, n¼57 Mortality OR adjusted 0.99 0.45 2.17 M Veve 2016 [73] Cohort retrospective UTI Enterobacterales 12.9 100 13.5 Targeted Fosfomycin oral, n¼89 Ertapenem, n¼89 Failure OR adjusted 0.59 0.19 1.8 H Wagenlehner 2016 [85] Subgroup analysis of RCT UTI Enterobacterales 100 Targeted Ceftazidime-avibactam, n¼68 Doripenem, n¼79 Microbiological cure Absolute difference 5 10.87 20.5 L Wang 2016 [65] Retrospective, propensitymatched BSI Enterobacterales 29.4 30.8 100 Empirical Cefepime, n¼17 Carbapenem, n¼51 Mortality HR PS-matched and adjusted 2.87 0.88 9.41 M Cheng 2017 [27] Cohort retrospective BSI Enterobacterales 40 18.8 100 Targeted Piperacillin-tazobactam, n¼88 Meropenemcefepime, n¼77 Mortality OR adjusted 0.5 0.13 2 H Cheng 2017 [27] Cohort retrospective BSI Enterobacterales 40 18.8 100 Targeted Piperacillin-tazobactam, n¼41 Meropenemcefepime, n¼41 Microbiological failure Propensitymatched 8/41 (20%) vs. 4/41 (10%), p 0.26 H Gudiol 2017 [29] Retrospective, propensitymatched BSI Enterobacterales 18.3 6.9 100 Empirical BLBLI, n¼35 Carbapenem, n¼35 Mortality PS-matched 7/35 vs. 4/35, p 0.99 H Gudiol 2017 [29] Retrospective, propensitymatched BSI Enterobacterales 18.3 6.9 100 Targeted BLBLI, n¼15 Carbapenem, n¼15 Mortality PS-matched 2/15 vs. 1/15, p 0.32 H Lo 2017 [67] Cohort retrospective BSI E. coli and K. pneumoniae 24.7 100 Targeted Fluoroquinolone, n¼24 Carbapenem, n¼275 Mortality OR adjusted 0.18 0.03 0.92 M Palacios-Baena 2017 [48] Cohort retrospective BSI Enterobacterales 16 40 100 Empirical Non-carbapenem, mostly aminoglycosides, n¼86 Carbapenem, n¼249 Mortality OR adjusted 0.75 0.38 1.48 M Palacios-Baena 2017 [48] Cohort retrospective BSI Enterobacterales 16 40 100 Empirical Non-carbapenem, mostly aminoglycosides, n¼86 Carbapenem, n¼249 Clinical failure OR adjusted 0.62 0.29 1.36 M Rattanaumpawan 2017 [54] RCT Any Enterobacterales 4.6 40.9 50 Targeted Ertapenem, n¼32 Group 2 carbapenems, n¼34 Mortality Absolute difference e20 e39.3 e0.08 M Rattanaumpawan 2017 [54] RCT Any Enterobacterales 4.6 40.9 50 Targeted Ertapenem, n¼32 Group 2 carbapenems, n¼34 Clinical cure Absolute difference 14 e2.4 31.1 M Rattanaumpawan 2017 [54] RCT Any Enterobacterales 4.6 40.9 50 Targeted Ertapenem, n¼32 Group 2 carbapenems, n¼34 Microbiological cure Absolute difference 4.1 e5 13.4 M Seo 2017 [32] RCT UTI E. coli 100 22.2 Targeted Piperacillin-tazobactam, n¼33 Ertapenem, n¼33 Mortality Crude 2/33 vs. 2/33 H Seo 2017 [32] RCT UTI E. coli 100 22.2 Targeted Piperacillin-tazobactam, n¼33 Ertapenem, n¼33 Clinical cure Crude 31/33 vs. 32/33, NS H Seo 2017 [32] RCT UTI E. coli 100 22.2 Targeted Piperacillin-tazobactam, n¼33 Ertapenem, n¼33 Microbiological cure Crude 32/33 vs. 32/33 H Solomkin 2017 [95] Subgroup analysis of RCT IAI Enterobacterales 0 Any Eravacycline, n¼21 Ertapenem, n¼18 Clinical cure Crude 19/21 (90.5%) vs. 15/18 (83.3%), NS L Torres 2017 [89] Subgroup analysis of RCT HAP/VAP Enterobacterales 0 Targeted Ceftazidime-avibactam, n¼34 Meropenem, n¼41 Clinical cure Crude 32/34 (94.1%) vs. 33/41 (80.5%), NS L Yoon 2017 [33] Cohort retrospective UTI E. coli 24.7 100 15.3 Targeted Piperacillin-tazobactam, n¼68 Ertapenem, n¼82 Failure OR adjusted 0.83 0.35 1.97 M (continued on next page) M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 529 pneumoniae in Italy, treatment including two or more in vitro active antibiotics was associated with lower 14-day mortality (OR 0.52, 95% CI 0.35e0.77) [164]. In the retrospective INCREMENT cohort such combination therapy was associated with lower 30-day mortality among patients with CRE BSI at high risk for death, with an INCREMENT score of 8e15 (n¼166; adjusted HR 0.56, 95% CI 0.34e0.91). Among patients with lower INCREMENT scores (n¼177), combination therapy was not associated with survival (adjusted OR 1.21) 95% CI 0.56e2.56) [152]. Use of two or more in vitro active antibiotics (including colistin, tigecycline, gentamicin, carbapenems, rifampin) was independently associated with 30-day survival in retrospective study including 111 critically ill patients with KPC-producing K. pneumoniae infections and septic shock [123]. Lower efficacy of a single drug regimen with these drugs has been attributed to the often suboptimal dosage and the unsuitable pharmacokineticsepharmacodynamics profile for some infection sites [174e176]. Unfortunately, none of these studies focused on specific antibiotic combinations, so information on which antimicrobials should be included in the treatment scheme cannot be derived even from higher-certainty evidence. When looking at smaller studies analysing specific drugs, polymyxin and tigecycline seemed the antimicrobials for which the addition of a companion drug seems more advisable [143,146,147,151e153,155e157,160,161,164,167,177,178]. Due to the high heterogeneity of treatment included, even in smaller studies, no firm conclusions can be drawn on which companion drug should be preferred when prescribing polymyxin and tigecycline, but treatment with more than one in vitro active antibiotic might be beneficial (moderate-certainty evidence). Carbapenem combination therapy. The inclusion of a carbapenem in the combination scheme for treating carbapenem-resistant infections has been a long-standing matter of debate. Two investigator-initiated RCT, the AIDA and OVERCOME trials, evaluated the efficacy of colistin monotherapy versus colistin-meropenem combination therapy in patients with severe infections caused by CRGNB, mainly HAP/VAP and BSI [160,179]. Subgroup analysis of patients with CRE infections did not show statistically significant differences in 28-day mortality between colistin monotherapy and colistin-carbapenem combination therapy in both trials: 12/34 (35%) versus 8/39 (21%) (p 0.24) in AIDA [160] and 11/35 (31%) versus 7/36 (19%) (p 0.25) in OVERCOME [179], respectively. In the retrospective Italian cohort study of patients' BSI and nonbacteraemic infections due to KPC-producing K. pneumoniae, combination therapy including a carbapenem was associated with lower 14-day mortality when the meropenem MIC were 8 mg/L [164]. A continuation and re-analysis of the same cohort showed a similar association between high-dose carbapenem-containing combinations (6 g/day, 3 hours infusion) and 14-day survival compared with non-carbapenem containing combinations, even when the MICs were higher (16 mg/L) [180]. We concluded low-certainty evidence for an advantage of highdose extended-infusion meropenem-polymyxin combination therapy over polymyxin monotherapy in the treatment of severe infections caused by CRE, mainly KPC-producing K. pneumoniae. Double-carbapenem combination therapy. The rationale for using double-carbapenem therapy for treating CRE infections is based on the higher affinity of ertapenem for carbapenemases and a hypothesis that consumption of the carbapnemases by ertapenem will allow for the action of the other carbapenem. In vitro data for synergistic interactions are conflicting [181,182]. Two observational studies from Italy and one from the USA suggested better survival in patients with invasive KPC infections treated with a double carbapenem regimen when compared with other regimens, even with high carbapenem MICs [183e185]. Lack of adjustment for confounders, small sample size and use of other drugs in the combinations made the authors of these studies conclude that, although promising, this option requires further evaluation (Insufficient evidence). New antibiotic combination therapies. Five retrospective cohorts enrolled a total of 824 patients from three countries (USA, Spain and Italy) and compared ceftazidime-avibactam in combination with other antibiotics versus ceftazidime-avibactam monotherapy, showing no difference in mortality and clinical failure in mixed infections caused by KPC and OXA-48 producers [99,154,186e188]. The largest study included 577 patients with KPC-producing K. pneumoniae infections, mostly BSI, in Italy and showed also that prolonged infusion (3 hours) of ceftazidime-avibactam and appropriate renal adjustment were associated with 30-day survival [188], supporting our good practice statement for optimal antibiotic administration schedules. Ceftazidime-avibactam in combination with aztreonam is active in vitro against a substantial proportion of MBL producers, for which treatment options are lacking [189,190]. Following a small case series reporting on patients with MBL-producing CRE treated with ceftazidime-avibactam-aztreonam [191], an observational prospective study was conducted including 102 patients with MBL- producing CRE bacteraemia (82 NDM-producing strains and 20 VIM-producing strains) treated with ceftazidime-avibactam in combination with aztreonam compared with other in vitro covering therapies, mostly combinations [192]. The isolates were mostly non-susceptible to aztreonam alone. Using propensity-score- adjusted multivariable regression, the study showed a significant independent association between ceftazidime-avibactam-aztreo- nam and lower 30-day mortality (HR 0.37, 95% CI 0.13e0.74), clinical failure and length of hospital stay, providing moderatecertainty evidence for ceftazidime-avibactam in combination with aztreonam against BSI caused by MBL-producing CRE susceptible to the combination. There are currently no standardized antimicrobial susceptibility testing methods recommended or clinical interpretative breakpoints approved for the combination. In the CREDIBLE RCT [121], an observational post-hoc comparison between patients receiving cefiderocol monotherapy versus cefiderocol combination therapy, clinical and microbiological cure rates were similar, but results were not presented separately for CRE and mortality data were not available. There are no studies addressing the clinical use in monotherapy versus combination of recently marketed antibiotics with activity against CRE (imipenem-relebactam, meropenem-vaborbactam, eravacycline and plazomicin). Despite numerous results of in vitro studies showing reduction in resistance development when polymyxin [7] and ceftazidimeavibactam [193] are combined with other antibiotics, these results are not confirmed in clinical studies. In two retrospective cohort studies of 77 and 577 patients with KPC-producing CRE infections treated with ceftazidime-avibactam, development of resistance to ceftazidime-avibactam occurred in 10.4% and 3.8%, respectively, and was not associated with its use as monotherapy or in combination regimens [186]. 3. Carbapenem-resistant Pseudomonas aeruginosa Question 3.1: What is the antibiotic of choice for CRPA Recommendations In patients with severe infections due to DTR-CRPA, we suggest therapy with ceftolozane-tazobactam if active in vitro (conditional recommendation for use, very low certainty of M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547536 evidence). Insufficient evidence is available for imipenem-rel- ebactam, cefiderocol and ceftazidime-avibactam at this time. In patients with non-severe or low-risk CRPA infections, under the consideration of antibiotic stewardship, we consider it good clinical practice to use the old antibiotics, chosen from among the in vitro active antibiotics on an individual basis and according to the source of infection (good practice statement). Review of the evidence The clinical evidence on management of DTR-CRPA is highly limited. Data from RCT for the new BLBLI are limited to small subgroup analyses of the registration trials, some of which are based on single patients There are no comparative RCT data on the effect of ceftolozane-tazobactam on CRPA infections, although this is the intended use of the drug. Overall, there is no high-certainty evidence pointing to a preferred antibiotic treatment for CRPA. New BLBLI. Of the potentially active new BLBLI, only imipenemrelebactam has been tested against CR-GNB in an RCT, in the RESTORE-IMI 1 trial. The trial included patients with HAP, VAP, UTI and IAI caused by CR-GNB, of which CRPA was the most common (16/21 patients allocated to imipenem-relebactam and 8/10 allocated to colistin with imipenem). A favourable overall response to treatment at 28 days, with a definition tailored per infection source, was observed in 13/16 with imipenem-relebactam compared with 5/8 with colistin and imipenem, adjusted difference 3.1 (95% CI e19.8 to 38.2) [118]. Of the RCT evaluating ceftolozane-tazobactam, the trial including patients with nosocomial pneumonia (ASPECT-NP) reported clinical cure among 4/10 versus 2/5 patients with XDR-PA treated with ceftolozane-tazobactam versus meropenem, respectively [90]. Data on CRPA, however, are not available. Treatment with ceftolozane-tazobactam (100 patients) was compared with polymyxins or aminoglycosides (100 patients), among patients with MDR/XDR P. aeruginosa mixed infections (mostly pneumonia) in a retrospective cohort study [194]. Clinical cure was higher (adjusted OR 2.63, 95% CI 1.31e5.30) and nephrotoxicity was lower (adjusted OR 0.08, 95% CI 0.03e0.22) with ceftolozane-tazobactam. Aminoglycoside/polymyxins were given mostly in combination therapies, patient selection was unclear, baseline difference between groups could not be fully adjusted and data on carbapenem resistance was not provided (high risk of bias). Overall, given the paucity of data on effects against CRPA, we conclude on very-low-certainty evidence for non-inferiority of imipenem-relebactam compared with colistin-meropenem combination therapy and superiority of ceftolozane-tazobactam compared with aminoglycoside/polymyxin combination therapies for CRPA infections with no evidence for other new BLBLI. Other antibiotics. In the CREDIBLE RCT, mortality at the end of the study was similar for patients with baseline monomicrobial CRPA infections for cefiderocol (2/11 patients) compared with BAT (2/11 patients). Clinical cure (7/12 versus 5/10 patients, respectively) and microbiological persistence (4/12 versus 2/10 patients, respectively) were not different, in very small numbers (very-low-cer- tainty evidence for non-inferiority of cefidrocol compared with BAT). A small, retrospective cohort of 49 patients with nosocomial pneumonia, mostly VAP, caused by CRPA intermediately susceptible to doripenem (MIC 4e8 mg/L), in Thailand compared high-dose, 4-hour infusion of doripenem versus colistin, both combined with fosfomycin. Unadjusted all-cause 30-day mortality was not different; 10/24 versus 10/25, respectively, as were clinical and microbiological cure rates [195]. No clinical comparative studies were found for intravenous fosfomycin or eravacycline. A beforeeafter retrospective study compared the nephrotoxicity of colistin and polymyxin B among critically ill patients with severe, at-risk infections, caused by MDR P. aeruginosa (46 patients) and A. baumannii (107 patients), showing higher RIFLE-defined nephrotoxicity with colistin (adjusted HR 2.27, 95% CI 1.35e3.82) [196]. Question 3.2: Should combination therapy be used for the treatment of CRPA? Recommendations Lacking evidence, we cannot recommend for or against the use of combination therapy with the new BLBLI (ceftazidime-avi- bactam and ceftolozane-tazobactam) or cefiderocol for CRPA infections. When treating severe infections caused by CRPA with polymyxins, aminoglycosides, or fosfomycin, we suggest treatment with two in vitro active drugs (conditional recommendation for use, very low certainty of evidence). No recommendation for or against specific combinations can be provided. In patients with non-severe infections or low-risk CRPA infections, under the consideration of antibiotic stewardship, we consider it good clinical practice to use monotherapy chosen from among the drugs active in vitro, on an individual basis and according to the source of infection (good practice statement). Review of the evidence Similar to the choice of monotherapy, there is a paucity of data on combination therapy for DTR-CRPA. Polymyxin-based combination therapy. Both in the AIDA and OVERCOME RCT comparing colistin with colistin-carbapenem therapy for severe infections caused by CR-GNB there were no significant differences in 28-day mortality in the subgroup of patients with P. aeruginosa infections (21 patients in AIDA and 43 in OVERCOME) [160,179]. In a retrospective study evaluating 114 patients with nosocomial pneumonia, including ventilator-associated pneumonia, with isolation of XDR-P. aeruginosa, colistin given alone or with a non-active antibiotic was associated with higher mortality than colistin combined with another active antibiotic (adjusted OR 6.63, 95% CI 1.99e22.05) [197]. From other observational studies, the results for the subgroup of patients with CRPA were non-adjusted. In a retrospective study evaluating critically ill patients with mixed infections caused by P. aeruginosa there was no difference in 30-day mortality among patients treated with polymyxin compared with polymyxin and a second in vitro inactive agent, overall; in a small subgroup of patients with XDR-P. aeruginosa, mortality was lower when combinations were used (14/15 dead with monotherapy versus 0/3 with combinations) [198]. In another retrospective analysis, Falagas et al. assessed clinical cure rates comparing colistin monotherapy with different combinations for mixed infections due to MDR-GN. There was no significant difference in outcomes in a small subgroup of patients with MDR-P. aeruginosa (9/12 were cured with colistin monotherapy compared with 42/56 with combinations) [199]. There was very low-certainty evidence for an advantage of polymyxin combined with another active antibiotic over polymyxin alone or combined with inactive antibiotics. There was low-certainty evidence on the lack of advantage of carbapenem-polymyxin combination therapy compared with polymyxin monotherapy for CRPA. Other combination therapy. A cohort study summarized retrospectively outcomes for patients treated with ceftolozane-tazobactam for MDR- or XDR-P. aeruginosa infections. There was no difference M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 537 in cure, defined as clinical and microbiological cure at day 7, between patients given ceftolozane-tazobactam monotherapy (14/21, 66.7%) and those treated with ceftolozane-tazobactam in combination with colistin or an aminoglycoside (21/35, 60%), without adjustment [200]. The study found no significant difference in development of resistance to ceftolozane-tazobactam during therapy between monotherapy and combination therapy. Overall, there was no evidence for other combination therapy for CRPA. 4. Carbapenem-resistant Acinetobacter baumannii Question 4.1: What is the antibiotic of choice for CRAB? Recommendations For patients with CRAB susceptible to sulbactam and HAP/VAP, we suggest ampicillin-sulbactam (conditional recommendation, low certainty of evidence). For patients with CRAB resistant to sulbactam, a polymyxin or high-dose tigecycline can be used if active in vitro. Lacking evidence, we cannot recommend on the preferred antibiotic. We conditionally recommend against cefiderocol for the treatment of infections caused by CRAB (conditional recommendations against use, low certainty of evidence). Review of the evidence Antibiotics active in vitro against CRAB have been directly compared, mostly in retrospective observational studies. The studies generally addressed all species within the A. baumannii complex, not specifically A. baumannii (genospecies 2 of the Acinetobacter calcoaceticus-A. baumannii complex), because automated detection tests do not discriminate between the different genospecies included in the A. baumannii complex (A. calcoaceticus, A. baumannii, genospecies 3 and genospecies 13TU). The most common infection described with CRAB is pneumonia, frequently VAP. As colistin's concentrations in epithelial lining fluid after intravenous administration are negligible [201,202], we were interested in separate assessment of pneumonia and other sources of infection, but the data were insufficient to provide recommendations by source of infection. Of the antibiotics that have been considered to date, EUCAST does not provide breakpoints for sulbactam and tigecycline, for Acinetobacter. Polymyxin versus ampicillin-sulbactam. Several small studies compared polymyxins, mostly colistin, with ampicillin-sulbactam. A small RCT using alternation as the randomization method (not true randomization) included 28 patients in ICU with VAP caused by CRAB susceptible to ampicillin-sulbactam and did not find a difference between ampicillin-sulbactam and colistin in mortality, or clinical or microbiological failure [203]. Nephrotoxicity was more common with colistin without statistical significance. An RCT evaluating 47 ICU patients diagnosed with CRAB VAP compared colistin and sulbactam, both combined with meropenem, with similar results [204]. A retrospective study including 167 patients with different CRAB infections, mostly in ICU and mostly with primary BSI or pneumonia, compared colistin or polymyxin B with ampicillin-sulbactam, with additional antibiotics not active in vitro in both groups [205]. Mortality at end of treatment (but not inhospital mortality) was significantly higher in the polymyxin group (adjusted OR 2.07, 95% CI 1.03e4.16). A retrospective cohort study of 98 patients in ICU with CRAB VAP compared low-dose colistin (6 MIU/day) with ampicillin-sulbactam, showing significantly higher all-cause mortality with colistin, higher microbiological failure and no difference in clinical failure [206]. A small RCT, presented as an interim study, compared colistin with extended infusion ampicillin-sulbactam (6 g intravenous ampicillin-sulbactam 2:1 four times a day) both combined with high-dose levofloxacin for the treatment of A. baumannii VAP in an ICU where all A. baumannii are carbapenem-resistant [207]. The study showed a large advantage to ampicillin-sulbactam in 14-day and 28-day mortality, clinical response and renal failure (28-day mortality 9/11 with colistin versus 5/12 with ampicillin-sulbactam). None of the studies addressed the comparative rates of resistance development during therapy. Most studies considered isolates with MIC 8/4 mg/L as susceptible to sulbactam. Dosing of ampicillin-sulbactam was quite heterogeneous across studies, ranging from 3 to 16 g/8 h (for ampicillin-sulbactam 2:1). The data support an advantage to ampicillin-sulbactam over polymyxins for CRAB, but the evidence is of low certainty. Polymyxin versus tigecycline. Colistin has been compared with tigecycline in four retrospective observational studies. Most included patients in ICU, mainly with pneumonia, and colistin and tigecycline were commonly combined with other antibiotics [132,208e210]. All studies, except one [132], demonstrated higher mortality and lower clinical response with tigecycline monotherapy, although without statistical significance. In one study, microbiological success was significantly better with colistin [210]. In three studies, nephrotoxicity was more frequent with colistin [208e210]. Low doses of tigecycline were commonly used (50 mg twice a day), while double dosing may be more appropriate [211]. From these data, no conclusion can be drawn (no evidence). Tigecycline versus sulbactam-based therapy. A comparison between tigecycline and sulbactam has been included in five retrospective cohort studies. A single-centre, hospital-wide, retrospective study in Taiwan included 386 patients and compared tigecycline-based therapy with sulbactam-based therapy for hospital-acquired infections caused by tigecycline and sulbactam-susceptible CRAB, respectively [212]. Sulbactam was combined with imipenem, and tigecycline was prescribed variably alone or with a carbapenem or another b -lactam. There was no significant difference in 30-day mortality or length of stay, but there was a significantly lower rate of clinical or microbiological failure in the tigecycline-based group. Another single-centre retrospective study in Taiwan included 84 patients with CRAB pneumonia that were matched to a historical cohort of 84 patients treated with sulbactam or ampicillin-sulbac- tam, mostly given in combination therapies [213]. Patients with BSI were excluded. There was no statistically significant difference between groups with respect to 30-day mortality or clinical failure, but there was a significant advantage to sulbactam-based therapy in microbiological cure. A multicentre study in Taiwan comparing retrospectively treatment strategies among critically ill patients hospitalized in ICU with CRAB pneumonia, included a comparison between sulbactam-based combination or monotherapy (12 patients) and tigecycline monotherapy (84 patients) [214]. ICU mortality (adjusted OR 0.12, 95% CI 0.01e1.02) and treatment failure (adjusted OR 0.14, 95% CI 0.04e0.55) were less frequent with sulbactam-based therapy. A single-centrer retrospective study in China included 210 patients with CRAB-BSI, mostly in ICU, comparing cefoperazone-sulbactam to tigecycline, both given mostly in combination with other antibiotics [215]. The study demonstrated significantly lower 28-day mortality with sulbactam-based treatment (adjusted HR 0.57, 95% CI 0.34e0.94), despite the fact that 80% of the isolates were resistant to sulbactam [215]. The last study, retrospectively evaluated 274 episodes of MDR-AB- BSI hospital-wide in one centre in China, showing unadjusted lower mortality with cefoperazone-sulbactam-containing regimens compared with tigecycline-based therapy, although non- M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547538 susceptibility rates to sulbactam were high [216]. An increased risk of death with tigecycline for HAP, VAP and bacteraemia has been reported, in general, not specifically for CR-GNB [92]. The data support low-certainty evidence for an advantage of sulbactambased therapy over tigecycline. Cefiderocol. Cefiderocol is a novel siderophore cephalosporin whose MIC 90 for A. baumannii is in the range of 1e8 mg. Cefiderocol was compared with BAT for CR-GNB infections in the previously described CREDIBLE RCT [121,217] Among patients with CRAB infections in the CREDIBLE trial, the 28-day mortality rates were 19/ 39 (49%) in the cefiderocol group (21/42, 50% with CR-Acinetobacter sp.) versus 3/17 (18%) in the BAT group. Overall, in the trial, there was no advantage to cefiderocol with respect to clinical or microbiological eradication. In the APEKS-NP RCT, similar mortality, clinical and microbiological outcomes were documented for cefiderocol versus high-dose extended-infusion meropenem, in the subgroup of 36 patients with pneumonia and A. baumannii species with meropenem MIC >8 m g/mL, evaluated before switching to in vitro covering therapy in the meropenem arm. Given the limited information available to date, we conclude on low-certainty evidence against cefiderocol treatment of CRAB infections. Eravacycline. Eravacycline is a novel synthetic tetracycline (fluorocycline) that has two-to eight-fold lower MICs than tigecycline against CRAB. It was evaluated in two RCT compared with ertapenem and meropenem for cIAI [95,141] Although potentially active in vitro, no data are available on its clinical efficacy against CRAB infections. Other antibiotics. Small retrospective studies evaluated treatment with aminoglycosides [218,219] and tetracyclines other than tigecycline [218,220] for infections caused by MDR-GNB and CRAB. These studies are small and show inconclusive data (no evidence). Question 4.2: Should combination therapy be used for the treatment of CRAB? Recommendations For all patients with CRAB infections, we do not recommend polymyxin-meropenem combination therapy (strong recommendation against use; high certainty of evidence)orpolymyxin-rifampin combination therapy (strong recommendation against use, moderate certainty of evidence). For patients with severe and high-risk CRAB infections, we suggest combination therapy including two in vitro active antibiotics among the available antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) (conditional recommendation for use, very low certainty of evidence). For patients with CRAB infections with a meropenem MIC <8 mg/L, we consider carbapenem combination therapy, using high-dose extended-infusion carbapenem dosing, as good clinical practice (good practice statement). Review of the evidence Combination therapy for CRAB has been suggested based on in vitro studies showing synergistic interactions between polymyxins and meropenem, imipenem, doripenem [7], rifampicin [4,221], vancomycin [222] and many antibiotics [223] and non-antibiotics [224]. Synergistic combinations might be associated with better survival [225], but for clinical adoption specific combination therapies need to be assessed in clinical studies. Most of the data on CRAB rely on low-certainty observational studies, assessing a large number of antibiotic regimens, many times grouped to ‘combination therapy’that does not allow the appraisal of specific antibiotics regimens with biological plausibility of a beneficial interaction. We identified 29 studies comparing monotherapy with combination therapy [160,198,199,209,214,215,226e248]; six of which were RCT [160,228,236,238,240,245]. Colistin-carbapenem combination therapy. The combination of colistin with meropenem was assessed in the previously described AIDA RCT, including 406 patients with CR-GNB overall and among them 312 with CRAB bacteraemia, VAP or hospital-acquired pneumonia [160]. There was no significant difference between colistin monotherapy and colistin-meropenem with respect to a primary composite outcome of clinical failure at day 14 or 14-day mortality overall in the randomized trial population (relative risk (RR) 0.93, 95% CI 0.83e1.03 for failure and RR 1.03, 95% CI 0.84e1.28 for mortality with colistin monotherapy) and among patients with CRAB (RR 0.97, 95% CI 0.87e1.09 and RR 1.11, 95% CI 0.82e1.52, respectively). A post-hoc analysis of this trial addressed the subgroup of patients with infections caused by CRAB resistant also to colistin by broth microdilution, showing no benefit to the combination over colistin among patients with colistin-resistant CRAB [237]. The OVERCOME trial was a double-blind RCT comparing colistin monotherapy with colistin-meropenem combination for HAP/VAP and BSI caused by CR-GNB that similarly included mostly patients with CRAB of infections [179]. Mortality at 28 days was similar for colistin monotherapy 76/165 (46%) and colistin-mer- openem 69/163 (42%) (p 0.5). Several observational studies, assessing the combination of polymyxins and carbapanems specifically, showed a significant association between use of the combination and survival or clinical cure [198,235,247] whereas others did not [199,244]. Many observational studies included patients treated with a polymyxin-car- bapenem combination in a larger group of patients treated with different combination therapies. These studies mostly showed an association between combination therapy and survival, compared with polymyxin monotherapy. However, from these studies the effects of a specific combination regimen cannot be assessed. The RCT, including a considerable sample of patients with severe, high-risk, infections caused by CRAB, contribute to high-cer- tainty evidence against carbapenem-polymyxin combination therapies for CRAB infections [160,179]. Acinetobacter baumannii when resistant to carbapenems is typically highly resistant, with MICs >16 mg/L. If isolates with lower MICs to a carbapenem are identified, or should these become prevalent, combination therapy with high-dose carbapenem may be considered, preferably administered through extended or continuous infusion. Colistin-rifampin combination therapy. The combination of colistin with rifampin has been assessed in three RCT [238,240,245]. In the only powered RCT, including 209 patients with CRAB infections, mostly pneumonia, there was no advantage to colistin-rifampin over colistin monotherapy with respect to 30-day mortality [238] Microbiological cure was higher with combination therapy, but surveillance for continued carriage of CRAB was not conducted. Another small trial included 43 patients in ICU with VAP caused by CRAB, showing no difference between colistin-rifampin and colistin monotherapy with respect to in-hospital mortality and microbiological failure [245]. The third RCT included only nine patients assessing death, and clinical and microbiological response, but the lack of differences between the groups are not informative in this small sample [240]. Rifampin was included in a few patients treated with combination therapy in an observational study comparing mixed combinations with polymyxin monotherapy [248], showing no significant survival advantage to the combination. Overall, there M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 539 was moderate certainty evidence against rifampin-colistin combination therapy for CRAB. Other combinations. Other combinations have been tested in single studies. Colistin-vancomycin has been assessed in a retrospective observational study among 57 patients in ICU mostly with CRAB pneumonia, compared with colistin monotherapy [239]. No difference in mortality or length of stay was observed, but there was a significantly higher rate of nephrotoxicity with the combination. In a retrospective study including critically ill patients in ICU treated with colistin-based regimens, colistin-glycopeptide combination therapy in 42 patients was not significantly different from colistin monotherapy administered to 61 patients with respect to 30-day mortality, ICU stay and hospital stay [241]. The study included a mix of MDR Gram-negative infections, most (59/103) with MDR A. baumannii. Colistin-fosfomycin was compared with colistin monotherapy in a small RCT including 94 patients with infections caused by CRAB, usually resistant to fosfomycin [228]. There was no significant difference between groups in 30-day mortality or adverse events, but combination resulted in lower microbiological failure. Other observational studies comparing monotherapy (usually colistin) with combination therapy (usually mixed) show conflicting results [198,199,209,214,215,226,227,229e235,243,244,246,247,249,250]; however, the bulk of the data seem to show no advantage to combination therapy (very-low-certainty evidence). Double covering therapy might be considered, provided that the CRAB is susceptible to more than one antibiotic. The combination of colistin and ampicillin-sulbactam versus colistin alone has been assessed in a small RCT including 49 patients in ICU with VAP caused by CRAB susceptible to ampicillin-sulbactam [236]. There was an advantage to combination therapy with respect to clinical failure, but no difference in 28-day mortality. A systematic review of observational studies showed an association between colistin monotherapy and mortality when compared with potentially double-covering antibiotic combinations (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) [172]. Very-low-certainty evidence exists for double covering combination therapy for CRAB. General practice recommendations and antibiotic stewardship considerations Optimal antibiotic dosing schemes should be used, with attention to adverse effects, especially with the old antibioticsdpolymyxins and aminoglycosides (good practice statement). Dosing and mode of administration should be optimized by pathogen and indication, with use of therapeutic drug monitoring whenever available (good practice statement). We recommend referring to EUCAST's recommended dosing (https://www.eucast.org/clinical_breakpoints/). Source control should always be a priority, to optimize outcomes and shorten antibiotic treatment durations. The guidelines do not address allergies to the recommended antibiotics that should be considered before antibiotic prescription. Nebulized antibiotics were not considered in the current guideline but were addressed by an ESCMID position statement [251]. Testing against the new BLBLI and polymyxins is recommended for CR-GNB that are resistant to all b - lactams. Follow-up cultures are recommended in case of treatment failure, especially for CR-GNB, to detect resistance development (good practice statement). For pan-resistant CR-GNB, the panel recommends selection of antibiotic treatment with the least resistant antibiotic/s based on MICs relative to the breakpoints, but mainly optimal source control (good practice statement). Throughout the current guideline, antibiotic stewardship considerations have been introduced. The most important concern the use of carbapenems for infections caused by 3GcephRE. In different epidemiological settings of cephalosporin resistance in Enterobacterales and prevalence of CR-GNB, the implications of adopting a sweeping practice of carbapenems for all 3GcephRE are variable. We addressed this recommendation by sepsis severity and source of infection, allowing the option of carbapenem-sparing therapy for non-severe infections and low-risk sources of infection, and addressing stepdown therapy. We support antibiotic stewardship considerations when using colistin (a last resort antibiotic for CRAB and MBL-producing Enterobacterales) and the new BLBLI. Many good practice statements are provided in the guidelines, when no evidence is available and clinical practice mandates decisionmaking. Many of them place a high value on antibiotic stewardship considerations and can be tailored locally. The current guidelines address antibiotic treatment targeted to specific pathogens. Empirically, before pathogen identification, these pathogens should be targeted among patients considered at high risk for CR-GNB infections. A difficult antibiotic stewardship balance exists between achieving appropriate empirical antibiotic therapy for patients with infections due to CR-GNB and the need to conserve last resort therapies for these bacteria. The empirical treatment phase is relevant to a much larger population than targeted treatment. Local guidelines, guided by the local epidemiology, should address the empirical treatment phase. The Infectious Diseases Society of America recently published guidance documents on the treatment of 3GcephRE, CRE, DTR P. aeruginosa and CRAB [252,253]. The guidance format, intended to address rapidly evolving topics, does not include a systematic review of the literature and does not use the formal GRADE process to appraise the evidence. Recommendations were developed by six infectious diseases specialists and were made also where evidence was lacking, thus addressing more specific scenarios. The paucity of the evidence on the effects of the new BLBLI against MDR-GNB, mainly CR-GNB, as well as antibiotic stewardship considerations (including also settings in which the new BLBLIs are not available) underly the main differences between our guidelines and the Infectious Diseases Society of America guidance. Our guidelines stress the situations where alternatives to carbapenems and the new BLBLI are possible, stratifying patients by sepsis severity and hence the urgency of sepsis control: piperacillin-tazobactam or amoxicillinclavulanate are considered in the treatment of 3GcephRE in our guidelines; aminoglycosides are considered for cUTI; and the scenarios in which sparing of the new BLBLI is possible are presented. Combination therapies are less strongly recommended in our guidelines that address the certainty of the evidence with respect to clinical outcomes. Considering costs and equity Antibiotics, both old and new, are not equally available worldwide. In low-resource settings, costs of the new antibiotics might prohibit their use; and even in other settings costs of the new antibiotics enter the consideration for use. Antibiotics critical to management of the priority pathogens should be defined and more efforts should be implemented to ensure the universal availability of these antibiotics. Differential costs of the new antibiotics for different socio-economic settings will allow better equity of patient management. Research needs Recommendations for further research were not developed formally and were not graded. Most recommendations in the guideline are based on very-low-certainty evidence or no evidence. Only RCT provided high-certainty evidence. RCT are needed that assess patients with infections due to 3GCephRE and CR-GNB; most M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547540 antibiotic approvaltrials of the new antibiotics were syndrome-based and included only a few patients with the MDR bacteria for which these antibiotics were developed. Although we intended by protocol to obtain data by source of infection, this was possible only for 3GCephRE and as a result infection source-specific guidance is mostly lacking. Investigator-initiated RCT are needed addressing these gaps. Concomitantly, observational studies can include a broaderand larger patient population and with improved methods to reduce bias can portray the real life and support decision-making. Antibiotic treatments addressed as the exposures in existing studies were frequently combined with otherantibiotics, switched and crossed; study designs allowing a cleaner assessment of individual antibiotics or specific combinations are needed. Studies addressing targeted treatment should address the empirical antibiotic treatment and report the phenotypic and genetic characterization of the isolated bacteria to direct more individualized treatment. The ecological impact of different treatment strategies should be evaluated. Evidence is lacking on the efficacy and safety of oral antibiotics (e.g. pivmecillinam, fosfomycin, amoxicillin/clavulanic acid), for initial treatment of clinically stable patients with UTI or as oral follow up, compared with continued definitive intravenous therapy. Furthermore, more studies are needed to establish optimal dosing regimens (dose, frequency, intermittent or prolonged administration) and treatment durations especially when using b - lactam antibiotics. Transparency declaration MP has received research grants from Pfizer. PR has sat on the advisory board of Shionogi. RAB has received research grants from Merck, Wockhardt, Entasis and Shionogi. Jan de Waele has received honoraria for educational activities from MSD and Pfizer. GLD has received honoraria for educational activities from, consulted for and sat on the advisory board of Pfizer, MSD and Shionogi. MA has received honoraria for educational activities from Pfizer, MSD, Gilead and Genentech, and received research support from Pfizer and Gilead. SH has sat on advisory boards for Sandoz and Bode. JG- M has received honoraria for educational activities from Shionogi and Pfizer. MT has sat on advisory boards for Menarini, MSD and Shionogi, and received honoraria from Pfizer. MB has received honoraria and sat on advisory boards for Angelini, Astellas, Bayer, Biom erieux, Cidara, Gilead, Menarini, MSD, Nabriva, Pfizer and Shionogi. EC, TT, RB, CP, BB, KS, PCL, SG, YY, JWM, ETand JRB have no conflicts of interest to declare. Funding These guidelines were supported in part by ESCMID. Updating the guideline The guidelines will be updated according to ESCMID recommendations. Acknowledgements We thank the five CMI reviewers and 18 commentators of the ESCMID open consultation who have made a significant contribution to the quality of this guideline. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2021.11.025. References [2] Cassini A, Hogberg LD, Plachouras D, Quattrocchi A, Hoxha A, Simonsen GS, et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis 2019;19:56e66. [3] Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:318e27. [4] 2020 Antibacterial agents in clinical and preclinical development: an overview and analysis. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Available from: https://www.who.int/publications/i/item/ 9789240021303. [5] Clancy CJ, Nguyen MH. Estimating the size of the United States market for new antibiotics with activity against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2019;63:e01733e819. [6] Scudeller L, Righi E, Chiamenti M, Bragantini D, Menchinelli G, Cattaneo P, et al. Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli. Int J Antimicrob Agents 2021;57:106344. [7] Zusman O, Avni T, Leibovici L, Adler A, Friberg L, Stergiopoulou T, et al. Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems. Antimicrob Agents Chemother 2013;57:5104e11. [8] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. [9] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801e10. [10] Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano- Pardo JR, et al. A predictive model of mortality in patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae. Mayo Clin Proc 2016;91:1362e71. [11] Palacios-Baena ZR, Gutierrez-Gutierrez B, De Cueto M, Viale P, Venditti M, Hernandez-Torres A, et al. Development and validation of the INCREMENTESBL predictive score for mortality in patients with bloodstream infections due to extended-spectrum-beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 2017;72:906e13. [12] Kadri SS, Adjemian J, Lai YL, Spaulding AB, Ricotta E, Prevots DR, et al. Difficult-to-treat resistance in Gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents. Clin Infect Dis 2018;67:1803e14. [13] Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. Newcastle- Ottawa quality assessment scale cohort studies. University of Ottawa; 2014. [14] Cochrane Effective Practice Organisation of Care. EPOC Resources for review authors. 2017. Available from: epoc.cochrane.org/resources/epoc-resources- review-authors. [15] Schünemann HBJ, Guyatt G, Oxman A, The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. 2013. Available from: guidelinedevelopment.org/handbook. [16] 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;320:984e94. [17] Paterson DL, Isler B, Harris PNA. PRO: carbapenems should be used for ALL infections caused by ceftriaxone-resistant Enterobacterales. JAC Antimicrob Resist 2021;3:dlab013. [18] Rodriguez-Bano J, Gutierrez-Gutierrez B, Pascual A. CON: carbapenems are NOT necessary for all infections caused by ceftriaxone-resistant Enterobacterales. JAC Antimicrob Resist 2021;3:dlaa112. [19] Marimuthu K, Ng OT, Cherng BPZ, Fong RKC, Pada SK, De PP, et al. Antecedent carbapenem exposure as a risk factor for non-carbapenemase-pro- ducing carbapenem-resistant Enterobacteriaceae and carbapenemaseproducing Enterobacteriaceae. Antimicrob Agents Chemother 2019;63: e00845e919. [20] Henderson A, Paterson DL, Chatfield MD, Tambyah PA, Lye DC, De PP, et al. Association between minimum inhibitory concentration, betalactamase genes and mortality for patients treated with piperacillin/ tazobactam or meropenem from the MERINO study. Clin Infect Dis 2020;73:e3842e50. [21] Stewart AG, Paterson DL, Young B, Lye DC, Davis JS, Schneider K, et al. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections caused by AmpC beta-lactamase-producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp., or Serratia marcescens: a pilot multicenter randomized controlled trial (MERINO-2). Open Forum Infect Dis 2021;8:ofab387. [22] Gutierrez-Gutierrez B, Perez-Galera S, Salamanca E, de Cueto M, Calbo E, Almirante B, et al. A multinational, preregistered cohort study of betalactam/beta-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2016;60:4159e69. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 541 [23] Harris PN, Yin M, Jureen R, Chew J, Ali J, Paynter S, et al. Comparable outcomes for beta-lactam/beta-lactamase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae. Antimicrob Resist Infect Control 2015;4:14. [24] 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;11:e0153696. [25] Tamma PD, Han JH, Rock C, Harris AD, Lautenbach E, Hsu AJ, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum beta-lacta- mase bacteremia. Clin Infect Dis 2015;60:1319e25. [26] 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 beta-lactamase-producing Proteus mirabilis. Diagn Microbiol Infect Dis 2014;80:222e6. [27] Cheng L, Nelson BC, Mehta M, Seval N, Park S, Giddins MJ, et al. Piperacillintazobactam versus other antibacterial agents for treatment of bloodstream infections due to AmpC beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2017;61:e00276e317. [28] Dizbay M, Ozger HS, Karasahin O, Karasahin EF. Treatment efficacy and superinfection rates in complicated urinarytract infections treated with ertapenem or piperacillin tazobactam. Turk J Med Sci 2016;46:1760e4. [29] Gudiol C, Royo-Cebrecos C, Abdala E, Akova M, Alvarez R, Maestro-de la Calle G, et al. Efficacy of beta-lactam/beta-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum-beta- lactamase-producing Enterobacteriaceae in hematological patients with neutropenia. Antimicrob Agents Chemother 2017;61:e00164e217. [30] 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;54:3551e6. [31] Rodriguez-Bano J, Navarro MD, Retamar P, Picon E, Pascual A. Extended- Spectrum Beta-Lactamases-Red Espanola de Investigacion en Patologia Infecciosa/Grupo de Estudio de Infeccion Hospitalaria G. beta-Lactam/betalactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis 2012;54:167e74. [32] Seo YB, Lee J, Kim YK, Lee SS, Lee JA, Kim HY, et al. Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase- producing Escherichia coli. BMC Infect Dis 2017;17:404. [33] Yoon YK, Kim JH, Sohn JW, Yang KS, Kim MJ. Role of piperacillin/tazobactam as a carbapenem-sparing antibiotic for treatment of acute pyelonephritis due to extended-spectrum beta-lactamase-producing Escherichia coli. Int J Antimicrob Agents 2017;49:410e5. [34] 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;12:611. [35] Sharara SL, Amoah J, Pana ZD, Simner PJ, Cosgrove SE, Tamma PD. Is piperacillin-tazobactam effective for the treatment of pyelonephritis caused by extended-spectrum beta-lactamase-producing organisms? Clin Infect Dis 2020;71:e331e7. [36] 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;8:144. [37] Ko JH, Lee NR, Joo EJ, Moon SY, Choi JK, Park DA, et al. Appropriate noncarbapenems are not inferior to carbapenems as initial empirical therapy for bacteremia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a propensity score weighted multicenter cohort study. Eur J Clin Microbiol Infect Dis 2018;37:305e11. [38] Meini S, Laureano R, Tascini C, Arena F, Fani L, Frullini A, et al. Clinical outcomes of elderly patients with bloodstream infections due to extendedspectrum beta-lactamase-producing Enterobacteriaceae in an Italian Internal Medicine ward. Eur J Intern Med 2018;48:50e6. [39] Namikawa H, Yamada K, Yamairi K, Shibata W, Fujimoto H, Takizawa E, et al. Mortality caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia; a case control study: alert to Enterobacteriaceae strains with high minimum inhibitory concentrations of piperacillin/tazobactam. Diagn Microbiol Infect Dis 2019;94:287e92. [40] Ray S, Anand D, Purwar S, Samanta A, Upadhye KV, Gupta P, et al. Association of high mortality with extended-spectrum beta-lactamase (ESBL) positive cultures in community acquired infections. J Crit Care 2018;44:255e60. [41] Ofer-Friedman H, Shefler C, Sharma S, Tirosh A, Tal-Jasper R, Kandipalli D, et al. Carbapenems versus piperacillin-tazobactam for bloodstream infections of nonurinary source caused by extended-spectrum beta-lactamase- producing Enterobacteriaceae. Infect Control Hosp Epidemiol 2015;36: 981e5. [42] Chaubey VP, Pitout JD, Dalton B, Ross T, Church DL, Gregson DB, et al. Clinical outcome of empiric antimicrobial therapy of bacteremia due to extendedspectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae. BMC Res Notes 2010;3:116. [43] 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-beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother 2012;56: 3936e42. [44] Falcone M, Vena A, Mezzatesta ML, Gona F, Caio C, Goldoni P, et al. Role of empirical and targeted therapy in hospitalized patients with bloodstream infections caused by ESBL-producing Enterobacteriaceae. Ann Ig 2014;26: 293e304. [45] Huang SS, Lee MH, Leu HS. Bacteremia due to extended-spectrum beta-lac- tamase-producing Enterobacteriaceae other than Escherichia coli and Klebsiella. J Microbiol Immunol Infect 2006;39:496e502. [46] To KK, Lo WU, Chan JF, Tse H, Cheng VC, Ho PL. Clinical outcome of extendedspectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity. Int J Infect Dis 2013;17:e120e4. [47] Meije Y, Pigrau C, Fernandez-Hidalgo N, Clemente M, Ortega L, Sanz X, et al. Non-intravenous carbapenem-sparing antibiotics for definitive treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum betalactamase (ESBL) or AmpC beta-lactamase: a propensity score study. Int J Antimicrob Agents 2019;54:189e96. [48] Palacios-Baena ZR, Gutierrez-Gutierrez B, Calbo E, Almirante B, Viale P, Oliver A, et al. Empiric therapy with carbapenem-sparing regimens for bloodstream infections due to extended-spectrum beta-lactamase-produc- ing Enterobacteriaceae: results from the INCREMENT Cohort. Clin Infect Dis 2017;65:1615e23. [49] Paterson DL, Ko WC, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis 2004;39: 31e7. [50] Collins VL, Marchaim D, Pogue JM, Moshos J, Bheemreddy S, Sunkara B, et al. Efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2012;56:2173e7. [51] Wu UI, Chen WC, Yang CS, Wang JL, Hu FC, Chang SC, et al. Ertapenem in the treatment of bacteremia caused by extended-spectrum beta-lactamase- producing Escherichia coli: a propensity score analysis. Int J Infect Dis 2012;16:e47e52. [52] Gutierrez-Gutierrez B, Bonomo RA, Carmeli Y, Paterson DL, Almirante B, Martinez-Martinez L, et al. Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational preregistered cohort study. J Antimicrob Chemother 2016;71:1672e80. [53] Lee NY, Huang WH, Tsui KC, Hsueh PR, Ko WC. Carbapenem therapy for bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae. Diagn Microbiol Infect Dis 2011;70:150e3. [54] Rattanaumpawan P, Werarak P, Jitmuang A, Kiratisin P, Thamlikitkul V. Efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: an open-label randomized controlled trial. BMC Infect Dis 2017;17:183. [55] Lee CH, Su LH, Tang YF, Liu JW. Treatment of ESBL-producing Klebsiella pneumoniae bacteraemia with carbapenems or flomoxef: a retrospective study and laboratory analysis of the isolates. J Antimicrob Chemother 2006;58:1074e7. [56] Yang CC, Li SH, Chuang FR, Chen CH, Lee CH, Chen JB, et al. Discrepancy between effects of carbapenems and flomoxef in treating nosocomial hemodialysis access-related bacteremia secondary to extended spectrum betalactamase producing Klebsiella pneumoniae in patients on maintenance hemodialysis. BMC Infect Dis 2012;12:206. [57] Lee CH, Su LH, Chen FJ, Tang YF, Li CC, Chien CC, et al. Comparative effectiveness of flomoxef versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae with emphasis on minimum inhibitory concentration of flomoxef: a retrospective study. Int J Antimicrob Agents 2015;46:610e5. [58] Matsumura Y, Yamamoto M, Nagao M, Komori T, Fujita N, Hayashi A, et al. Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-beta-lactamase-producing Escherichia coli bacteremia. Antimicrob Agents Chemother 2015;59:5107e13. [59] Fukuchi T, Iwata K, Kobayashi S, Nakamura T, Ohji G. Cefmetazole for bacteremia caused by ESBL-producing Enterobacteriaceae comparing with carbapenems. BMC Infect Dis 2016;16:427. [60] Lee NY, Lee CC, Huang WH, Tsui KC, Hsueh PR, Ko WC. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spec- trum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 2013;56:488e95. [61] Tamma PD, Girdwood SC, Gopaul R, Tekle T, Roberts AA, Harris AD, et al. The use of cefepime for treating AmpC beta-lactamase-producing Enterobacteriaceae. Clin Infect Dis 2013;57:781e8. [62] Blanchette LM, Kuti JL, Nicolau DP, Nailor MD. Clinical comparison of ertapenem and cefepime for treatment of infections caused by AmpC betalactamase-producing Enterobacteriaceae. Scand J Infect Dis 2014;46:803e8. [63] Lee NY, Lee CC, Li CW, Li MC, Chen PL, Chang CM, et al. Cefepime therapy for monomicrobial enterobacter cloacae bacteremia: unfavorable outcomes in patients infected by cefepime-susceptible dose-dependent isolates. Antimicrob Agents Chemother 2015;59:7558e63. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547542 [64] Siedner MJ, Galar A, Guzman-Suarez BB, Kubiak DW, Baghdady N, Ferraro MJ, et al. Cefepime vs other antibacterial agents for the treatment of Enterobacter species bacteremia. Clin Infect Dis 2014;58:1554e63. [65] Wang R, Cosgrove SE, Tschudin-Sutter S, Han JH, Turnbull AE, Hsu AJ, et al. Cefepime therapy for cefepime-susceptible extended-spectrum betalactamase-producing Enterobacteriaceae bacteremia. Open Forum Infect Dis 2016;3:ofw132. [66] Endimiani A, Luzzaro F, Perilli M, Lombardi G, Coli A, Tamborini A, et al. Bacteremia due to Klebsiella pneumoniae isolates producing the TEM-52 extended-spectrum beta-lactamase: treatment outcome of patients receiving imipenem or ciprofloxacin. Clin Infect Dis 2004;38:243e51. [67] Lo CL, Lee CC, Li CW, Li MC, Hsueh PR, Lee NY, et al. Fluoroquinolone therapy for bloodstream infections caused by extended-spectrum beta-lactamase- producing Escherichia coli and Klebsiella pneumoniae. J Microbiol Immunol Infect 2017;50:355e61. [68] Punjabi C, Tien V, Meng L, Deresinski S, Holubar M. Oral fluoroquinolone or trimethoprim-sulfamethoxazole vs b -lactams as step-down therapy for Enterobacteriaceae bacteremia: systematic review and meta-analysis. Open Forum Infect Dis 2019;6:ofz364. [69] Zohar I, Schwartz O, Yossepowitch O, David SSB, Maor Y. Aminoglycoside versus carbapenem or piperacillin/tazobactam treatment for bloodstream infections of urinary source caused by Gram-negative ESBL-producing Enterobacteriaceae. J Antimicrob Chemother 2020;75:458e65. [70] Kang CI, Wi YM, Ko KS, Chung DR, Peck KR, Lee NY, et al. Outcomes and risk factors for mortality in community-onset bacteremia caused by extendedspectrum beta-lactamase-producing Escherichia coli, with a special emphasis on antimicrobial therapy. Scand J Infect Dis 2013;45:519e25. [71] Kaye KS, Rice LB, Dane AL, Stus V, Sagan O, Fedosiuk E, et al. Fosfomycin for injection (ZTI-01) versus piperacillin-tazobactam for the treatment of complicated urinary tract infection including acute pyelonephritis: ZEUS, a phase 2/3 randomized trial. Clin Infect Dis 2019;69:2045e56. [72] Sojo-Dorado J, L opez-Hern andez I, Borreguero I, et al., editors. Fosfomycin vs meropenem or ceftriaxone for bacteraemic urinary tract infections caused by multidrug-resistant Escherichia coli: a randomised trial (FOREST) 30th European Congress of Clinical Microbiology &Infectious Diseases. Basel: European Society of Infectious Diseases; 2020. [73] Veve MP, Wagner JL, Kenney RM, Grunwald JL, Davis SL. Comparison of fosfomycin to ertapenem for outpatient or step-down therapy of extendedspectrum beta-lactamase urinary tract infections. Int J Antimicrob Agents 2016;48:56e60. [74] Wagenlehner FME, Cloutier DJ, Komirenko AS, Cebrik DS, Krause KM, Keepers TR, et al. Once-daily plazomicin for complicated urinary tract infections. N Engl J Med 2019;380:729e40. [75] Beaucaire G. Does once-daily dosing prevent nephrotoxicity in all aminoglycosides equally? Clin Microbiol Infect 2000;6:355e60. [76] Doi A, Shimada T, Harada S, Iwata K, Kamiya T. The efficacy of cefmetazole against pyelonephritis caused by extended-spectrum beta-lactamase-pro- ducing Enterobacteriaceae. Int J Infect Dis 2013;17:e159e63. [77] Pilmis B, Parize P, Zahar JR, Lortholary O. Alternatives to carbapenems for infections caused by ESBL-producing Enterobacteriaceae. Eur J Clin Microbiol Infect Dis 2014;33:1263e5. [78] Senard O, Lafaurie M, Lesprit P, Nguyen Y, Lescure X, Therby A, et al. Efficacy of cefoxitin versus carbapenem in febrile male urinary tract infections caused by extended spectrum beta-lactamase-producing Escherichia coli: a multicenter retrospective cohort study with propensity score analysis. Eur J Clin Microbiol Infect Dis 2020;39:121e9. [79] Kim SA, Altshuler J, Paris D, Fedorenko M. Cefepime versus carbapenems for the treatment of urinary tract infections caused by extended-spectrum betalactamase-producing Enterobacteriaceae. Int J Antimicrob Agents 2018;51: 155e8. [80] Delory T, Gravier S, Le Pluart D, Gaube G, Simeon S, Davido B, et al. Temocillin versus carbapenems for urinary tract infection due to ESBL-producing Enterobacteriaceae: a multicenter matched caseecontrol study. Int J Antimicrob Agents 2021;58:106361. [81] Lee B, Kang SY, Kang HM, Yang NR, Kang HG, Ha IS, et al. Outcome of antimicrobial therapy of pediatric urinary tract infections caused by extendedspectrum beta-lactamase-producing Enterobacteriaceae. Infect Chemother 2013;45:415e21. [82] Park SH, Choi SM, Chang YK, Lee DG, Cho SY, Lee HJ, et al. The efficacy of noncarbapenem antibiotics for the treatment of community-onset acute pyelonephritis due to extended-spectrum beta-lactamase-producing Escherichia coli. J Antimicrob Chemother 2014;69:2848e56. [83] Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenemcilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin 2012;28: 1921e31. [84] Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidimeresistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 2016;16: 661e73. [85] Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016;63:754e62. [86] Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). The Lancet 2015;385:1949e56. [87] Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis 2010;68:140e51. [88] Zanetti G, Bally F, Greub G, Garbino J, Kinge T, Lew D, et al. Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study. Antimicrob Agents Chemother 2003;47:3442e7. [89] Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidimeavibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 2018;18:285e95. [90] Kollef MH, Novacek M, Kivistik U, Rea-Neto A, Shime N, Martin-Loeches I, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019;19:1299e311. [91] Goethaert K, Van Looveren M, Lammens C, Jansens H, Baraniak A, Gniadkowski M, et al. High-dose cefepime as an alternative treatment for infections caused by TEM-24 ESBL-producing Enterobacter aerogenes in severely-ill patients. Clin Microbiol Infect 2006;12:56e62. [92] FDA. FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/ fda-drug-safety-communication-fda-warns-increased-risk-death-iv- antibacterial-tygacil-tigecycline. [93] Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016;62:1380e9. [94] Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, et al. Ceftolozane/tazobactam plus metronidazole for complicated intraabdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis [Internet] 2015;60:1462e71. Available from: http://onlinelibrary.wiley.com/o/ cochrane/clcentral/articles/510/CN-01088510/frame.html. [95] Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intraabdominal infections in the investigating Gram-negative infections treated with eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg 2017;152:224e32. [96] van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenemresistant Enterobacteriaceae. Clin Infect Dis 2018;66:163e71. [97] Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 2017;61:e00883e917. [98] Caston JJ, Lacort-Peralta I, Martin-Davila P, Loeches B, Tabares S, Temkin L, et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis 2017;59:118e23. [99] Tumbarello M, Trecarichi EM, Corona A, De Rosa FG, Bassetti M, Mussini C, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Infect Dis 2019;68:355e64. [100] Alraddadi BM, Saeedi M, Qutub M, Alshukairi A, Hassanien A, Wali G. Efficacy of ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. BMC Infect Dis 2019;19:772. [101] Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis 2016;63:1615e8. [102] Both A, Buttner H, Huang J, Perbandt M, Belmar Campos C, Christner M, et al. Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate. J Antimicrob Chemother 2017;72:2483e8. [103] Humphries RM, Yang S,Hemarajata P,WardKW, Hindler JA,Miller SA, etal. First report of ceftazidime-avibactam resistance in a KPC-3-expressing Klebsiella pneumoniae isolate. Antimicrob Agents Chemother 2015;59:6605e7. [104] Raisanen K, Koivula I, Ilmavirta H, Puranen S, Kallonen T, Lyytikainen O, et al. Emergence of ceftazidime-avibactam-resistant Klebsiella pneumoniae during treatment, Finland. Euro Surveill 2018;24:1900256. 2019. [105] Zhang P, Shi Q, Hu H, Hong B, Wu X, Du X, et al. Emergence of ceftazidime/ avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China. Clin Microbiol Infect 2020;26:124e1e4. [106] Livermore DM, Warner M, Jamrozy D, Mushtaq S, Nichols WW, Mustafa N, et al. In vitro selection of ceftazidime-avibactam resistance in M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 543 Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob Agents Chemother 2015;59:5324e30. [107] Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al. Emergence of ceftazidime-avibactam resistance due to plasmid-borne bla(KPC-3) mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother 2017;61:e02097e116. [108] Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, et al. Ceftazidime-avibactam use for Klebsiella pneumoniae carbapenemaseproducing K. pneumoniae infections: a retrospective observational multicenter study. Clin Infect Dis 2021;73:1664e76. [109] Voulgari E, Kotsakis SD, Giannopoulou P, Perivolioti E, Tzouvelekis LS, Miriagou V. Detection in two hospitals of transferable ceftazidime-avibactam resistance in Klebsiella pneumoniae due to a novel VEB beta-lactamase variant with a Lys234Arg substitution, Greece, 2019. Euro Surveill 2020;25:1900766. [110] Galani I, Karaiskos I, Souli M, Papoutsaki V, Galani L, Gkoufa A, et al. Outbreak of KPC-2-producing Klebsiella pneumoniae endowed with ceftazidimeavibactam resistance mediated through a VEB-1-mutant (VEB-25), Greece, September to October 2019. Euro Surveill 2020;25:2000028. [111] Petty LA, Henig O, Patel TS, Pogue JM, Kaye KS. Overview of meropenemvaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect Drug Resist 2018;11: 1461e72. [112] Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazquez J, et al. Effect and safety of meropenem-vaborbactam versus bestavailable therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II Randomized Clinical Trial. Infect Dis Ther 2018;7: 439e55. [113] Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 2013;68:2286e90. [114] Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, et al. Phase 2, Dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother 2016;60:6234e43. [115] Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, et al. Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother 2017;72:2616e26. [116] Titov I, Wunderink RG, Roquilly A, Rodriguez Gonzalez D, David-Wang A, Boucher HW, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/ tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis 2020;73:e4539e48. [117] Chen LF, Young K, Hilbert DW, Losada MC, Deryke CA, Du J, et al., editors. Imipenem/cilastatin (IMI)/relebactam (REL) for treatment of Hospital- Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP) caused by imipenem-nonsusceptible pathogens: subgroup analysis of the RESTOREIMI 2 trial. 31st European congress of clinical microbiology &infectious diseases. Basel: European Society of Infectious Diseases; 2021. [118] Motsch J, Murta de Oliveira C, Stus V, Koksal I, Lyulko O, Boucher HW, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis 2020;70:1799e808. [119] Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319e28. [120] Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye KS, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2021;21: 213e25. [121] Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis 2021;21:226e40. [122] Poeylaut-Palena AA, Tomatis PE, Karsisiotis AI, Damblon C, Mata EG, Vila AJ. A minimalistic approach to identify substrate binding features in B1 Metallobeta-lactamases. Bioorg Med Chem Lett 2007;17:5171e4. [123] Falcone M, Russo A, Iacovelli A, Restuccia G, Ceccarelli G, Giordano A, et al. Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clin Microbiol Infect 2016;22:444e50. [124] Messina JA, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, et al. Hospital readmissions in patients with carbapenem-resistant Klebsiella pneumoniae. Infect Control Hosp Epidemiol 2016;37:281e8. [125] van Duin D, Cober E, Richter SS, Perez F, Kalayjian RC, Salata RA, et al. Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae. J Antimicrob Chemother 2015;70:1203e11. [126] Satlin MJ, Kubin CJ, Blumenthal JS, Cohen AB, Furuya EY, Wilson SJ, et al. Comparative effectiveness of aminoglycosides, polymyxin B, and tigecycline for clearance of carbapenem-resistant Klebsiella pneumoniae from urine. Antimicrob Agents Chemother 2011;55:5893e9. [127] Gonzalez-Padilla M, Torre-Cisneros J, Rivera-Espinar F, Pontes-Moreno A, Lopez-Cerero L, Pascual A, et al. Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae. J Antimicrob Chemother 2015;70:905e13. [128] Freire MP, de Oliveira Garcia D, Cury AP, Francisco GR, Dos Santos NF, Spadao F, et al. The role of therapy with aminoglycoside in the outcomes of kidney transplant recipients infected with polymyxin- and carbapenemresistant Enterobacteriaceae. Eur J Clin Microbiol Infect Dis 2019;38:755e65. [129] Liang Q, Huang M, Xu Z. Early use of polymyxin B reduces the mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection. Braz J Infect Dis 2019;23:60e5. [130] Nguyen M, Eschenauer GA, Bryan M, O'Neil K, Furuya EY, Della-Latta P, et al. Carbapenem-resistant Klebsiella pneumoniae bacteremia: factors correlated with clinical and microbiologic outcomes. Diagn Microbiol Infect Dis 2010;67:180e4. [131] Ji S, Lv F, Du X, Wei Z, Fu Y, Mu X, et al. Cefepime combined with amoxicillin/ clavulanic acid: a new choice for the KPC-producing K. pneumoniae infection. Int J Infect Dis 2015;38:108e14. [132] Ku K, Pogue JM, Moshos J, Bheemreddy S, Wang Y, Bhargava A, et al. Retrospective evaluation of colistin versus tigecycline for the treatment of Acinetobacter baumannii and/or carbapenem-resistant Enterobacteriaceae infections. Am J Infect Control 2012;40:983e7. [133] Garbati MA, Sakkijha H, Abushaheen A. Infections due to carbapenem resistant Enterobacteriaceae among Saudi Arabian hospitalized patients: a matched caseecontrol study. Biomed Res Int 2016;2016:3961684. [134] De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, et al. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care 2014;18:R90. [135] Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections: a retrospective cohort study. Medicine (Balt) 2018;97:e9961. [136] Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin Microbiol Infect 2010;16:184e6. [137] Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drugresistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents 2014;43:52e9. [138] Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, Spyridopoulou K, Daikos GL. Emergence of resistance to fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: report of three cases. J Antimicrob Chemother 2012;67:2777e9. [139] Liao Y, Hu GH, Xu YF, Che JP, Luo M, Zhang HM, et al. Retrospective analysis of fosfomycin combinational therapy for sepsis caused by carbapenemresistant Klebsiella pneumoniae. Exp Ther Med 2017;13:1003e10. [140] Luterbach CL, Boshe A, Henderson HI, Cober E, Richter SS, Salata RA, et al. The role of trimethoprim/sulfamethoxazole in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Open Forum Infect Dis 2019;6: ofy351. [141] Solomkin JS, Gardovskis J, Lawrence K, Montravers P, Sway A, Evans D, et al. IGNITE4: results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections. Clin Infect Dis 2019;69:921e9. [142] McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I, Smith A, et al. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med 2019;380:791e3. [143] Bergamasco MD, Barroso Barbosa M, de Oliveira Garcia D, Cipullo R, Moreira JC, Baia C, et al. Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in solid organ transplantation. Transpl Infect Dis 2012;14:198e205. [144] Capone A, Giannella M, Fortini D, Giordano A, Meledandri M, Ballardini M, et al. High rate of colistin resistance among patients with carbapenemresistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect 2013;19:E23e30. [145] Chang YY, Chuang YC, Siu LK, Wu TL, Lin JC, Lu PL, et al. Clinical features of patients with carbapenem nonsusceptible Klebsiella pneumoniae and Escherichia coli in intensive care units: a nationwide multicenter study in Taiwan. J Microbiol Immunol Infect 2015;48:219e25. [146] Crusio R, Rao S, Changawala N, Paul V, Tiu C, van Ginkel J, et al. Epidemiology and outcome of infections with carbapenem-resistant Gram-negative bacteria treated with polymyxin B-based combination therapy. Scand J Infect Dis 2014;46:1e8. [147] Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58:2322e8. [148] de Maio Carrilho CM, de Oliveira LM, Gaudereto J, Perozin JS, Urbano MR, Camargo CH, et al. A prospective study of treatment of carbapenem-resistant M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547544 Enterobacteriaceae infections and risk factors associated with outcome. BMC Infect Dis 2016;16:629. [149] Diaz A, Ortiz DC, Trujillo M, Garces C, Jaimes F, Restrepo AV. Clinical characteristics of carbapenem-resistant Klebsiella pneumoniae infections in ill and colonized children in Colombia. Pediatr Infect Dis J 2016;35:237e41. [150] Freire MP, Pierrotti LC, Filho HH, Ibrahim KY, Magri AS, Bonazzi PR, et al. Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae in cancer patients. Eur J Clin Microbiol Infect Dis 2015;34: 277e86. [151] Gomez-Simmonds A, Nelson B, Eiras DP, Loo A, Jenkins SG, Whittier S, et al. Combination regimens for treatment of carbapenem-resistant Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother 2016;60: 3601e7. [152] Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano- Pardo JR, et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 2017;17:726e34. [153] Katsiari M, Panagiota G, Likousi S, Roussou Z, Polemis M, Alkiviadis Vatopoulos C, et al. Carbapenem-resistant Klebsiella pneumoniae infections in a Greek intensive care unit: molecular characterisation and treatment challenges. J Glob Antimicrob Resist 2015;3:123e7. [154] King M, Heil E, Kuriakose S, Bias T, Huang V, El-Beyrouty C, et al. Multicenter study of outcomes with ceftazidime-avibactam in patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother 2017;61:e00449e517. [155] Kontopidou F, Giamarellou H, Katerelos P, Maragos A, Kioumis I, Trikka- Graphakos E, et al. Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and therapeutic options. Clin Microbiol Infect 2014;20:O117e23. [156] Machuca I, Gutierrez-Gutierrez B, Gracia-Ahufinger I, Rivera Espinar F, Cano A, Guzman-Puche J, et al. Mortality associated with bacteremia due to colistin-resistant Klebsiella pneumoniae with high-level meropenem resistance: importance of combination therapy without colistin and carbapenems. Antimicrob Agents Chemother 2017;61:e00406e17. [157] Malande OO, Du Plessis A, Rip D, Bamford C, Eley B. Invasive carbapenemresistant Enterobacteriaceae infection at a paediatric hospital: a case series. S Afr Med J 2016;106:877e82. [158] Nelson BC, Eiras DP, Gomez-Simmonds A, Loo AS, Satlin MJ, Jenkins SG, et al. Clinical outcomes associated with polymyxin B dose in patients with bloodstream infections due to carbapenem-resistant Gram-negative rods. Antimicrob Agents Chemother 2015;59:7000e6. [159] Papadimitriou-Olivgeris M, Fligou F, Bartzavali C, Zotou A, Spyropoulou A, Koutsileou K, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infection in critically ill patients: risk factors and predictors of mortality. Eur J Clin Microbiol Infect Dis 2017;36:1125e31. [160] Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 2018;18:391e400. [161] Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56:2108e13. [162] Shields RK, Clancy CJ, Press EG, Nguyen MH. Aminoglycosides for treatment of bacteremia due to carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother 2016;60:3187e92. [163] Tofas P, Skiada A, Angelopoulou M, Sipsas N, Pavlopoulou I, Tsaousi S, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: analysis of 50 cases. Int J Antimicrob Agents 2016;47:335e9. [164] Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 2015;70:2133e43. [165] Tuon FF, Graf ME, Merlini A, Rocha JL, Stallbaum S, Arend LN, et al. Risk factors for mortality in patients with ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae. Braz J Infect Dis 2017;21:1e6. [166] Villegas MV, Pallares CJ, Escandon-Vargas K, Hernandez-Gomez C, Correa A, Alvarez C, et al. Characterization and clinical impact of bloodstream infection caused by carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS One 2016;11:e0154092. [167] Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 2011;17:1798e803. [168] Medeiros GS, Rigatto MH, Falci DR, Zavascki AP. Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents 2019;53:152e7. [169] Su CF, Chuang C, Lin YT, Chan YJ, Lin JC, Lu PL, et al. Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan. Eur J Clin Microbiol Infect Dis 2018;37:651e9. [170] Lin YT, Su CF, Chuang C, Lin JC, Lu PL, Huang CT, et al. Appropriate treatment for bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae and Escherichia coli: a nationwide multicenter study in Taiwan. Open Forum Infect Dis 2019;6:ofy336. [171] Errico G, Gagliotti C, Monaco M, Masiero L, Gaibani P, Ambretti S, et al. Colonization and infection due to carbapenemase-producing Enterobacteriaceae in liver and lung transplant recipients and donor-derived transmission: a prospective cohort study conducted in Italy. Clin Microbiol Infect 2019;25:203e9. [172] Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother 2017;72:29e39. [173] Schmid A, Wolfensberger A, Nemeth J, Schreiber PW, Sax H, Kuster SP. Monotherapy versus combination therapy for multidrug-resistant Gramnegative infections: systematic review and meta-analysis. Sci Rep 2019;9: 15290. [174] Wang J, Pan Y, Shen J, Xu Y. The efficacy and safety of tigecycline for the treatment of bloodstream infections: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob 2017;16:24. [175] Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol 2011;7:1459e70. [176] Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the American college of clinical pharmacy (ACCP), European society of clinical microbiology and infectious diseases (ESCMID), infectious diseases society of America (IDSA), international society for antiinfective pharmacology (ISAP), society of critical care medicine (SCCM), and society of infectious diseases pharmacists (SIDP). Pharmacotherapy 2019;39:10e39. [177] de Oliveira MS, de Assis DB, Freire MP, Boas do Prado GV, Machado AS, Abdala E, et al. Treatment of KPC-producing Enterobacteriaceae: suboptimal efficacy of polymyxins. Clin Microb Infect 2015;21:179.e1e7. [178] Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH, et al. Excess mortality associated with colistin-tigecycline compared with colistincarbapenem combination therapy for extensively drug-resistant Acinetobacter baumannii bacteremia: a multicenter prospective observational study. Crit Care Med 2015;43:1194e204. [179] Kaye KS, Marchaim D, Thamlikitkul V, et al., editors. Results from the OVERCOME Trial: colistin monotherapy versus combination therapy for the treatment of pneumonia or bloodstream infection due to extensively drug resistant Gram-negative bacilli. 31st European congress of clinical microbiology &infectious diseases. Basel: European Society of Infectious Disease; 2021. 2021. [180] Giannella M, Trecarichi EM, Giacobbe DR, De Rosa FG, Bassetti M, Bartoloni A, et al. Effect of combination therapy containing a high-dose carbapenem on mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents 2018;51:2448. [181] Erdem F, Abulaila A, Aktas Z, Oncul O. In vitro evaluation of double carbapenem and colistin combinations against OXA-48, NDM carbapenemaseproducing colistin-resistant Klebsiella pneumoniae strains. Antimicrob Resist Infect Control 2020;9:70. [182] Oliva A, Gizzi F, Mascellino MT, Cipolla A, D'Abramo A, D'Agostino C, et al. Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae. Clin Microbiol Infect 2016;22:147e53. [183] Cancelli F, Oliva A, De Angelis M, Mascellino MT, Mastroianni CM, Vullo V. Role of double-carbapenem regimen in the treatment of infections due to carbapenemase producing carbapenem-resistant Enterobacteriaceae:a single-center, observational study. Biomed Res Int 2018;2018:2785696. [184] De Pascale G, Martucci G, Montini L, Panarello G, Cutuli SL, Di Carlo D, et al. Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched caseecontrol study. Crit Care 2017;21:173. [185] Venugopalan V, Nogid B, Le TN, Rahman SM, Bias TE. Double carbapenem therapy (DCT) for bacteremia due to carbapenem-resistant Klebsiella pneumoniae (CRKP): from test tube to clinical practice. Infect Dis (Lond) 2017;49: 867e70. [186] Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidimeavibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother 2018;62. [187] De la Calle C, Rodriguez O, Morata L, Marco F, Cardozo C, Garcia-Vidal C, et al. Clinical characteristics and prognosis of infections caused by OXA-48 carbapenemase-producing Enterobacteriaceae in patients treated with ceftazidime-avibactam. Int J Antimicrob Agents 2019;53:520e4. [188] Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, et al. Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study. Clin Infect Dis 2021;73:1664e76. [189] Karlowsky JA, Kazmierczak KM, de Jonge BLM, Hackel MA, Sahm DF, Bradford PA. In vitro activity of aztreonam-avibactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015. Antimicrob Agents Chemother 2017;61: e00472e517. M. Paul et al. / Clinical Microbiology and Infection 28 (2022) 521e547 545