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International Journal of Antimicrobial Agents 57 (2021) 106344 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: www.elsevier.com/locate/ijantimicag Review Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli ∗ Luigia Scudeller a,1, Elda Righi b,1, , Margherita Chiamenti b, Damiano Bragantini b, Giulia Menchinelli c,d, Paolo Cattaneo b, Christian G. Giske e, Thomas Lodise f, Maurizio Sanguinetti c,d, Laura J.V. Piddock g, François Franceschi g, Sally Ellis g, ∗ Elena Carrara b, Alessia Savoldi b, Evelina Tacconelli b,h,i, a Clinical Epidemiology and Biostatistics, IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano Foundation, Milan, Italy b Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, P.Le L.A. Scuro 10, 37134 Verona, Italy c Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy d Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy e Clinical Microbiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden f Albany College of Pharmacy and Health Sciences, Albany, New York, USA g Global Antibiotic Research & Development Partnership (GARDP), 15 Chemin Louis-Dunant, Geneva, Switzerland h Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Otfried Müller Straße 12, 72074 Tübingen, Germany i German Centre for Infection Research (DZIF), Clinical Research Unit for Healthcare Associated Infections, Tübingen, Germany a r t i c l e i n f o a b s t r a c t Article history: The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) in- Received 20 January 2021 fections remains controversial. In vitro models may predict the efficacy of antibiotic regimens Accepted 3 April 2021 against CR-GNB. A systematic review and meta-analysis was performed including pharmacoki- netic/pharmacodynamic (PK/PD) and time–kill (TK) studies examining the in vitro efficacy of antibi- Editor: Dr Jim Gray otic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary out- come was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35 < ES < Keywords: 0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal ef- In vitro synergy Antibiotic combination fect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for PK/PD risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most Time–kill frequently analysed classes were polymyxins and carbapenems. Limited data were available for cef- Carbapenem-resistant bacteria tazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence in- terval (CI) 0.44–1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66– 1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21–1.00). Com- pared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria. ©2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) 1. Introduction ∗ Corresponding authors. Tel.: + 39 045 812 8284. The rapid emergence and dissemination of multidrug-resistant E-mail address: [email protected] (E. Tacconelli). 1 These two authors contributed equally to this study. (MDR) Gram-negative bacilli (GNB) is recognised as a major public https://doi.org/10.1016/j.ijantimicag.2021.106344 0924-8579/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) L. Scudeller, E. Righi, M. Chiamenti et al. International Journal of Antimicrobial Agents 57 (2021) 106344 health issue [ 1 , 2 ]. Treatment options against carbapenem-resistant 2018. All search strings were discussed with a qualified librarian. (CR) GNB remain limited [3] . To direct research and development Details of the bibliographic search strategy are listed in the Sup- of new antibiotics, in 2017 the World Health Organization (WHO) plementary methods. Bibliographies of reviews and original pub- published a list of pathogens prioritising CR Acinetobacter bau- lications were hand-searched for further studies. To reduce publi- mannii , CR Pseudomonas aeruginosa and CR Enterobacteriaceae [4] . cation bias, the Infectious Diseases Society of America (IDSA) and Novel compounds displaying in vitro activity against CR-GNB have European Congress of Clinical Microbiology and Infectious Diseases been mainly tested in clinical trials, often including carbapenem- (ECCMID) conference proceedings for the years 2016–2018 were susceptible bacteria [3] . Other antibiotic classes (e.g. polymyxins, also reviewed. carbapenems, aminoglycosides) have been used against CR-GNB alone or in combination in observational studies [ 5 , 6 ]. The ra- tionale for combining two or more antibiotics against CR-GNB is 2.2. Selection criteria based on the possibility to achieve a higher rate of bacterial killing and to reduce the development of resistance. Despite promising re- Reports including data of bacterial killing curves from PK/PD sults highlighted by some studies, pooled data from meta-analyses and TK studies analysing combination therapies against CR-GNB have not shown clear evidence to support the use of antibiotic were included. Any type of study except reviews, editorials and combinations in the treatment of CR-GNB infections [5–8] . More- protocol papers was eligible for inclusion, and all antibiotic dosage over, results from well-designed clinical trials including infections schedules and frequencies were considered. Standard inoculum × 5 by MDR-GNB are lacking, limiting the evidence on the effectiveness sizes (4 10 CFU/mL or the nearest available value) were selected of older compared with novel compounds. [14]. Gold-standard broth microdilution was considered as the sus- The COHERENCE project (COmbination tHErapy to treat sepsis ceptibility testing method. due to carbapenem-Resistant bacteria in adult and pediatric popu- lations: EvideNCE and common practice) aimed to coherently and 2.3. Data extraction comprehensively analyse data on the use of antibiotic combina- tions for treating severe infections caused by CR-GNB. The project Two investigators (MC and DB) independently assessed each was commissioned by the Global Antibiotic Research and Develop- potentially relevant study for eligibility. Disagreements were re- ment Partnership (GARDP) and was intended to have a global per- solved by consultation with a third party (ER). If eligibility could spective from real-world clinical practice assessment of published not be determined, the full article was retrieved. evidence from in vitro and clinical studies. The present article re- A standardised data extraction method was used to record rel- ports data deriving from the meta-analyses performed on in vitro evant features of each study in a database, including study char- studies. acteristics (year of publication, country, type of in vitro combina- In vitro assessments of bacterial killing and antibiotic synergism tion testing), bacterial characteristics (type of bacterial strain and can be used to support the effectiveness of antibiotic combinations number of isolated tested, method of antimicrobial susceptibility against MDR-GNB [9]. A recent meta-analysis including 26 clinical testing and carbapenemase identification) and antimicrobial ther- cases from 11 reports showed that synergy-guided antibiotic com- apy (type and dose of antibiotic administration, treatment dura- bination therapy against MDR-GNB (54% P. aeruginosa, 27% Enter- tion). Bacterial isolates were considered resistant to carbapenems obacteriaceae and 19% A. baumannii) was significantly associated according to the local interpretive criteria. Unless otherwise speci- = with survival [odds ratio (OR) 0.44, 95% confidence interval (CI) fied, resistance was determined according to European Committee 0.20–0.98] [10]. on Antimicrobial Susceptibility Testing (EUCAST) 2019 breakpoints There are currently only two meta-analyses assessing the ef- [15] . Combination therapy was defined as the association of at least fectiveness of antibiotic combinations against CR GNB, including two or more antibiotics used to treat CR-GNB. in vitro studies up to March 2013 and July 2014, respectively Primary outcome assessed was in vitro synergy or antagonism [11,12]. These reviews, however, restricted the search only to se- > of combination therapy defined as a 2 log10 reduction or increase, lected pathogens and to a limited number of antibiotic dosages and respectively, in CFU/mL
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