Luigia Scudeller1, Elda Righi2, Margherita Chiamenti2, Damiano Bragantini2, Giulia Menchinelli3, Paolo Cattaneo2, Christian Giske4, Thomas Lodise5, Maurizio Sanguinetti3, Laura Jv Piddock6, Francois Franceschi6, Sally Ellis6, Elena Carrara2, Alessia Savoldi2, Evelina Tacconelli7. 1. Clinical Epidemiology and Biostatistics, IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Foundation, Milan, Italy. 2. Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, P.Le L.A. Scuro 10, 37134, Verona, Italy. 3. Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Roma, Italy; Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy. 4. Clinical Microbiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. 5. Albany College of Pharmacy and Health Sciences, Albany, New York, USA. 6. Global Antibiotic Research & Development Partnership (GARDP), 15 Chemin Louis-Dunant, Geneva, Switzerland. 7. Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, P.Le L.A. Scuro 10, 37134, Verona, Italy; Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Otfried Müller Straße 12, 72074 Tübingen, Germany;; German Centre for Infection Research (DZIF), Clinical Research Unit for healthcare associated infections, Tübingen, Germany.. Electronic address: evelina.tacconelli@univr.it.
Abstract
BACKGROUND: The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. METHODS: A systematic review and meta-analysis were performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining in vitro efficacy of antibiotic combinations against CR-GNB. Prospero registration number is CRD42019128104. Primary outcome was in vitro synergy (effect size, ES: high ≥ 0•75, moderate 0•35 < ES < 0•75, low ≤ 0•35, absent = 0). A network meta-analysis assessed bactericidal effect and regrowth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk of bias assessment. FINDINGS: Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin-rifampicin combination against Acinetobacter baumannii (ES 0•91, 95% CI 0•44 - 1•00), polymyxin-fosfomycin against Klebsiella pneumoniae (ES 1•00, 95% CI 0•66 - 1•00) and for imipenem and amikacin against Pseudomonas aeruginosa (ES 1•00, 95% CI 0•21 - 1•00). Compared to monotherapy, increased bactericidal activity and lower regrowth rates were reported for colistin-fosfomycin and polymyxin-rifampicin in K. pneumoniae and for imipenem-amikacin or tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. INTERPRETATION: Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and improve the armamentarium against CR bacteria.
BACKGROUND: The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. METHODS: A systematic review and meta-analysis were performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining in vitro efficacy of antibiotic combinations against CR-GNB. Prospero registration number is CRD42019128104. Primary outcome was in vitro synergy (effect size, ES: high ≥ 0•75, moderate 0•35 < ES < 0•75, low ≤ 0•35, absent = 0). A network meta-analysis assessed bactericidal effect and regrowth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk of bias assessment. FINDINGS: Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin-rifampicin combination against Acinetobacter baumannii (ES 0•91, 95% CI 0•44 - 1•00), polymyxin-fosfomycin against Klebsiella pneumoniae (ES 1•00, 95% CI 0•66 - 1•00) and for imipenem and amikacin against Pseudomonas aeruginosa (ES 1•00, 95% CI 0•21 - 1•00). Compared to monotherapy, increased bactericidal activity and lower regrowth rates were reported for colistin-fosfomycin and polymyxin-rifampicin in K. pneumoniae and for imipenem-amikacin or tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. INTERPRETATION: Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and improve the armamentarium against CR bacteria.
Authors: Minyon L Avent; Kate L McCarthy; Fekade B Sime; Saiyuri Naicker; Aaron J Heffernan; Steven C Wallis; David L Paterson; Jason A Roberts Journal: Microbiol Spectr Date: 2022-04-20