Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli

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 ≥ 075, moderate 035 < ES < 075, low ≤ 035, 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 091, 95% CI 044 - 100), polymyxin-fosfomycin against Klebsiella pneumoniae (ES 100, 95% CI 066 - 100) and for imipenem and amikacin against Pseudomonas aeruginosa (ES 100, 95% CI 021 - 100). 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.