Systematic Review and Meta-Analysis ofIn VitroSynergy of Polymyxins and Carbapenems

Abstract

ABSTRACTOur objective was to examine the evidence ofin vitrosynergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examiningin vitrointeractions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of ≤0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) forAcinetobacter baumannii, 44% (95% CI, 30 to 59%) forKlebsiella pneumoniae, and 50% (95% CI, 30 to 69%) forPseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. ForA. baumannii, meropenem was more synergistic than imipenem, whereas forP. aeruginosathe opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance developmentin vitro. The combination of a carbapenem with a polymyxin against GNB, especiallyA. baumannii, is supportedin vitroby high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.