In vitro evaluation of double-carbapenem combinations against OXA-48-producing Klebsiella pneumoniae isolates using time-kill studies

Purpose. The aim of this study was to evaluate the in vitro activity of double-carbapenem combinations against OXA-48-producing Klebsiella pneumoniae clinical isolates. Methodology. Double combinations of ertapenem, meropenem and imipenem were evaluated for synergy and bactericidal activity using the time-kill methodology. All antibiotics were tested at 10 mg l(-1) and at a sub-inhibitory concentration of 0.5x minimum inhibitory concentration (MIC) for isolates with a carbapenem MIC <= 8 mg l(-1). Synergy was defined as a >= 2log(10) colony-forming units (c.f.u.) ml(-1) decrease of viable colonies at 24 h compared to the most active carbapenem alone. Results. Ten distinct K. pneumoniae clinical isolates were tested. All carried bla(OXA)(-)(48) and bla(CTX-M-15), and exhibited an MIC range of 64-128, 4-32 and 1-32 mg l(-1) for ertapenem, meropenem and imipenem, respectively. Out of 48 isolate-combinations, synergy was observed in 9 (18.8 %) and cidal activity was observed in 13 (27.1 %). In vitro synergistic activity was noted for 5 out of 29 (17.2 %) ertapenem-, 6 out of 29 (20.7 %) meropenem- and 7 out of 38 (18.4 %) imipenem-containing combinations. No combination exhibited antagonism. Bactericidal activity was observed in 7 (24.1 %) ertapenem-, 8 (27.6 %) meropenem- and 11 (28.9 %) imipenem-containing combinations. Among the sub-inhibitory concentration combinations, three (15 %) ertapenem-, four (20 %) meropenem- and three (15 %) imipenem-containing ones showed synergistic interaction. Conclusion. Dual combinations of carbapenems, including those containing sub-inhibitory concentrations of antibiotics, were synergistic against multidrug-resistant (MDR) and extensively drug-resistant (XDR) K. pneumoniae isolates harbouring bla(OXA-48).