In Vitro Activity of Carbapenems Alone and in Combination With Amikacin Against KPC-Producing Klebsiella Pneumoniae

BACKGROUND Although carbapenems are the primary treatment strategy for invasive infections caused by ESBL bacteria, case reports of these pathogens with reduced carbapenem susceptibility have emerged. One potential treatment modality is to optimize the use of anti-infectives with combination therapy. We evaluated the activity of carbapenems alone and in combination with amikacin against these clinical isolates. METHODS Time-kill studies evaluated ertapenem (ETP), imipenem (IPM), meropenem (MEM), and amikacin (AMK) against 4 non-duplicate clinical isolates of Klebsiella pneumoniae that were resistant to these antibiotics. Synergy was defined as ≥ 2 log(10) decrease CFU/mL at 24 h for the combination when compared with the most active single agent of the combination, plus the number of surviving organisms for the antimicrobial combination was ≥ 2 log(10) less than the initial inoculum. RESULTS All isolates carried bla(KPC-3) and genes encoding TEM-1 and SHV-11/-36; and were resistant to carbapenems (MIC at ≥ 8 g/mL for ETP, MEM and IPM) and AMK (MIC 32 g/mL) using broth microdilution. As monotherapy, none of the carbapenems nor AMK achieved and maintained bactericidal activity defined as ≥ 99.9% or > 3 log(10) killing. From time-kill studies, synergy was demonstrated for MEM and IPM in combination with AMK over the entire 24 h against all isolates. In addition, MEM and IPM with AMK achieved and maintained bactericidal activity (≥ 99.9% killing) at 24 h against 2 and 1 isolate(s), respectively. Bactericidal activity and synergy were not observed for ETP combinations. CONCLUSIONS The combination of MEM or IPM with AMK displayed synergistic activity against KPC-3-producing K. pneumoniae isolates. KEYWORDS ESBL; Klebsiella pneumoniae; KPC; Carbapenemase; Time-kill; Meropenem; Amikacin; Imipenem; Ertapenem; Carbapenem; Synergy.