In vitro synergy of β-lactam combinations against KPC-producing Klebsiella pneumoniae strains

Background: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other beta-lactams and beta-lactamase inhibitors to provide synergistic activity with carbapenems is unclear. Objectives: This study sought to investigate the in vitro synergistic potential of other beta-lactam/beta-lactamase combinations with meropenem against KPC producers. Methods: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by >= 2 log(10) at 24h as compared with the single most active agent. Results: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a >= 4 log(10) cfu/mL reduction at 24h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations. Conclusions: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic.