Carbapenemase type-dependent pharmacodynamic activity of minocycline-biapenem combination against carbapenemase-producing Klebsiella pneumoniae.

OBJECTIVES: The activity of antimicrobial combinations against carbapenemase-producing Klebsiella pneumoniae (CPKP) is likely to depend on the underlying resistance mechanism; however, this has not been systematically evaluated. We assessed the in vitro activity of minocycline in combination with biapenem across major carbapenemase types. METHODS: A total of 79 clinical CPKP isolates from Japan (n = 30) and Bangladesh (n = 49), including New Delhi metallo-β-lactamase (NDM) (n = 40), imipenemase (IMP) (n = 10), K. pneumoniae carbapenemase (KPC) (n = 10), oxacillinase-48-like (OXA-48-like) (n = 16) and NDM+OXA-48-like (n = 3), were analysed. MICs were determined by broth microdilution in accordance with CLSI guidelines. Combination activity was evaluated using checkerboard assays to calculate fractional inhibitory concentration indices (FICIs), and cumulative growth inhibition was analysed across concentration matrices. RESULTS: Single-agent MIC90 values of minocycline were 32, 16, 8, 32 and 32 mg/L for NDM, IMP, KPC, OXA-48-like and NDM+OXA-48-like isolates, respectively; corresponding biapenem MIC90 values were 32, 2, 256, 8 and 256 mg/L. Synergistic interactions (FICI ≤0.5) with the minocycline-biapenem combination were observed against 98% of NDM, 80% of IMP, 60% of KPC, 38% of OXA-48-like and 100% of NDM+OXA-48-like isolates. At minocycline 4 mg/L plus biapenem 1 mg/L, inhibition rates were 98%, 100%, 80% and 63% for NDM, IMP, KPC and OXA-48-like isolates, respectively. CONCLUSIONS: The activity of the minocycline-biapenem combination differs substantially according to carbapenemase type. These findings indicate that combination efficacy is not predictable from single-agent susceptibility alone and highlight the importance of pharmacodynamic evaluation when optimizing treatment strategies for CPKP.