Meropenem and fosfomycin against K. pneumoniae: towards a combination breakpoint using a pharmacometric approach.

OBJECTIVES To quantify the antibacterial effects and pharmacodynamic interactions of meropenem and fosfomycin combinations against multidrug-resistant (MDR) Klebsiella pneumoniae through pharmacometric analysis, and to support an evidence-based rationale for combined clinical breakpoints.

METHODS In vitro data from 12 clinical Klebsiella pneumoniae strains (carrying genes such as KPC, NDM, OXA-48, VIM, CTX-M, SHV, etc.), generated in dynamic in vitro infection model experiments mimicking human pharmacokinetics of meropenem and fosfomycin, were analysed using pharmacodynamic modelling. A nonlinear mixed-effects model, incorporating MICs as covariates, was developed. Simulations using published population pharmacokinetic models evaluated 9 mono and combination dosing regimens (IV meropenem 2 g q8h; IV fosfomycin 6-24 g total daily dose q6h, q8h, or continuous infusion) and calculated probability of target attainment (PTA) (for bacteriostasis, 1-log, and 2-log killing after 24 h) for each dosing regimen across wide meropenem and fosfomycin MICs.

RESULTS Meropenem and fosfomycin monotherapies achieved PTA ≥90% only for low MICs (≤4 mg/L for meropenem, ≤4 mg/L for fosfomycin). In contrast, combination therapy enabled PTA ≥90% for bacteriostasis at MICs up to 32 mg/L (meropenem) and 512 mg/L (fosfomycin), and for 1-log killing at 32 mg/L | 256 mg/L, using low-dose regimens (meropenem 2 g + fosfomycin 2 g q8h). For high-dose combinations (meropenem 2 g + fosfomycin 8 g q8h), PTA ≥90% was achieved for 1-log and 2-log killing at even higher MICs. In total, the model captured time-kill dynamics for all 12 strains and 9 distinct drug regimens.

CONCLUSIONS This study demonstrates that meropenem-fosfomycin combination therapy produces robust synergy against MDR Klebsiella pneumoniae strains, and expands attainable clinical breakpoints compared to monotherapy. These findings provide evidence for reintroducing a fosfomycin breakpoint in combination with meropenem and supports further clinical validation of the proposed dosing regimens in patients with severe infections.