Meropenem and fosfomycin against Klebsiella 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 Klebsiella pneumoniae through pharmacometric analysis, and to support an evidence-based rationale for combined clinical breakpoints. METHODS: In vitro data from 12 clinical K. 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 nine mono and combination dosing regimens (intravenous [i.v.] meropenem 2 g every 8 hours; i.v. fosfomycin 6-24 g total daily dose every 6 hours, every 8 hours, or continuous infusion) and calculated probability of target attainment (PTA) (for bacteriostasis, 1-log, and 2-log killing after 24 hours) 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 and 256 mg/L, using low-dose regimens (meropenem 2 g + fosfomycin 2 g every 8 hours). For high-dose combinations (meropenem 2 g + fosfomycin 8 g every 8 hours), 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 multidrug-resistant K. pneumoniae strains, and expands attainable clinical breakpoints compared with monotherapy. These findings provide evidence for reintroducing a fosfomycin breakpoint in combination with meropenem and support further clinical validation of the proposed dosing regimens in patients with severe infections.