PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC.

Background: Carbapenem-resistant bacteria pose a threat to public health. Characterizing the pharmacokinetics-pharmacodynamics (PKPD) of meropenem longitudinally in vivo against resistant bacteria could provide valuable information for development and translation of carbapenem-based therapies.

Objectives: To assess the time course of meropenem effects in vivo against strains with high MIC to predict PK/PD indices and expected efficacy in patients using a modelling approach.

Methods: A PKPD model was built on longitudinal bacterial count data to describe meropenem effects against six Escherichia coli and Klebsiella pneumoniae strains (MIC values 32-128 mg/L) in a 24h mouse thigh infection model. The model was used to derive PK/PD indices from simulated studies in mice and to predict the efficacy of different infusion durations with high-dose meropenem (2 g q8h/q12h for normal/reduced kidney function) in patients.

Results: Data from 592 mice were available for model development. The estimated meropenem concentration-dependent killing rate was not associated with differences in MIC. The fraction of time that unbound concentrations exceeded EC₅₀ (fT_>EC50, EC₅₀=1.01 mg/L) showed higher correlations than fT_>MIC. For all investigated strains, bacteriostasis at 24h was predicted for prolonged infusions of high-dose meropenem monotherapy in >90% of patients.

Conclusions: The developed PKPD model successfully described bacterial growth and meropenem killing over time in the thigh infection model. For the investigated strains the MIC, determined in vitro, or MIC-based PK/PD indices, did not predict in vivo response. Simulations suggested prolonged infusions of high-dose meropenem to be efficacious in patients infected by the studied strains.