Advancing the COMBINE pneumonia Model: PK/PD Evaluation of Meropenem and Levofloxacin Against Standardized K. Pneumoniae & P. aeruginosa Strains in Two Independent Laboratories
Abstract
Introduction The COMBINE consortium within the IMI AMR Accelerator has developed standardized preclinical infection models (1, 2) and a Preclinical Bacterial Strain Repository (3) to improve reproducibility and translational relevance of antimicrobial efficacy data. Building on this framework, we performed a comprehensive pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of meropenem and levofloxacin using clinically relevant exposures against COMBINE Klebsiella pneumoniae and Pseudomonas aeruginosa reference strains at two laboratories, Statens Serum Institut (SSI) and Paul Ehrlich Institut (PEI), using the COMBINE standardized protocol. Method Mouse infection and treatment studies were conducted in accordance with the COMBINE pneumonia model. In short, neutropenic female CD 1 mice were given an intranasal instillation of log phase bacteria resulting in a 2h baseline bacterial load of 6 7 log 10 CFU. Treatment was initiated two hours after inoculation and maintained q4h for meropenem ( MEM) or q8h for levofloxacin LFX) using a dose range projected to overlap with clinically relevant exposures. Endpoint was 24h after start of treatment. N=5 for all treated groups and controls. PK experiments in infected mice were conducted at separate laboratories using antibiotics formu lated for human use using identical protocol and sampling procedures. Bioanalysis was conducted at a central site. Population PK models were developed using plasma concentration time data. PK/PD…
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