Is One Sample Enough? {beta}-lactam Target Attainment and Penetration into Epithelial Lining Fluid based on Multiple Bronchoalveolar Lavage Sampling Time Points in a Swine Pneumonia Model [Pharmacology]

Describing the disposition of antimicrobials agents at the site of infection is crucial to guide optimal dosing for investigational agents. For antibiotics in development for nosocomial pneumonia, concentrations are frequently determined in the epithelial lining fluid (ELF) of the lung from a bronchoscopy at a single time point. The influence of profiles constructed from a single ELF concentration point for each subject has never been reported. This study compares the pharmacokinetics of two β-lactams, ceftolozane and piperacillin, among different ELF sampling approaches using simulated human regimens in a swine pneumonia model. Plasma and ELF concentration-time profiles were characterized in two-compartment models by robustly sampled ELF concentrations and by random selection of one or two ELF concentrations from each swine. A 5,000 subject Monte Carlo simulation was performed for each model to define the ELF penetration, as described by the ratio area under the concentration curve (AUC) in ELF to free AUC in plasma (AUC_ELF/fAUC_plasma) and probability of target attainment (PTA). Given the intersubject variability of ELF penetrations observed, differences between models developed using robust versus one or two ELFs per swine were minimal for both drugs (maximum dispersion < 20%). Using a threshold exposure of 60% free time above the MIC, ceftolozane and piperacillin regimens achieved PTAs of ≥90% at MICs up to 4 and 1 µg/mL, respectively, among different ELF sampling strategies. These models suggest that ELF models constructed from sparse ELF time points result in similar exposure estimates to robustly sampled ELF profiles.

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