Intravenous Ampicillin/Sulbactam in Critically Ill Dogs has Variable Pharmacokinetics

Abstract

Achieving therapeutic plasma concentrations is essential for effective antimicrobial drug (AMD) treatment. Critical illness alters drug distribution and clearance, potentially impacting AMD effectiveness. We conducted a prospective observational study in 25 critically ill dogs to evaluate the pharmacokinetics (PK) of intravenous (IV) ampicillin/sulbactam and achievement of the efficacy target of ≥ 50% of the dosing interval with unbound plasma drug concentrations above the minimum inhibitory concentration (fT > MIC). All dogs received IV ampicillin/sulbactam from a commercial formulation at a dosage of 20 mg/kg ampicillin/10 mg/kg sulbactam. Plasma concentrations were measured using liquid chromatography–mass spectrometry. PK modeling determined best-fit compartmental models, and Monte Carlo simulations evaluated the probability of target attainment for bacterial MICs. A one-compartment model best described ampicillin PK, while a two-compartment model fit sulbactam. Monte Carlo simulations indicated a 90% probability that ampicillin at 20 mg/kg IV q8 h would achieve the Clinical and Laboratory Standards Institute (CLSI) veterinary breakpoint of 0.25 μg/mL for > 50% of the dosing interval. There was only a 10% probability of achieving the human breakpoint of 8 μg/mL. At 0.25 μg/mL, most Enterobacterales isolates would be resistant. The ampicillin/sulbactam dosage tested meets veterinary CLSI standards for ampicillin but might not effectively treat Enterobacterales infections in critically ill dogs.