Population Pharmacokinetics and Dosing Simulations of Ampicillin and Sulbactam in Hospitalised Adult Patients.

Abstract

The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., <60mL/min). This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure. Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics®. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥90% and ≥95% was used to define both optimal PTA and FTA, respectively. The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6L and 15.36L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs≤8 and ≤4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae. Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.