Abstract / Summary
Abstract Background To study a pharmacokinetics model of sulbactam and optimal dosing regimens to achieve a time above a minimal inhibitory concentration (fT > MIC) of 50%, 75%, and 100% in patients with Carbapenem-Resistant Acinetobacter baumannii (CRAB) infection. Methods This prospective pharmacokinetic study was conducted on patients with pneumonia or bacteremia due to CRAB infection at Phramongkutklao Hospital in Bangkok, Thailand, from January 2021 to May 2023. The sulbactam administration protocol involved a daily dose of 9–12 g, adjusted according to renal function. Blood samples were also collected from the patients at different time points over a period of 7 days. Pharmacokinetic modeling was performed using NONMEM version 7.5.1, and a Monte Carlo simulation with Crystal Ball was used to determine the optimal sulbactam dose. Results Overall, the 55 patients had 268 points of sulbactam concentration. The final model was a two-compartment model with first-order elimination and an objective function value (OFV) of 2377. Additionally, the estimated typical values of clearance (CL) were 3.17 L/h, the volume of the central compartment (V 1 ) was 14.98 L, the volume of the peripheral compartment (V 2 ) was 9.21 L, and the intercompartment clearance (Q) was 4.84 L/h. Creatinine clearance (CrCL) was the only significant covariate affecting apparent clearance and central compartment volume. A daily dose of 12 g was sufficient in patients with normal renal function. For pathogens with an MIC of 32 µg/mL, 4 g q8h extended infusion over 4 h achieved PTA > 80% for the 50% fT > MIC target in patients with CrCL 61–120 mL/min, while a 12 g/day continuous infusion achieved PTA > 90% for all fT > MIC targets. Conclusion This study established a two-compartment model for sulbactam in CRAB infections, highlighting creatinine clearance as a key factor affecting clearance and central volume. Monte Carlo simulations indicated that higher doses, up to 12 g/day adjusted for renal function, may be necessary to meet pharmacodynamic targets in critically ill patients. These results offer a dosing framework to optimize the treatment of resistant A. baumannii infections when therapeutic drug monitoring is unavailable. Clinical trial number Not applicable.