1652. Sulbactam against Acinetobacter baumannii Pneumonia: Pharmacokinetic/Pharmacodynamic Appraisal of Current Dosing Recommendations

Abstract

Abstract Background Sulbactam (SUL), available in the USA as ampicillin-sulbactam, is a first line treatment for Acinetobacter baumannii infections. SUL is bactericidal against A. baumannii through affinity to penicillin-binding proteins with no synergy upon ampicillin addition. Despite its wide use, SUL dosing has not been standardized for management of A. baumannii infections. Herein, we examined SUL pharmacokinetic/pharmacodynamic (PK/PD) targets against A. baumannii in a neutropenic murine pneumonia model followed by estimation of the probability of target attainment (PTA) across a range of clinical SUL doses. Methods Eight clinical A. baumannii isolates (SUL MICs 1–16 mg/L) were tested. Mice were inoculated intranasally with 107 colony forming units (CFU)/mL bacterial suspensions. Two hours post inoculation, escalating SUL doses (1–200 mg/kg) were administered q8h for 24 h as ampicillin-sulbactam, while control mice received saline. Efficacy was measured as the change in log10 CFU/ lungs at 24 h compared with 0 h controls. PK and ex vivo protein binding of SUL were assessed in infected mice to determine the free systemic exposures of the regimens utilized. The percentages of dosing interval in which the free plasma concentration exceeded the SUL MIC (%fT > MIC) required to achieve 1- and 2-log kill against each isolate were estimated using Hill-equation. Monte Carlo simulations were performed to determine PTA for these endpoints with various clinically-utilized SUL dosing regimens. Mean and standard deviation values for SUL PK parameters were derived from patients with nosocomial pneumonia due to A. baumannii. Results Median (Interquartile range, IQR) %fT > MIC needed for 1-log and 2-log kill at 24 h were 27.36 (19.94 – 35.11) and 48.36 (38.18 – 58.01), respectively. The corresponding PTA following the maximum FDA-approved SUL dose for pneumonia (1g q6h, 0.5 h infusion) and three off-label doses are reported in the table. Conclusion Currently approved dose of SUL for pneumonia (1g q6h, 0.5 h infusion) provides effective exposure against A. baumannii at the current FDA/CLSI susceptibility breakpoint (SUL MIC ≤ 4 mg/L). Higher and/or more frequent SUL dosing provides additional coverage with 3 g q8h extended infusion further enhancing the PK/PD exposure against isolates with SUL MICs up to 16 mg/L. Disclosures Yasmeen Abouelhassan, PhD, Pfizer: spouse salary Joseph L. Kuti, PharmD, Abbvie: Honoraria|bioMeriuex: Advisor/Consultant|bioMeriuex: Grant/Research Support|Contrafect: Grant/Research Support|Entasis: Grant/Research Support|Merck and Co: Grant/Research Support|Roche Diagnostics: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Summit: Grant/Research Support David P. Nicolau, PharmD, Shionogi: Grant/Research Support Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support.