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

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.

In vivoefficacy & resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam or meropenem using human-simulated regimens versusAcinetobacter baumannii

“…The free-sulbactam plasma concentration in the mice mimicked the plasma pharmacodynamic profile (free-time above MIC, free C max and free-AUC) achieved in healthy volunteers treated with 3 g IV q8h as a 4 h infusion using previously established pharmacokinetic parameters from mice and humans. 6 , 22 , 23 Once defined, the murine free plasma profile of the HSR was reassessed. Confirmatory pharmacokinetic studies after the administration of sulbactam (with ampicillin) at 10, 12 and 7.5 mg/kg at 0, 1.5 and 3 h, respectively (repeated ever 8 h), produced observed concentrations similar to the murine predicted and human-simulated profiles (Table S1 , Figure S1 , available as Supplementary data at JAC Online).…”

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

“…Its utility, however, is dependent upon achieving PD targets for sulbactam with the commercially available 2:1 formulation of ampicillin-sulbactam (2 g of ampicillin, 1 g of sulbactam). Like other β-lactams, the time free sulbactam concentrations are above the minimum inhibitory concentration ( f T > MIC) is the driver of efficacy in murine infection models [ 50 , 51 ]; however, drug exposures vary widely across critically ill patients [ 52 ]. Using a target of 60% f T > MIC for patients with a creatinine clearance ranging between 90 and 120 mL/minute, sulbactam doses of 1 g every 6 hours or 2 g every 8 hours as a 4-hour prolonged infusion are needed to achieve a more than 90% probability of target attainment when MICs are less than 4 mg/L [ 52 ].…”

“…These data provide support for an ampicillin-sulbactam regimen of 3 g every 4 hours when isolates test susceptible or intermediate to ampicillin-sulbactam. For isolates testing resistant (MIC ≥16 mg/L), however, ampicillin-sulbactam optimized regimens of 9 g every 8 hours administered as a 4-hour infusion are needed to achieve PK-PD targets [ 51 ]. The importance of sulbactam dose optimization cannot be understated given that most clinical isolates of CRAB test non-susceptible to ampicillin-sulbactam when applying Clinical and Laboratory Standards Institute (CLSI) interpretive criteria [ 19 ].…”

Treatment of Acinetobacter baumannii

“…The beta-lactamases produced by CRAB can lyse sulbactam, which is observed in vitro and reflected in the international surveillance systems, such as The Clinical and Laboratory Standards Institute (CLSI) [55]. But this was not observed in clinical trials, where sulbactam activity is intact even for MIC>16 mg/L, when given as 9 gram/day dosing over 4 hours infusion [56]. At this dose, sulbactam overcomes resistance by Oxa-23 beta-lactamases and has shown effectiveness more with meropenem [42, 57,58].…”