Semi-mechanistic modeling and simulation of sulbactam against Acinetobacter baumannii based on time-kill pharmacodynamics in vitro and population pharmacokinetics in humans

[Speaker] Yuta Yokoyama:1
[Co-author] Kazuro Ikawa:2, Kazuaki Matsumoto:3, Tomonori Nakamura:1, Norifumi Morikawa:2
1:Division of Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, Japan, 2:Department of Clinical Pharmacotherapy, Hiroshima University, Japan, 3:Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Japan

[BACKGROUND] We previously performed in vitro and in vivo pharmacokinetic/pharmacodynamic (PK/PD) analyses of sulbactam, a potent inhibitor of β-lactamases, to determine the sulbactam regimen against Acinetobacter baumannii infections1. The semi-mechanistic PK/PD model based on in vitro time-kill curve profile can be applied to evaluate antibacterial dosing regimens for other types of bacteria. However, PK/PD analysis using time-kill curve of sulbactam against A. baumannii has not yet been performed. Therefore, this study was to predict the clinical bacteriological efficacy to determine dosing regimens of sulbactam against A. baumannii using a semi-mechanistic PK/PD modeling and simulation.
[METHODS] The minimum inhibitory concentration (MIC) was determined by E-test, time-kill curves were performed using sulbactam concentrations of 0, 1, 4, and 16 × MIC. A semi-mechanistic PK/PD model consisting of drug-susceptible and -resistant compartments was developed to characterize the relationship between drug exposure and bacterial response for the time-kill curves. The semi-mechanistic PK/PD model was developed using NONMEM program and utilized to assess dosing regimens of sulbactam in patient populations with various degrees of creatinine clearance (CLcr).
[RESULTS] The MIC of sulbactam against A. baumannii ATTC 19606 and 3 clinical strains were 0.5, 2, 4, and 6 µg/mL, respectively. The time-kill curve for sulbactam showed that bacterial cell numbers decreased time-dependently. Based on the results of PK/PD modeling and simulation, the simulated profile of viable counts of A. baumannii estimated PK/PD breakpoints and times to eradication for sulbactam regimens. Against the A. baumannii with MIC of 4 µg/mL, regimens of 1 g three times daily, 1 g four times daily, 2 g four times daily and 3 g four times daily achieved ≥3 log10 CFU/mL reduction for patients with CLcr of 15, 30, 60 and 90 mL/min, respectively. These results of PK/PD breakpoints with variable dose and interval were similar to our previous results in patients for A. baumannii infections with impaired renal function1.
[CONCLUSION] The results of the semi-mechanistic PK/PD modeling and simulation are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A. baumannii.
1. Yokoyama Y et al., J Infect Chemother. 2015; 21: 284-289.
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