Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii

Abstract

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant <i>Acinetobacter baumannii</i> at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit <i>in vitro</i> synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of <i>A. baumannii</i> harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (<i>f</i>T_MSW) and the fraction of time that the free drug concentration was above the MPC (<i>f</i>T_>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant <i>A. baumannii</i> and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize <i>f</i>T_MSW and <i>f</i>T_>MPC from drug exposures in the blood. Mean <i>f</i>T_>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean <i>f</i>T_MSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.