AUTHOR=Zhu Shixing , Song Chu , Zhang Jiayuan , Diao Shuo , Heinrichs Tobias M. , Martins Frederico S. , Lv Zhihua , Zhu Yuanqi , Yu Mingming , Sy Sherwin K. B. 

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

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.1013939

DOI=10.3389/fmicb.2022.1013939

ISSN=1664-302X

ABSTRACT=<p>Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant <italic>Acinetobacter baumannii</italic> at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit <italic>in vitro</italic> synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of <italic>A. baumannii</italic> 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 (<italic>f</italic>T<sub>MSW</sub>) and the fraction of time that the free drug concentration was above the MPC (<italic>f</italic>T<sub>&gt;MPC</sub>) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant <italic>A. baumannii</italic> and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize <italic>f</italic>T<sub>MSW</sub> and <italic>f</italic>T<sub>&gt;MPC</sub> from drug exposures in the blood. Mean <italic>f</italic>T<sub>&gt;MPC</sub> were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean <italic>f</italic>T<sub>MSW</sub> was reduced to &lt;30% and &lt;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.</p>