AUTHOR=Zhang Jiayuan , Diao Shuo , Liu Yanfei , Wang Hongxiang , Liu Yuwei , Zhu Shixing , Feng Kun , Tang Xiaoqian , Oo Charles , Zhu Peijuan , Lv Zhihua , Yu Mingming , Sy Sherwin K. B. , Zhu Yuanqi 

TITLE=The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.1024702

DOI=10.3389/fmicb.2022.1024702

ISSN=1664-302X

ABSTRACT=The objective of this study was to evaluate whether sulbactam/meropenem/polymyxin-B combination could reduce or close the gap of mutant selection window (MSW) of individual antibiotic against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials alone or in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations (MPC) in 4 of the above 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the parameters for the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC)  were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h/2.5 mg/kg loading dose followed by 1.5 mg/kg q12h/3g q8h in patients with normal renal function.  Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies.  Future clinical confirmation is warranted.