In vitro synergistic effects of mefloquine combined with other antimicrobial agents on carbapenem-resistant Enterobacterales

Purpose: Human health is seriously threatened by carbapenem-resistant Enterobacterales (CRE) due to the lack of effective treatment. The purpose of this study is to examine the efficacy of mefloquine (MEF) together with multiple drugs against 96 clinical CRE isolates including 94 Klebsiella pneumoniae carbapenemase (KPC)-producers or Metallo-β-lactamases (MBLs)-producers and 2 colistin antibiotic resistance enzyme MCR-1-producers. Methods: Using the broth microdilution method, MICs of MEF in combination with multiple antimicrobial agents, including colistin (COL), imipenem, aztreonam-avibactam (ATM-AVI), ceftazidime-avibactam (CAZ-AVI) for 96 CRE isolates were determined. Time-kill assays were implemented for 3 colistin-resistant (COL-R) isolates to analyze in vitro synergistic impacts of COL combined with MEF. Results: MEF alone showed little antibacterial activity with MICs greater than 128 µg/mL for all the 96 clinical CRE isolates. The addition of MEF (32 µg/mL) increased the sensitivity of almost all strains (98.9%, 95/96) to COL, reducing the MICs range of COL from ≤ 0.0625->8 µg/mL to ≤ 0.004-0.5 µg/mL. In particular, we observed that COL-MEF combination therapy had a significant effect on COL-R isolates, reducing their MICs from resistance to susceptibility. Moreover, the MIC₅₀ and MIC₉₀ of imipenem were both reduced by 2-fold in almost all strains with the addition of MEF (32 µg/mL), and in single MBL-producers, the MIC₅₀ (from 16 to 4 µg/mL) and MIC₉₀ (from 128 to 32 µg/mL) were both reduced by 4-fold. In addition, the MIC₅₀ and MIC₉₀ values of 96 CRE isolates of CAZ-AVI and ATM-AVI did not decrease significantly after combined with MEF (32 µg/mL). For the time-kill assays of 3 COL-R isolates, COL or MEF alone had almost no killing effect, however, when MEF was combined with COL, the isolates were completely killed within 4 h, and NDM-5-producing Klebsiella pneumoniae did not regenerate within 24 h. Conclusions: According to our study, COL-MEF may offer a potential alternative for treating CRE infections, especially COL-R Gram-negative bacterial infections.