Evaluation of the in vitro synergy of polymyxin B-based combinations against polymyxin B -resistant gram-negative bacilli

Abstract

Objectives: This study aimed to evaluate the in vitro synergy of polymyxin B (PMB) combined with 11 other antibiotics against PMB-resistant gram-negative bacilli (GNBs).

Methods: Thirty-six clinical isolates of PMB-resistant GNBs were used. The MICs of all the antimicrobials tested were determined by the broth microdilution method and the checkerboard assay method. Carbapenemase genes were detected by PCR. In vitro synergy results were interpreted using the fractional inhibitory concentration index (FICI). Four combinations that showed positive interactions were subsequently evaluated in a time-kill study.

Results: Among the 36 strains, 15 harboured the carbapenemase gene, and blaKPC was the predominant carbapenemase. The resistance rates of the 36 strains to tigecycline, meropenem, ceftazidime, and cefepime were 100% (36/36), 97% (35/36), 94% (34/36), and 97% (35/36), respectively. For Enterobacteriaceae and Pseudomonas aeruginosa, the resistance rates to aztreonam and ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L) were 95% (19/20) and 25% (5/20), respectively. The PMB-based combinations exhibited synergism to a certain degree. The most synergistic combinations were PMB plus meropenem-avibactam (avibactam at a fixed concentration of 4 mg/L) and PMB plus tigecycline, with the synergy rates of 83.3% and 80.6%, respectively. Compared to tazobactam- and sulbactam-based β-lactam-β-lactamase inhibitor combinations (BL-BLIs), PMB with avibactam-based BL-BLIs exhibited a better synergistic effect. For Acinetobacter baumannii, PMB plus sulbactam exhibited a strong synergism with a 2∼7-fold MIC reduction of PMB. In time-kill studies, the highest degree of synergism was observed for PMB with cefepime-avibactam on all the tested isolates. For isolates with low-level resistance to PMB, PMB combined with other partner antimicrobials also showed a certain degree of synergism.

Conclusions: PMB in combination with tigecycline and avibactam-based BL-BLIs could be a potential clinical option for clinical treatment of infections caused by PMB -resistant GNBs.

Keywords: Combination; Gram-negative bacilli; Polymyxin B; Resistant; Synergy.