Significance and Impact of the Study: This study demonstrated for the first time that fosfomycin combined with rifampin showed strong synergistic effects against Pseudomonas aeruginosa, with 100% synergistic rates. Furthermore, we confirmed the antibiofilm activity of fosfomycin combined with rifampin against carbapenem-resistant P. aeruginosa. This study provides new insights that fosfomycin + rifampin may be a promising option for clinical treatment.

Abstract

The increasing prevalence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains in the hospital setting represents an emerging challenge to clinical treatment for Pseudomonas aeruginosa (PA) infections, as the range of therapeutic agents active against these pathogens becomes increasingly constrained. This study demonstrated for the first time that fosfomycin (FOS) combined with rifampin (RIF) showed strong synergistic effects against CRPA and carbapenem-susceptible PA, with 100% synergistic rates. Additionally, the time-killing curve further proves the dynamic antibacterial activity of FOS + RIF against CRPA. Further experiments determined that antibacterial mechanisms of FOS + RIF might be inhibition of biofilm formation and eradication of preformed biofilm. The results of the inhibition biofilm formation assay demonstrated that RIF and FOS at 1/8MIC, 1/16MIC and 1/32MIC have better inhibitory effects on CRPA biofilm formation VS FOS alone (96, 90 and 78% vs 29, 24 and 22%) (P < 0·0001) or RIF alone (96, 90 and 78% vs 86, 67 and 29%) (P < 0·01). The rates of eradicating preformed biofilm with combination therapy at 1/2MIC, 1/4MIC and 1/8MIC of both antibiotics, increased 46, 61 and 55% compared with FOS alone (P < 0·001) and 37, 33 and 46% compared with RIF alone (P < 0·01). This finding will provide new insights into the treatment of bacterial infections caused by CRPA, which can be further explored in clinical practice.