In Vitro Pharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacae and Klebsiella aerogenes

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 9
• Main Authors: Lim, Tze-Peng, Teo, Jocelyn Qi-Min, Goh, Audrey Wei-Ling, Tan, Si-Xuan, Koh, Tse-Hsien, Lee, Winnie Hui-Ling, Cai, Yiying, Tan, Thuan-Tong, Kwa, Andrea Lay-Hoon
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.08.2020
• Subjects: Experimental Therapeutics; Klebsiella aerogenes; Enterobacter cloacae; carbapenem resistance; fosfomycin; pharmacodynamics; CRE
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00536-20

The increase of carbapenem-resistant (CRE) and lack of therapeutic options due to the scarcity of new antibiotics has sparked interest toward the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the pharmacodynamics of fosfomycin against carbapenem-resistant and Time-kill studies and population analysis profiles were performed with eight clinical CRE isolates, which were exposed to fosfomycin concentrations ranging from 0.25 to 2,048 mg/liter. The 24-h mean killing effect was characterized by an inhibitory sigmoid maximum effect ( ) model. Whole-genome sequencing was performed to elucidate known fosfomycin resistance mechanisms. Fosfomycin MICs ranged from 0.5 to 64 mg/liter. The isolates harbored a variety of carbapenemase genes including , , and Five out of eight isolates harbored the gene, while none harbored the recently discovered -like gene. Heteroresistant subpopulations were detected in all isolates, with two out of eight isolates harboring heteroresistant subpopulations at up to 2,048 mg/liter. In time-kill studies, fosfomycin exhibited bactericidal activity at 2 to 4 h at several fosfomycin concentrations (one isolate at ≥16 mg/liter, two at ≥32 mg/liter, two at ≥64 mg/liter, two at ≥128 mg/liter, and one at ≥512 mg/liter). At 24 h, bactericidal activity was only observed in two isolates (MICs, 0.5 and 4 mg/liter) at 2,048 mg/liter. From the model, no significant bacterial killing was observed beyond 500 mg/liter. Our findings suggest that the use of fosfomycin monotherapy may be limited against CRE due to heteroresistance and rapid bacterial regrowth. Further optimization of intravenous fosfomycin dosing regimens is required to increase efficacy against such infections.