Update on fosfomycin-modified genes in Enterobacteriaceae

Abstract

The long-used antibiotic fosfomycin has recently been re-evaluated as a potential regimen for treating extended-spectrum β-lactamases (ESBLs) and carbapenem-resistant Enterobacteriaceae (CRE). Fosfomycin is known for its robust bactericidal effect against ESBL-producing Enterobacteriaceae and CRE. However, fosfomycin-modified genes have been reported in transposon elements and conjugative plasmids, resulting in fosfomycin resistance in parts of East Asia. Here we review reports of fosfomycin-modified (fos) genes in Enterobacteriaceae and assess the efficacy of fosfomycin against multidrug-resistant Enterobacteriaceae infections. At least 10 kinds of fos genes have been identified in the past decade; of these, fosA (and fosA subtypes) and fosC2 are primarily found in Enterobacteriaceae. All fosA subtypes except fosA2 are found in plasmids and transposons, nearby insertion sequence elements, or integrons, indicating that mobilizing elements also play an important role in plasmid-mediated fos genes in Enterobacteriaceae. fosA3, which is prevalent in East Asia, has been transmitted (mostly by animals) within and across continents via IS26 mobile elements. The acquisition of multiple antibiotic resistance genes via plasmids and mobile elements has resulted in a need for combined treatments for Enterobacteriaceae cases. The combination of fosfomycin and carbapenem has been the focus of many in vitro studies, but there is a clear need for additional in vivo investigations involving pharmacokinetics.

Keywords: Combinational therapy; Fosfomycin-modified genes.