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.

How is Fosfomycin Resistance Developed in Escherichia Coli ?

“…Note that fosA3 has been frequently associated with IS26-type composite transposons located on conjugative plasmids that co-harbor bla CTX-M genes [13]. A co-occurrence of fosA3 with genes conferring resistance to other antibiotic classes, such as β-lactams, aminoglycosides, fluoroquinolones, sulphonamides or tetracyclines has also been reported [1,13]. Finally, the fosC2 gene has been found in plasmid-borne class 1 integrons [13].…”

“…However, it has also emerged in other parts of the World, such as in the USA and in Europe [14,15]. Note that fosA3 has been frequently associated with IS26-type composite transposons located on conjugative plasmids that co-harbor bla CTX-M genes [13]. A co-occurrence of fosA3 with genes conferring resistance to other antibiotic classes, such as β-lactams, aminoglycosides, fluoroquinolones, sulphonamides or tetracyclines has also been reported [1,13].…”

“…In Enterobacteriaceae, these are glutathione S-transferase enzymes (FosA and its subtypes; FosC2) that are responsible for fosfomycin resistance among clinical isolates. Out of the six FosA subtypes (FosA, FosA2, FosA3, FosA4, FosA5 and FosA6), FosA3 is by far the most frequently found variant in E. coli [12,13]. Initially identified from Japan in 2006, it has mainly been reported from Asian countries, especially in PR China [13].…”

“…Out of the six FosA subtypes (FosA, FosA2, FosA3, FosA4, FosA5 and FosA6), FosA3 is by far the most frequently found variant in E. coli [12,13]. Initially identified from Japan in 2006, it has mainly been reported from Asian countries, especially in PR China [13]. However, it has also emerged in other parts of the World, such as in the USA and in Europe [14,15].…”

Identification of FosA8, a Plasmid-Encoded Fosfomycin Resistance Determinant from Escherichia coli, and Its Origin in Leclercia adecarboxylata

“…Among the seven known FosA variants, four (FosA3, FosA4, FosA5, and FosA6) have been identified as acquired resistance determinants in E. coli isolates (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The FosA3 variant is the most widespread fosfomycin resistance determinant in E. coli, reported in human and animal isolates from Asia, Europe, and the United States (6, 7, 16-19).…”