**2.1 Resistance to fosfomycin**

Fosfomycin is receiving renewed worldwide attention as one of the most active agents for sparing carbapenems in extended-spectrum β-lactamase (ESBL)–producing isolates and for treatment of carbapeneme-resistant *Enterobacteriaceae* (CRE) in combination with colistin [18].

The mechanism of *E. coli* resistance to fosfomycin is through the production of *fos*A, a glutathione S-transferase that inactivates fosfomycin by the addition of a glutathione residue [19]**.** The mechanism of action of Fosfomycin is inhibition of the initial step in peptidoglycan synthesis by blocking *Mur*A irreversibly in both grampositive and -negative bacteria. It is imported through the inner membrane through the glycerol-3-phosphate (G3P) transporter GlpT and the glucose-6-phosphate (G6P) transporter UhpT. Reduced expression or mutations in *glpT* or *uhpT* genes are the most common causes leading to lowered susceptibility [20]. Another mechanism is the production of *fos*A, a glutathione *S*-transferase that inactivates fosfomycin by addition of a glutathione residue. This mechanism is particularly relevant because it is disseminative and frequently associated with ESBL-producing *Escherichia coli*. Plasmid-mediated *fosA3* and, less frequently, *fosA5* (formerly *fosKp96*), are mostly associated with *CTX*-M and co-harbored on a conjugative plasmid. The possible dissemination of this gene is worrisome because *fos*A*3* is generally surrounded by the IS*26* insertion sequence on a composite transposon borne by the IncFII conjugative plasmid, which is known to be a dissemination vector of resistance genes worldwide [21].
