Emergence of Plasmid-Mediated Fosfomycin-Resistance Genes among <i>Escherichia coli</i> Isolates, France

Benzerara, Yahia; Gallah, Salah; Hommeril, Baptiste; Genel, Nathalie; Decré, Dominique; Rottman, Martin; Arlet, Guillaume

doi:10.3201/eid2309.170560

Cited by 41 publications

(44 citation statements)

References 13 publications

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“…In 2010, this enzyme was observed in an E. coli isolate in the USA [13], then in France [15] and in Switzerland (this study) in 2012, highlighting its worldwide dissemination. Intriguingly, similar to one isolate from 2013 carrying the fosA3 gene detected in our study, another FosA3-producing ST69 E. coli had been recovered in France in 2014, suggesting a clonal relationship [15].…”

Section: Discussionmentioning

confidence: 63%

“…The FosA3 variant is the most relevant since it has been extensively reported in humans and animals, mainly in Asia but also in Europe and the USA [12][13][14]. The FosA3 encoding gene is located onto conjugative plasmids coencoding ESBLs of the CTX-M-type [15]. Hence, selective pressure with fosfomycin and/or broad-spectrum cephalosporins may lead to acquisition of those plasmid and consequently to co-resistance to those drugs.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence of fosfomycin resistance among ESBL-producing Escherichia coli isolates in the community, Switzerland

Mueller

Cimen

Poirel

et al. 2019

Eur J Clin Microbiol Infect Dis

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Our aim was to evaluate the prevalence of fosfomycin-resistant strains among ESBL-producing Escherichia coli isolates recovered from community patients in Switzerland. A total of 1225 ESBL-producing E. coli isolates were collected between 2012 and 2013 from a private and community laboratory. Fosfomycin resistance was assessed by using the novel rapid fosfomycin/E. coli NP test and agar dilution method. Resistant isolates were further investigated for acquired resistance genes fosA1-7 by PCR and sequencing. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed to evaluate the clonal relationship among fosA3-carrying isolates. Out of the 1225 ESBL-producing E. coli isolates analyzed in this study, 1208 were fosfomycin susceptible while 17 were fosfomycin resistant. No discrepancy was observed between the rapid fosfomycin/ E. coli NP test and the agar dilution method taken as the gold standard. Five out of the 17 resistant isolates carried a fosA-like gene. No clonal relationship was observed among those isolates. Here, the prevalence of fosfomycin resistance among ESBLproducing E. coli isolates in the community is reported for the first time in Switzerland, being ca. 1.4%. Among the five isolates carrying a fosA gene, four encoded the FosA3 enzyme, being the most prevalent fosfomycin-resistant determinant. An excellent correlation was observed between minimum inhibitory concentration-based susceptibility categorization and results of the rapid fosfomycin/E. coli NP test, further indicating the excellent sensitivity and specificity of this recently developed rapid test whose results are obtained in less than 2 h.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Prevalence of fosfomycin resistance among ESBL-producing Escherichia coli isolates in the community, Switzerland

Mueller

Cimen

Poirel

et al. 2019

Eur J Clin Microbiol Infect Dis

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“…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]. Note that fosA3 has been frequently associated with IS26-type composite transposons located on conjugative plasmids that co-harbor bla CTX-M genes [13].…”

Section: Enzymatic Drug Inactivationmentioning

confidence: 99%

How is Fosfomycin Resistance Developed in Escherichia Coli ?

Cattoir

Guérin

2018

Future Microbiol.

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Discovered in 1969, fosfomycin is a phosphonic acid-derived bactericidal antibiotic that has been used in clinics for greater than 40 years, especially for the single-dose (3 g) oral therapy of uncomplicated lower urinary tract infections (UTIs) [1]. It exhibits a broad spectrum of antimicrobial activity that comprises Gram-positive cocci, Enterobacteriaceae (incl. Escherichia coli) and Pseudomonas aeruginosa [1]. Due to the worldwide spread of antimicrobial resistance and the paucity of novel drugs in the development pipeline, there has been a renewed interest of fosfomycin as an alternative option for the treatment of infections caused by multidrug-resistant Gram-negative bacilli [1]. Mechanism of action Fosfomycin acts by inhibiting the initial enzymatic step of peptidoglycan biosynthesis, which takes place into the cytoplasm [2]. As a phosphoenolpyruvate (PEP) analog, it covalently binds to the key residue Cys115 in the active site of the UDP-N-acetylglucosamine-3-O-enolpyruvyl transferase (named MurA), preventing the formation of UDP-N-acetylglucosamine-3-O-enolpyruvate from UDP-N-acetylglucosamine and PEP [2]. In E. coli, fosfomycin actively enters the cell via two nutrient transporters belonging to the major facilitator superfamily: the glycerol-3-phosphate transporter (GlpT) that is constitutively expressed and the hexose-6-phosphate transporter (UhpT) that is induced by extracellular glucose-6-phosphate (G6P) [3]. Moreover, the full expression of both glpT and uhpT genes requires high levels of cyclic AMP (cAMP) along its receptor protein complex (CRP) [3]. In Enterobacteriaceae, cAMP synthesis depends on the activity of the adenyl cyclase (CyaA), while intracellular cAMP levels are also regulated by the phosphotransferase enzyme PstI, which is a component of the PEP sugar phosphotransferase transport system [3]. Furthermore, the expression of uhpT is locally controlled by uhpA, uhpB and uhpC genes [3]. The integral membrane protein UhpC detects the extracellular signal (i.e., G6P) and activates UhpB by phosphorylation. UhpB is a sensor histidine kinase that is part of the two-component regulatory system UhpAB. UhpA is the cognate DNA-binding response regulator that binds to the uhpT promoter. Then, activation of UhpB leads to the phosphorylation of UhpA that binds to the uhpT promoter and then induces uhpT transcription. Antimicrobial susceptibility testing Concerning antimicrobial susceptibility testing, MICs of fosfomycin should be determined using the agar dilution reference method on Mueller-Hinton supplemented with 25 mg/l of G6P [2]. According to EUCAST, an isolate of E. coli is categorized as susceptible or as resistant with an MIC of ≤32 and >32 mg/l, respectively. Note that CLSI breakpoints for E. coli are different: ≤64 mg/l for susceptibility and ≥256 mg/l for resistance. Susceptibility testing for fosfomycin can also be performed using the disk diffusion method knowing that squatter inner colonies

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“…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).…”

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confidence: 99%

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

Poirel

Vuillemin

Kieffer

et al. 2019

Antimicrob Agents Chemother

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A plasmid-located fosfomycin resistance gene, fosA8, was identified from a CTX-M-15-producing Escherichia coli isolate recovered from urine. Identification of this gene was obtained by whole-genome sequencing. It encoded FosA8, which shares 79% and 78% amino acid identity with the most closely related FosA2 and FosA1 enzymes, respectively. The fosA8 gene was located on a transferable 50-kb plasmid of IncN type encoding high-level resistance to fosfomycin. In silico analysis and cloning experiments identified fosA8 analogues (99% identity) in the genome of Leclercia decarboxylata, which is an enterobacterial species with natural resistance to fosfomycin. This finding adds L. decarboxylata to the list of enterobacterial species that are a reservoir of fosA-like genes which have been captured from the chromosome of a progenitor and are then acquired by E. coli.

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Emergence of Plasmid-Mediated Fosfomycin-Resistance Genes among Escherichia coli Isolates, France

Cited by 41 publications

References 13 publications

Prevalence of fosfomycin resistance among ESBL-producing Escherichia coli isolates in the community, Switzerland

Prevalence of fosfomycin resistance among ESBL-producing Escherichia coli isolates in the community, Switzerland

How is Fosfomycin Resistance Developed in Escherichia Coli ?

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

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