Activity of the combination of colistin and fosfomycin against NDM-1-producing Escherichia coli with variable levels of susceptibility to colistin and fosfomycin in a murine model of peritonitis

Author:

Le Menestrel Alice1,Guerin François2ORCID,Chau Françoise1,Massias Laurent13,Benchetrit Laura1,Cattoir Vincent24ORCID,Fantin Bruno15ORCID,de Lastours Victoire15ORCID

Affiliation:

1. IAME Research Group, UMR-1137, Université de Paris and INSERM, Paris, France

2. CHU de Rennes, Service de Bactériologie-Hygiène Hospitalière & CNR de la Résistance aux Antibiotiques (Laboratoire Associé ‘Entérocoques’), Rennes, France

3. Service de Pharmacologie, Hôpital Bichat, Assistance-Publique Hôpitaux de Paris, Paris, France

4. Université de Rennes 1, Unité Inserm U1230, Rennes, France

5. Service de Médecine Interne, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France

Abstract

Abstract Background Alternative treatments are needed against NDM-1-producing Escherichia coli. Colistin (COL) and fosfomycin (FOS) often remain active in vitro but selection of resistant mutants is frequent if used separately. We determined whether the combination of colistin and fosfomycin may be useful to treat infections with NDM-1-producing E. coli with varying levels of resistance. Methods Isogenic derivatives of E. coli CFT073 with blaNDM-1 and variable levels of resistance to colistin and fosfomycin (CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively) were used. The combination (colistin + fosfomycin) was tested in vitro and in a fatal peritonitis murine model. Mortality and bacterial loads were determined and resistant mutants detected. Results Colistin MICs were 0.5, 16 and 0.5 mg/L and fosfomycin MICs were 1, 1 and 32 mg/L against CFT073-NDM1, CFT073-NDM1-COL and CFT073-NDM1-FOS, respectively. In time–kill curves, combining colistin with fosfomycin was synergistic and bactericidal against CFT073-NDM1 and CFT073-NDM1-FOS, with concentrations of 4× MIC (for both drugs), but not against CFT073-NDM1-COL (concentrations of colistin = 0.5× MIC), due to regrowth with fosfomycin-resistant mutants. Mice died less and bacterial counts were lower in spleen with the combination compared with monotherapy against all strains; the combination prevented selection of resistant mutants except for CFT073-NDM1-COL where fosfomycin-resistant mutants were found in all mice. Conclusions Combining colistin and fosfomycin was beneficial in vitro and in vivo against NDM-1-producing E. coli, even with strains less susceptible to colistin and fosfomycin. However, the combination failed to prevent the emergence of fosfomycin-resistant mutants against colistin-resistant strains. Combining colistin and fosfomycin constitutes an alternative for treatment of NDM-1 E. coli, except against colistin-resistant strains.

Funder

IAME

Fondation pour la Recherche Médicale’ (Equipe FRM 2016

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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