title: A combination of mecillinam and amoxicillin/clavulanate can restore susceptibility of high-level TEM-1-producing Escherichia coli to mecillinam.
abstract: Mecillinam is recommended in France as a first-line treatment for lower urinary tract infections, due to the large increase in resistance of Escherichia coli to other oral treatments, such as co-trimoxazole or fluoroquinolones, its limited impact on faecal microbiota and its stability in the presence of numerous β-lactamases. However, we recently identified several mecillinam-resistant E. coli isolates with a high-level expression penicillinase (HEP) phenotype that merit further study.
  
  
  
  We studied two isogenic clinical isolates from one patient (one susceptible to mecillinam and one resistant to mecillinam) by WGS to determine the mechanism of mecillinam resistance and compared it with other mecillinam-resistant E. coli . We evaluated the synergistic combination of amoxicillin/clavulanate and mecillinam using a simple test, suitable for daily laboratory practice, to determine the MIC of this combination.
  
  
  
  We showed that the presence of an SNP in the promoter of the plasmidic TEM-1 β-lactamase gene is sufficient to confer resistance to mecillinam. This mechanism was present in 67% of HEP-phenotype E. coli tested. Combining mecillinam with amoxicillin/clavulanate abolished resistance, with an MIC compatible with clinical use. This association was not sensitive to the inoculum effect, in contrast to mecillinam alone.
  
  
  
  An HEP phenotype can confer mecillinam resistance in vitro . This resistance is abolished, regardless of the inoculum, by combining mecillinam with amoxicillin/clavulanate, and can be easily tested in the laboratory. This combination may be used as an oral relay treatment of non-complicated pyelonephritis due to multiresistant E. coli strains.
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Birgy
authors.affiliation: Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Delecourt
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Geslain
authors.affiliation: Service de Pédiatrie Générale, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Desselas
authors.affiliation: Service de Pédiatrie Générale, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Caseris
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Magnan
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Mariani-Kurkdjian
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bidet
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Service de Microbiologie, Hôpital Robert-Debré, AP-HP, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bonacorsi
mesh_terms: D000560:Amdinocillin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005602:France; D016680:Genome, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D010405:Penicillinase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000382:microbiology; D001618:beta-Lactamases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D010405:Penicillinase; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; D000560:Amdinocillin