title: Missense mutations in PBP2A Affecting ceftaroline susceptibility detected in epidemic hospital-acquired methicillin-resistant Staphylococcus aureus clonotypes ST228 and ST247 in Western Switzerland archived since 1998.
abstract: The development and maintenance of an arsenal of antibiotics is a major health care challenge. Ceftaroline is a new cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA); however, no reports concerning MRSA ceftaroline susceptibility have been reported in Switzerland. We tested the in vitro activity of ceftaroline against an archived set of 60 MRSA strains from the University Hospital of Geneva collected from 1994 to 2003. Our results surprisingly revealed ceftaroline-resistant strains (MIC, >1 μg/ml in 40/60 strains; EUCAST breakpoints, susceptible [S], ≤1 μg/ml; resistant [R], >1 μg/ml) were present from 1998 to 2003. The detected resistant strains predominantly belonged to sequence type 228 (ST228) (South German clonotype) but also to ST247 (Iberian clonotype). A sequence analysis of these strains revealed missense mutations in the penicillin-binding protein 2A (PBP2A) allosteric domain (N146K or E239K and N146K-E150K-G246E). The majority of our ST228 PBP2A mutations (N146K or E150K) were distinct from ST228 PBP2A allosteric domain mutations (primarily E239K) recently described for MRSA strains collected in Thailand and Spain during the 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance program. We also found that similar allosteric domain PBP2A mutations (N146K) correlated with ceftaroline resistance in an independent external ST228 MRSA set obtained from the nearby University Hospital of Lausanne, Lausanne, Switzerland, collected from 2003 to 2008. Thus, ceftaroline resistance was observed in our archived strains (including two examples of an MIC of 4 µg/ml for the Iberian ST247 clonotype with the triple mutation N146K/E150K/G246E), at least as far back as 1998, considerably predating the commercial introduction of ceftaroline. Our results reinforce the notion that unknown parameters can potentially exert selective pressure on PBP2A that can subsequently modulate ceftaroline resistance.
authors.affiliation: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland.
authors.forename: William L
authors.initials: WL
authors.lastname: Kelley
authors.affiliation: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Ambre
authors.initials: A
authors.lastname: Jousselin
authors.affiliation: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Barras
authors.affiliation: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lelong
authors.affiliation: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland adriana.renzoni@hcuge.ch.
authors.forename: Adriana
authors.initials: A
authors.lastname: Renzoni
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002511:Cephalosporins / Q000494:pharmacology*; D003428:Cross Infection / Q000382:microbiology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense / Q000235:genetics*; D046915:Penicillin-Binding Proteins; D013203:Staphylococcal Infections / Q000382:microbiology*; D013557:Switzerland / Q000453:epidemiology; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D000097583:Ceftaroline; C487789:mecA protein, Staphylococcus aureus