Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline

• Published in: Journal of antimicrobial chemotherapy 2015-09, Vol.70 (9), p.2488-2498
• Main Authors: Lahiri, Sushmita D, McLaughlin, Robert E, Whiteaker, James D, Ambler, Jane E, Alm, Richard A
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Bacterial Proteins - genetics; Binding sites; Biosynthesis; Ceftaroline; Cephalosporins - pharmacology; Drug resistance; Genetic Variation; Genotype; Gram-positive bacteria; Humans; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Methicillin-Resistant Staphylococcus aureus - isolation & purification; Microbial Sensitivity Tests; Penicillin-Binding Proteins - genetics; Staphylococcal Infections - microbiology
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv131

The objectives of this study were to characterize contemporary MRSA isolates and understand the prevalence and impact of sequence variability in PBP2a on ceftaroline susceptibility. A total of 184 MRSA isolates collected from 28 countries were collected and characterized. WT PBP2a proteins were found in MRSA distributed evenly over the ceftaroline MIC range of 0.5-2 mg/L (n=56). PBP2a variations found in 124 isolates fell into two categories: (i) 12 isolates contained a substitution in the transpeptidase pocket located in the penicillin-binding domain and exhibited significantly decreased ceftaroline susceptibility (typically 8 mg/L); and (ii) isolates with substitutions in the non-penicillin-binding domain (nPBD) in a region proposed to be functionally important for cell wall biogenesis. The majority (71%) of isolates containing only nPBD variations were inhibited by 2 mg/L ceftaroline, 23% by ≤1 mg/L and 6% by 4 mg/L. These data suggest that the WT MRSA distribution extends beyond the current EUCAST and CLSI susceptible breakpoints and includes isolates inhibited by 2 mg/L ceftaroline. SCCmec type IV was the predominant type in the ceftaroline-susceptible population (68%), whereas it only represented 6% of the non-susceptible population. The variations of MLST lineages were fewer among the non-susceptible group. This study suggests that MRSA populations with a WT PBP2a and those with nPBD variations overlap significantly and that PBP2a sequence-independent factors contribute to ceftaroline susceptibility. Whereas characterization of isolates with a ceftaroline MIC of 2 mg/L enriched for isolates with nPBD variations, it was not a discrete population. In contrast, the rare isolates containing a substitution in the transpeptidase-binding pocket were readily differentiated.