Objectives: Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of ceftaroline resistance.
Methods: MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses.
Results: The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to ceftaroline were epidemiologically related.
Conclusions: Mutations in PBP2a can affect the activity of ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin-binding domain together with a second-step in the penicillin-binding domain may result in elevation of the ceftaroline MIC to >2 mg/L.
Keywords: MRSA; penicillin-binding proteins; resistance.
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