Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline

Infections caused by MRSA continue to cause significant morbidity worldwide. Ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) is a cephalosporin that possesses activity against MRSA due to its having high affinity for PBP2a while maintaining activity against the other essential PBPs. PBP2a sequence variations, including some outside of the transpeptidase binding pocket, impact ceftaroline susceptibility. This study evaluated the potential of ceftaroline to select for resistant Staphylococcus aureus clones in isolates containing a variety of PBP2a alleles and with a range of ceftaroline MIC values from different MLST lineages.

Direct resistance selection experiments were performed by plating 20 S. aureus isolates (18 MRSA and 2 MSSA) on agar plates containing increasing concentrations of ceftaroline. Colonies that emerged were tested by standard broth microdilution for changes in ceftaroline susceptibility and genetically characterized.

The frequency of spontaneous resistance to ceftaroline was low for all isolates and, although resistant variants were not obtained on plates containing ≥4-fold the MIC of ceftaroline, six MRSA isolates had a small number of colonies emerge on plates containing 2-fold the MIC of ceftaroline and had a 2- to 8-fold elevation of the ceftaroline MIC, while also impacting the MIC of methicillin compared with the parental isolate. Additional PBP2a mutations located in the ceftaroline-binding pocket, Y446N or A601S, were observed in several of the resistant isolates.

These studies demonstrate that there is a low risk of generating ceftaroline-resistant MRSA isolates, which appears independent of any pre-existing variation in the PBP2a protein sequence or initial ceftaroline MIC.