Ceftaroline Activity against mecC-Containing Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) remains one of the leading causes of nosocomial infections worldwide, although several different epidemiological lineages are now recognized. A recent emerging lineage of MRSA is livestock-associated methicillin-resistant S. aureus (LA-MRSA). First isolated from a bovine milk sample in Great Britain (1), these pathogens have now been isolated from a wide range of animal species in a large number of European and Asian countries (2–4). In addition, there have been several reports of isolates from LA-MRSA lineages causing a variety of severe infections in humans, from skin and skin structure infections to bacteremia (2). The LA-MRSA isolates carry a horizontally acquired SCCmec type XI cassette which encodes an alternative penicillin-binding protein called MecC which has been demonstrated to be sufficient and responsible for mediating resistance to methicillin (5). The cephalosporin ceftaroline fosamil has been approved for the treatment of acute bacterial skin and skin structure infections as well as community-acquired pneumonia. The major area of differentiation from other -lactam drugs is the activity of ceftaroline (the active metabolite of ceftaroline fosamil) against MRSA, which is the result of improved affinity against the alternative penicillin-binding protein PBP2a (or MecA) that is also horizontally acquired on other SCCmec cassettes. However, substitutions in MecA have been linked to decreased susceptibility to ceftaroline, although those present in the non-penicillin-binding domain (nPBD) have less effect than those in the transpeptidase active site in the penicillin-binding domain (PBD) (6–10). During the genetic characterization of MRSA isolates collected during a 2012 surveillance program, a MRSA isolate (TRN6234) that contained a MecC protein identical to the protein encoded by LA-MRSA isolate LGA251 was identified from a patient in a German hospital with a serious wound infection (1). This mecC-containing MRSA isolate, which belonged to the ST-130 group, was susceptible to ceftaroline (MIC, 1 g/ml) but was resistant, as expected, to other -lactam drugs (methicillin, 128 g/ml; oxacillin, 16 g/ml; meropenem, 4 g/ ml; cefepime, 64 g/ml; ceftazidime, 256 g/ml). An alignment demonstrates that MecA from S. aureus N315 (GenBank accession number BAB41256) and MecC (GenBank accession number KT192641) share only 63% identity (84% similarity) across the entire protein. However, the penicillin-binding domain (residues 327 to 668) is more highly conserved (75.2% identity and 93.3% similarity) than the non-penicillin-binding (also called the dimerization or allosteric) domain (residues 1 to 326) (50.3% identity and 74.2% similarity), which is likely indicative of the functional importance of the respective domains (Fig. 1). The crystal structure of MecA in complex with ceftaroline has recently been solved (PDB accession number 3ZG0) (11). Analysis of this structure suggests that 19 residues (Gly402, Ser403, Lys406, Tyr446, Glu447, Ser461, Ser462, Asn464, Tyr519, Gly520, Gln521, Thr582, Lys597, Ser598, Gly599, Thr600, Ala601, Glu602, and Ala642) are involved in binding interactions with ceftaroline in