Ceftaroline Resistance Selection of Methicillin-Resistant Involves Different Genetic Pathways.

The pathways in the development of ceftaroline resistance of methicillin-resistant (MRSA) isolates belonging to the ST8, ST239, and ST228 were evaluated. Ceftaroline-resistant derivatives were isolated through selection during 40 passages. Ceftaroline MIC measurements and whole-genome sequencing were performed after 5, 20, and 40 passages. In two ST8 derivative isolates, ceftaroline MIC increased up to 128 mg/L. Mutations were acquired in and in one isolate after 20 passages and in in another after 40 passages. MIC for two ST239 derivatives increased to 128 mg/L. Substitutions in Pbp4 and polymorphisms in the upstream region of were identified in both derivatives after 40 passages. In one isolate, additional mutation in and deletion in were detected. In an ST228 derivative, MIC increased to 32 mg/L with one mutation in penicillin-binding protein 2a (Y446N) detected after five passages and a second (E447K) after 20 passages. Three pathways in the development of ceftaroline resistance were identified. For ST8 and ST239 derivatives mutations were detected in and , respectively, whereas in ST228 - in . Most derivatives harbored additional mutations whose potential role in the development of resistance has not been determined.