Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae.

OBJECTIVES: This study evaluated the affinity of ceftaroline and comparator beta-lactams for penicillin-binding proteins (PBPs) of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and Streptococcus pneumoniae with varying susceptibility to penicillin. Ceftaroline is currently in Phase 3 development for the treatment of complicated skin and skin structure infections and community-acquired pneumonia, including infections caused by MRSA and multidrug-resistant S. pneumoniae. METHODS: Binding affinities (IC(50)s) of ceftaroline, ceftriaxone, oxacillin and penicillin G for PBPs were measured in a competition assay by adding various concentrations of the test drugs to membranes or whole cells. PBPs were labelled using the fluorescent reporter molecule Bocillin FL. RESULTS: Overall, ceftaroline exhibited greater binding affinity for the range of PBPs tested, as compared with comparator beta-lactams. The high affinity of ceftaroline for PBPs 1-3 of MSSA and PBP2a of MRSA correlates well with its efficacy against these organisms, as determined by MIC. Similarly, efficient binding of ceftaroline to key S. pneumoniae PBPs, such as PBP2x/2a/2b, taken together, correlates well with its low MICs for penicillin-resistant isolates of S. pneumoniae. CONCLUSIONS: The high affinities of ceftaroline for MRSA PBP2a, MSSA PBPs 1-3 and S. pneumoniae PBP2x/2a/2b support the potential efficacy of ceftaroline in the treatment of infections caused by MRSA and S. pneumoniae.

Transcriptional analysis of antibiotic resistance and virulence genes in multiresistant hospital-acquired MRSA.

The staphylococcal chromosome cassette mec cannot solely explain the multiresistance phenotype or the relatively mild virulence profile of hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA). This study reports that several multiresistant HA-MRSA strains differently expressed genes that may support antibiotic resistance, modify the bacterial surface and influence the pathogenic process. Genes encoding efflux pumps (norA, arsB, emrB) and the macrolide resistance gene ermA were found to be commonly expressed by HA-MRSA strains, but not in the archetypal MRSA strain COL. At equivalent cell density, the agr system was considerably less activated in all MRSA strains (including COL) in comparison with a prototypic antibiotic-susceptible strain. These results are in contrast to those observed in recent community-acquired MRSA isolates and may partly explain how multiresistant HA-MRSA persist in the hospital setting.