title: In vitro evaluation of the antimicrobial activity of ceftaroline against cephalosporin-resistant isolates of Streptococcus pneumoniae.
abstract: Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae. In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of S. pneumoniae. The MICs of ceftaroline and comparators were determined by broth microdilution. In total, 120 U.S. isolates of cefotaxime-resistant (MIC > or = 4 microg/ml) S. pneumoniae were tested along with 18 laboratory-derived R6 strains with known penicillin-binding protein (PBP) mutations. Clinical isolates were characterized by multilocus sequence typing, and the DNAs of selected isolates were sequenced to identify mutations affecting pbp genes. Ceftaroline (MIC(90) = 0.5 microg/ml) had greater in vitro activity than penicillin, cefotaxime, or ceftriaxone (MIC(90) = 8 microg/ml for all comparators) against the set of highly cephalosporin-resistant clinical isolates of S. pneumoniae. Ceftaroline was also more active against the defined R6 PBP mutant strains, which suggests that ceftaroline can overcome common mechanisms of PBP-mediated cephalosporin resistance. These data indicate that ceftaroline has significant potency against S. pneumoniae strains resistant to existing parenteral cephalosporins and support its continued development for the treatment of infections caused by resistant S. pneumoniae strains.
authors.affiliation: Emory University, Atlanta, Georgia 30322, USA. lmcgee@sph.emory.edu
authors.forename: Lesley
authors.initials: L
authors.lastname: McGee
authors.forename: Donald
authors.initials: D
authors.lastname: Biek
authors.forename: Yigong
authors.initials: Y
authors.lastname: Ge
authors.forename: Magderie
authors.initials: M
authors.lastname: Klugman
authors.forename: Mignon
authors.initials: M
authors.lastname: du Plessis
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Smith
authors.forename: Bernard
authors.initials: B
authors.lastname: Beall
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Whitney
authors.forename: Keith P
authors.initials: KP
authors.lastname: Klugman
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015373:Bacterial Typing Techniques; D002511:Cephalosporins / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000187:drug effects / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D046915:Penicillin-Binding Proteins / Q000235:genetics; D011008:Pneumococcal Infections / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004269:DNA, Bacterial; D046915:Penicillin-Binding Proteins; D000097583:Ceftaroline