title: Evaluation of ceftaroline activity versus ceftriaxone against clinical isolates of Streptococcus pneumoniae with various susceptibilities to cephalosporins in an in vitro pharmacokinetic/pharmacodynamic model.
abstract: Drug resistance in Streptococcus pneumoniae, a frequent pathogen in community-acquired pneumonia, is increasing. Ceftaroline (active metabolite of ceftaroline fosamil) is a broad-spectrum intravenous cephalosporin with activity in vitro against drug-resistant Gram-positive organisms. We investigated ceftaroline at 600 mg every 12 h (q12h) (maximum concentration of the free, unbound drug in serum [fC(max)] is 15.2 μg/ml, and half-life [T(1/2)] is 2.5 h) versus ceftriaxone at 1 g q24h (fC(max) = 23 μg/ml, T(1/2) = 8 h) against six clinical S. pneumoniae isolates in a one-compartment in vitro pharmacokinetic/pharmacodynamic 96-h model (starting inoculum of 10(7) CFU/ml). Differences in CFU/ml (at 24 to 96 h) were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥ 3 log(10) CFU/ml decrease from the initial inoculum. Ceftaroline MICs were 0.06, 0.015, ≤ 0.008, 0.25, 0.25, and 0.5 μg/ml, and ceftriaxone MICs were 0.5, 0.25, 0.25, 4, 4, and 8 μg/ml for SP 1477, SP 669, SP 132, SP 211, SP 90, and SP 1466, respectively. Against the ceftaroline- and ceftriaxone-susceptible strain SP 1477, ceftaroline displayed sustained bactericidal activity (3 to 96 h, -5.49 log(10) CFU/ml) and was significantly (P ≤ 0.012) better than ceftriaxone (72 to 96 h, -2.03 log(10) CFU/ml). Against the ceftriaxone-resistant strains, ceftaroline displayed sustained bactericidal activity at 96 h and was significantly better than ceftriaxone (SP211 [-5.91 log(10) CFU/ml, P ≤ 0.002], SP 90 [-5.26 log(10) CFU/ml, P ≤ 0.008], and SP1466 [-5.14 log(10) CFU/ml, P ≤ 0.042]). Ceftaroline was the more effective drug and displayed sustained bactericidal activity. Ceftaroline fosamil may provide a therapeutic option to treat ceftriaxone-resistant S. pneumoniae infections.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Steed
authors.forename: Céline
authors.initials: C
authors.lastname: Vidaillac
authors.forename: Patricia
authors.initials: P
authors.lastname: Winterfield
authors.forename: Donald
authors.initials: D
authors.lastname: Biek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002443:Ceftriaxone / Q000493:pharmacokinetics / Q000494:pharmacology*; D018550:Cephalosporin Resistance / Q000187:drug effects; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000382:microbiology; D003470:Culture Media; D006207:Half-Life; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011018:Pneumonia, Pneumococcal / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002511:Cephalosporins; D003470:Culture Media; D000097583:Ceftaroline