title: Assessment of the activity of ceftaroline against clinical isolates of penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae with elevated MICs of ceftaroline using an in vitro pharmacodynamic model.
abstract: OBJECTIVE
  This study assessed the pharmacodynamics of ceftaroline against penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae with elevated MICs of ceftaroline using an in vitro pharmacodynamic model.
  
  
  METHODS
  Nine isolates of S. pneumoniae, including one penicillin-susceptible isolate, one penicillin-intermediate isolate and seven penicillin-resistant isolates, were tested. The pharmacodynamic model was inoculated with a concentration of 1 × 10(6) cfu/mL and ceftaroline was dosed twice daily (at 0 and 12 h) to simulate the fC(max) (maximum free concentration in serum) and t(1/2) (half-life in serum) obtained after 600 mg intravenous doses every 12 h (fC(max), 16 mg/L; t(1/2), 2.6 h). Ceftaroline was compared with ceftriaxone dosed once daily to simulate the fC(max) and t(1/2) obtained after a 1 g dose (fC(max), 18 mg/L; t(1/2), 8.0 h). Samples were collected over 24 h to assess viable growth and possible changes in ceftaroline MICs over time.
  
  
  RESULTS
  Ceftaroline fT(>MIC) (time of free serum concentration over the MIC) of 100% (ceftaroline MICs, ≤ 0.5 mg/L) was bactericidal (≥ 3 log(10) killing) against all isolates at 6 h and completely eradicated all organisms at 12 and 24 h. No bacterial regrowth occurred over the study period and no changes in ceftaroline MICs were observed. Upon ceftriaxone exposure, S. pneumoniae isolates with ceftriaxone MICs of 0.12 and 0.25 mg/L were eradicated, but isolates with ceftriaxone MICs of 1-8 mg/L resulted in initial bacterial reduction at 6 h with organism regrowth at 12 h and no reduction in organism concentration, relative to the starting inoculum, at 24 h.
  
  
  CONCLUSIONS
  Ceftaroline fT(>MIC) of 100% (ceftaroline MICs, ≤ 0.5 mg/L) was bactericidal (≥ 3 log(10) killing) and eradicated all S. pneumoniae at 12 and 24 h with no regrowth.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, MS673 Health Sciences Centre, 820 Sherbrook Street, Winnipeg R3A 1R9, Canada. ggzhanel@pcs.mb.ca
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Chris
authors.initials: C
authors.lastname: Yachison
authors.forename: Kim
authors.initials: K
authors.lastname: Nichol
authors.forename: Heather
authors.initials: H
authors.lastname: Adam
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Noreddin
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
authors.forename: James A
authors.initials: JA
authors.lastname: Karlowsky
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008962:Models, Theoretical; D010403:Penicillin Resistance; D011008:Pneumococcal Infections / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000302:isolation & purification*; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000097583:Ceftaroline