title: Minimal inhibitory and mutant prevention concentrations of azithromycin, clarithromycin and erythromycin for clinical isolates of Streptococcus pneumoniae.
abstract: BACKGROUND
  Previous work showed a higher prevalence of macrolide/azalide resistance in provinces of Canada where azithromycin was the major treatment for Streptococcus pneumoniae as compared with regions where clarithromycin was the dominant treatment. These data provided a way to test the mutant selection window hypothesis, which predicts that the serum drug concentration (AUC(24)) relative to the mutant prevention concentration (MPC) would be higher for clarithromycin than for azithromycin.
  
  
  METHODS
  The MIC and MPC were determined for 191 penicillin/macrolide-susceptible clinical isolates of S. pneumoniae with azithromycin, clarithromycin and erythromycin using agar plate assays.
  
  
  RESULTS
  The MIC(50/90) (mg/L) and MPC(50/90) (mg/L), respectively, were as follows: azithromycin 0.13/0.25 and 1/4; clarithromycin 0.031/0.063 and 0.13/0.5; erythromycin 0.063/0.13 and 0.25/2. We calculated from published pharmacokinetic values that the AUC(24)/MPC(90) for azithromycin was 0.85; for clarithromycin it was 96, and for erythromycin base and estolate it was 4 and 10, respectively. Thus the AUC(24)/MPC(90) was about 50 times higher for clarithromycin than for azithromycin.
  
  
  CONCLUSIONS
  The elevated prevalence of azithromycin resistance may derive in part from a low value of AUC(24)/MPC(90) and/or time above MPC, since previous work indicates that the number of prescriptions per person was similar in the geographical regions examined.
authors.affiliation: Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Kelli
authors.initials: K
authors.lastname: Metzler
authors.forename: Karl
authors.initials: K
authors.lastname: Drlica
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Blondeau
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001288:Attention; D017963:Azithromycin / Q000494:pharmacology*; D002170:Canada; D017291:Clarithromycin / Q000494:pharmacology*; D004917:Erythromycin / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011008:Pneumococcal Infections / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin; D017963:Azithromycin; D017291:Clarithromycin