title: Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing.
abstract: OBJECTIVE
  According to the mutant selection window (MSW) hypothesis, resistant mutants are selected or enriched at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). To test this hypothesis, Streptococcus pneumoniae ATCC 49619 (MIC 0.1 mg/L; MPC 0.5 mg/L) was exposed to moxifloxacin concentrations below the MIC, above the MPC and between the MIC and MPC, i.e. within the MSW.
  
  
  METHODS
  Daily administration of moxifloxacin for 3 consecutive days was mimicked using a two-compartment dynamic model with peripheral units containing a starting inoculum of 10(8) cfu/mL S. pneumoniae. Changes in susceptibility were examined by repeated MIC determinations and by plating the specimens on agar containing zero, 2 x MIC, 4 x MIC and 8 x MIC of moxifloxacin.
  
  
  RESULTS
  Both in terms of the MIC and resistance frequency, S. pneumoniae resistance developed at concentrations that fell inside the MSW [ratios of 24 h area under the curve (AUC24) to MIC between 24 and 47 h]. A Gaussian-like function fitted the AUC24/MIC-dependent increases in MIC and resistance frequency with central points at AUC24/MICs of 38 and 42 h, respectively, where resistant mutants are enriched selectively. Selective enrichment of resistant mutants was not seen at AUC24/MICs <10 h or >100 h.
  
  
  CONCLUSIONS
  These data suggest that AUC24/MICs >100 h may protect against the selection of resistant S. pneumoniae mutants. Since the usual 400 mg dose of moxifloxacin provides much higher AUC24/MIC (270 h), it is expected to prevent mutant selection at clinically achievable concentrations. Also, these data provide further support for the MSW hypothesis.
authors.affiliation: Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.forename: Irene Yu
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Deborah
authors.initials: D
authors.lastname: Gilbert
authors.forename: Kelly
authors.initials: K
authors.lastname: Simmons
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhao
authors.forename: Karl
authors.initials: K
authors.lastname: Drlica
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
mesh_terms: D019540:Area Under Curve; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000502:physiology; D024841:Fluoroquinolones; D008826:Microbial Sensitivity Tests / Q000379:methods; D008954:Models, Biological; D000077266:Moxifloxacin; D009154:Mutation; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin