title: A pharmacodynamic approach to antimicrobial activity in serum and epithelial lining fluid against in vivo-selected Streptococcus pneumoniae mutants and association with clinical failure in pneumonia.
abstract: OBJECTIVE
  Emergence of resistance may be prevented by killing both the parental infecting strain and subsequent less susceptible step-mutants. The present study analyses eradication and resistance selection in Streptococcus pneumoniae with moxifloxacin, levofloxacin and azithromycin, using a parental serotype 3 clinical strain (strain A) and its correspondent step-mutant derivatives resistant to these antibiotics (B, C, D), which were selected in vivo in a patient with pneumonia.
  
  
  METHODS
  Moxifloxacin, levofloxacin and azithromycin MICs were 1, 2 and 0.5 mg/L for the parental strain; 4, 16 and 4 mg/L for isolate B; and 4, 16 and >128 mg/L for isolates C and D, respectively. A pharmacokinetic computerized device was used to simulate serum and epithelial lining fluid (ELF) concentrations. Initial inoculum was approximately 10(8) cfu/mL. Population analysis profiles were performed using plates with increasing antimicrobial concentrations.
  
  
  RESULTS
  In ELF simulations, moxifloxacin showed a bactericidal pattern against all isolates with a minority (approximately 100 cfu/mL) of the surviving population (isolates B, C and D) growing on plates with moxifloxacin concentrations just above those in ELF. Levofloxacin and azithromycin showed a bactericidal pattern only against isolate A, with the whole population of isolates B, C and D growing on plates with levofloxacin concentrations higher (16-64 mg/L) than those in ELF and in plates with azithromycin concentrations as high as 2048 mg/L (for isolates C and D).
  
  
  CONCLUSIONS
  Antimicrobial activity in pulmonary tissue against possible emerging resistant mutants during pneumonia treatment may prevent failures more than the solely activity against the S. pneumoniae parental infecting strain.
authors.affiliation: Microbiology Department, School of Medicine, Universidad Complutense Avda. Complutense s/n, 28040 Madrid, and Microbiology Department, Hospital Donostia, San Sebastián, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.forename: María-José
authors.initials: MJ
authors.lastname: Giménez
authors.forename: David
authors.initials: D
authors.lastname: Sevillano
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Aguilar
authors.forename: Fabio
authors.initials: F
authors.lastname: Cafini
authors.forename: Olatz
authors.initials: O
authors.lastname: Echeverría
authors.forename: Emilio
authors.initials: E
authors.lastname: Pérez-Trallero
authors.forename: José
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D001372:Aza Compounds / Q000097:blood / Q000494:pharmacology*; D017963:Azithromycin / Q000097:blood / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000382:microbiology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D000077266:Moxifloxacin; D009154:Mutation; D015242:Ofloxacin / Q000097:blood / Q000494:pharmacology*; D011018:Pneumonia, Pneumococcal / Q000382:microbiology; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D015610:Serum Bactericidal Test; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D017963:Azithromycin; D015242:Ofloxacin; D000077266:Moxifloxacin