title: Antibacterial effects of moxifloxacin and levofloxacin simulating epithelial lining fluid concentrations against community-acquired methicillin-resistant Staphylococcus aureus.
abstract: OBJECTIVE
  Current North American guidelines advocate the use of respiratory fluoroquinolones for the empirical management of community-acquired pneumonia (CAP). While community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a pathogen frequently encountered in skin and skin structure infections, it has also now been recognised as a causative pathogen in CAP. Since fluoroquinolones may be used empirically to treat unsuspected CA-MRSA pneumonia, the objective of this study was to evaluate the antibacterial properties of levofloxacin and moxifloxacin using human simulated drug exposures in epithelial lining fluid (ELF).
  
  
  METHODS
  An in vitro model was used to simulate the ELF concentrations, previously determined in older adults receiving multiple doses, of levofloxacin 500 mg once daily and moxifloxacin 400mg once daily. Four CA-MRSA isolates were studied at a starting inoculum of 10(6) colony-forming units (CFU)/mL; selected isolates were also studied at 10(8) CFU/mL. Bacterial density and resistance were quantitatively assessed over 48 hours. Drug exposure (area under the concentration-time curve [AUC]) was confirmed using validated drug assays.
  
  
  RESULTS
  At a standard 10(6) starting inoculum, sustained bacterial kill (3.6-4.5 log) with both fluoroquinolones was noted for CA-MRSA isolates 27 and 44 (AUC/minimum inhibitory concentration [MIC] = 383-3923). Despite an MIC of 8 microg/mL (AUC/MIC = 25) for isolate 3, levofloxacin displayed a 2.8 log kill, while moxifloxacin (MIC 1 microg/mL) sustained a 4.5 log kill (AUC/MIC = 207) over 48 hours. Against isolate 59, levofloxacin displayed no antibacterial effect (AUC/MIC = 3), while moxifloxacin with an MIC of 8 microg/mL (AUC/MIC = 31) killed 4.6 log. At a high inoculum (10(8)), both fluoroquinolones showed 5.2-5.6 log kill for the susceptible isolate (44), while moxifloxacin showed no antibacterial activity against isolate 59. Drug exposure (AUC/MIC) appeared to correlate well (r(2) = 0.99) with the change in log CFU/mL. Maximal activity was observed for both drugs at an AUC/MIC of approximately 30.
  
  
  CONCLUSIONS
  When evaluated at human simulated ELF concentrations, both levofloxacin and moxifloxacin appeared to demonstrate sustained antibacterial activity for CA-MRSA isolates with MICs <or=8 microg/mL at a starting inoculum of 10(6). Use of a high inoculum (10(8)) appeared to compromise the antimicrobial activity of the fluoroquinolones when the MIC was 8 microg/mL, but did not mitigate antibacterial kill for susceptible isolates.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Fan
authors.forename: Christina
authors.initials: C
authors.lastname: Sutherland
authors.forename: Andrew C
authors.initials: AC
authors.lastname: DeRyke
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000188:drug therapy* / Q000378:metabolism; D003470:Culture Media; D004848:Epithelium / Q000378:metabolism*; D024841:Fluoroquinolones; D064704:Levofloxacin; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D003470:Culture Media; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin