Antibacterial Effects of Moxifloxacin and Levofloxacin Simulating Epithelial Lining Fluid Concentrations gainst Community-Acquired Methicillin-Resistant

Background and 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 500mg 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 μg/ mL (AUC/MIC = 25) for isolate 3, levofloxacin displayed a 2.8 log kill, while moxifloxacin (MIC 1 μg/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 μg/mL (AUC/MIC = 31) killed 4.6 log. At a high inoculum (108), 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. Conclusion : When evaluated at human simulated ELF concentrations, both levofloxacin and moxifloxacin appeared to demonstrate sustained antibacterial activity for CA-MRSA isolates with MICs ≤ 8 μg/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 μg/mL, but did not mitigate antibacterial kill for susceptible isolates.