title: Rapid drug tolerance and dramatic sterilizing effect of moxifloxacin monotherapy in a novel hollow-fiber model of intracellular Mycobacterium kansasii disease.
abstract: Mycobacterium kansasii is the second most common mycobacterial cause of lung disease. Standard treatment consists of rifampin, isoniazid, and ethambutol for at least 12 months after negative sputum. Thus, shorter-duration therapies are needed. Moxifloxacin has good MICs for M. kansasii. However, good preclinical models to identify optimal doses currently are lacking. We developed a novel hollow fiber system model of intracellular M. kansasii infection. We indexed the efficacy of the standard combination regimen, which was a kill rate of -0.08 ± 0.05 log10 CFU/ml/day (r(2) = 0.99). We next performed moxifloxacin dose-effect and dose-scheduling studies at a half-life of 11.1 ± 6.47 h. Some systems also were treated with the efflux pump inhibitor reserpine. The highest moxifloxacin exposure, as well as lower exposures plus reserpine, sterilized the cultures by day 7. This suggests that efflux pump-mediated tolerance at low ratios of the area under the concentration-time curve from 0 to 24 h (AUC0 - 24) to MICs is an early bacterial defense mechanism but is overcome by higher exposures. The highest rate of moxifloxacin monotherapy sterilization was -0.82 ± 0.15 log10 CFU/ml/day (r(2) = 0.97). The moxifloxacin exposure associated with 80% of maximal kill (EC80) was an AUC0-24/MIC of 317 (the non-protein-bound moxifloxacin AUC0-24/MIC was 158.5). We performed Monte Carlo simulations of 10,000 patients in order to identify the moxifloxacin dose that would achieve or exceed the EC80. The simulations revealed an optimal moxifloxacin dose of 800 mg a day. The MIC susceptibility breakpoint at this dose was 0.25 mg/liter. Thus, moxifloxacin, at high enough doses, is suitable to study in patients for the potential to add rapid sterilization to the standard regimen.
authors: Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Shashikant
authors: S
authors: Srivastava
authors: Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Jotam
authors: J
authors: Pasipanodya
authors: Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Carleton M
authors: CM
authors: Sherman
authors: School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors: Claudia
authors: C
authors: Meek
authors: School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
authors: Richard
authors: R
authors: Leff
authors: Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Medicine, University of Cape Town, Observatory, Cape Town, South Africa Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA tawanda.gumbo@baylorhealth.edu.
authors: Tawanda
authors: T
authors: Gumbo
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones / Q000494:pharmacology / Q000627:therapeutic use*; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy*; D019909:Mycobacterium kansasii / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology; D013242:Sterilization
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D012110:Reserpine; D000077266:Moxifloxacin
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