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Improving the treatment of experimental tuberculosis with combined rifapentine- and moxifloxacin-containing drug regimens

Posted on:2008-11-05Degree:Ph.DType:Dissertation
University:The Johns Hopkins UniversityCandidate:Rosenthal, Ian MFull Text:PDF
GTID:1444390005958514Subject:Biology
Abstract/Summary:PDF Full Text Request
Rationale. Standard treatment of tuberculosis requires the administration of a combination of 4 antibiotics for at least 6 months. Poor provider and patient adherence to such a demanding treatment is a key factor in therapeutic failure and development of drug resistance. Therefore, shorter drug regimens are urgently needed. Here we evaluate whether increasing rifamycin exposure by replacing rifampin with a long-lived rifamycin congener, rifapentine, and replacing isoniazid with moxifloxacin can simplify and shorten the current standard treatment.;Methods. Using a well validated murine model of tuberculosis, we compared the efficacy of intermittent and daily rifapentine- and moxifloxacin-containing treatment to that of standard intermittent and daily rifampin- and isoniazid-containing treatment. Efficacy was assessed by the reduction of lung colony forming unit counts in treated mice and by the proportion of mice with culture-positive relapse after various durations of treatment. Pharmacokinetic studies were performed to determine the pharmacodynamic advantage of rifapentine over that of rifampin.;Results. We first demonstrated that once-weekly treatment with rifapentine and moxifloxacin significantly decreased the culture-positive relapse rate as compared to the standard twice-weekly treatment with rifampin and isoniazid when given during the 4 month continuation phase of therapy. Because the pharmacodynamic parameters of intermittent P administration were superior to those of daily rifampin administration, we hypothesized that increasing the rhythm of rifapentine and moxifloxacin administration would further increase antimycobacterial activity. Indeed, twice-weekly, thrice-weekly and daily treatment with rifapentine, moxifloxacin and pyrazinamide was not only more bactericidal but also more effective in preventing culture-positive relapse: relapse-free survival was achieved after 4 months of twice-weekly rifapentine plus moxifloxacin-containing treatment and after 3 months of daily and thrice-weekly rifapentine plus moxifloxacin-containing treatment, whereas it was achieved after 6 months with standard daily treatment.;Conclusion. A new drug regimen consisting of rifapentine, moxifloxacin and pyrazinamide is far more active than the standard drug regimen of rifampin, isoniazid and pyrazinamide, and may dramatically improve the treatment of tuberculosis by decreasing the current 6 month duration of treatment to 3 months or less.
Keywords/Search Tags:Tuberculosis, Rifapentine, Months, Moxifloxacin, Drug, Standard, Administration
PDF Full Text Request
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