Phase 2 Pharmacodynamic Study of High-dose Levofloxacin in MDR-TB Treatment

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DESCRIPTION (provided by applicant): Multiple Drug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR- TB) are rapidly growing threats to the world's health. Nearly 500,000 new cases of MDR-TB occurred in 2006, and reports of highly lethal XDR-TB have been documented from 45 countries. Current treatment regimens are inadequate, with failure in a quarter of cases of MDR-TB and three-quarters of cases of XDR-TB, resulting in spread of the disease to many others. NIAID, the World Health Organization, and the STOP-TB Partnership have identified research on and treatment of MDR-TB and XDR-TB as urgent global health priorities. The fluoroquinolones (FQ) are the most active class of antimycobacterial agents currently available for use in patients with MDR-TB. However, no prospective clinical trials have been performed to define the optimal way to use FQ for MDR-TB treatment. Several lines of evidence suggest that current doses are suboptimal, and may even promote acquisition of resistance. Maximizing AUC/MIC ratio is likely to lead to optimal antimycobacterial effect, as it does in serious bacterial infections. The investigators, Drs. Horsburgh, Tupasi, Burman, Drusano, Mitnick and Metchock, have been working together for three years, and the clinical site in Manila has experience with clinical trials of both drug- susceptible and MDR-TB. This planning grant will support preparation for initiation of the proposed clinical trial, surrogate marker and pharmacodynamic studies by developing materials, identifying and resolving logistical problems, and securing regulatory approval for these studies. All activities will be carried out in collaboration with NIAID, CDC and regulatory agencies. The U01 proposal that will result will have three Specific Aims: 1) To define in man the optimal pharmacodynamic parameters of FQ for achieving sputum culture conversion of MDR-TB. 2) To validate a surrogate marker of TB treatment response, rate of rise in time to positivity in liquid medium, that will allow reduced sample sizes in future MDR-TB trials. 3) To define the completion, failure, loss-to-follow-up and relapse rates achieved with the initially implemented MDR-TB treatment regimen when given for 18 months following sputum culture conversion. This clinical trial will increase our ability to cure MDR-TB by optimizing dosing and thereby improving the effectiveness of an existing antimycobacterial agent, using a novel and versatile study design which more rapidly and efficiently provides advances in this critical area. Validation of surrogate markers for clinical response to antituberculosis treatment will streamline subsequent trials of combination treatment regimens for MDR-TB. Determining the rates of and risk factors for long term outcomes of optimized therapy for MDR-TB will facilitate planning future studies to improve outcomes of patients with MDR-TB and prevent emergence of XDR-TB. PUBLIC HEALTH RELEVANCE (provided by applicant): Multi-drug-resistant tuberculosis affects nearly 500,000 persons each year around the world. This type of tuberculosis is very difficult to treat, and many patients die from it. New drugs are urgently needed to treat this disease. This application proposes a study to determine the best way of using levofloxacin, an effective antibiotic, to treat multi-drug-resistant tuberculosis. The patients will receive their usual treatment, plus the normal dose of levofloxacin or a higher dose. The study will be performed in the Philippines, where multi-drug-resistant TB is common.