bedaquiline and terizidone

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.

Topics: Antitubercular Agents; Clarithromycin; Cycloserine; Dapsone; Diarylquinolines; Erythromycin; Female; Humans; Isoxazoles; Male; Ofloxacin; Oxazolidinones; Quinolines; Tuberculosis, Multidrug-Resistant

Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown.. In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment.. Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 -.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1-1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97).. Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings.

Topics: Adult; Antitubercular Agents; Coinfection; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Female; HIV; HIV Infections; Humans; Isoniazid; Isoxazoles; Levofloxacin; Male; Mycobacterium tuberculosis; Oxazolidinones; Pyrazinamide; Retrospective Studies; South Africa; Survival Analysis; Treatment Outcome; Tuberculosis, Multidrug-Resistant

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Topics: Adenosine Triphosphatases; Amides; Amino Acids; Antitubercular Agents; Cycloserine; Diarylquinolines; Drug Tolerance; Ethambutol; Ethionamide; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Humans; Isoniazid; Isoxazoles; Metabolic Networks and Pathways; Models, Biological; Mycobacterium bovis; Mycobacterium tuberculosis; Oxazolidinones; Spiro Compounds; Thiazines; Tuberculosis