ethionamide and bedaquiline

A new class of antibacterials, diarylquinolines, was identified. The lead compound, R207910 (TMC207), was able to inhibit Mycobacterium tuberculosis in vitro, in mice and in patients. R207910 targets the mycobacterial ATP synthase. In vitro, it displayed potent activities against both drug-sensitive and multidrug-resistant strains of M. tuberculosis. It was also strongly active against dormant bacilli in the Wayne's dormancy culture system, hypoxia and nitric oxide models. In the murine model, when used alone, it was as active as the triple combination of rifampicin+isoniazid+pyrazinamide. When added to the previous combination or substituted for isoniazid or rifampicin, the treatment including the combinations containing R207910 led to culture conversion after 2 months of therapy. When added to the combination used to treat MDR-TB or substituted for moxifloxacin or ethionamide, the combinations containing R207910 led to culture conversion after 2 months of therapy. In MDR-TB infected patients, R207910 combined with second line drugs was able to convert more sputum cultures (47.6%) than the placebo combined to second line drugs regimen (8.7%).

Topics: Animals; Anti-Infective Agents; Antitubercular Agents; Aza Compounds; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Ethionamide; Fluoroquinolones; Humans; Mice; Moxifloxacin; Mycobacterium tuberculosis; Placebos; Quinolines; Tuberculosis

Drug-resistant tuberculosis is an increasing healthcare challenge. Drug regimen building demands the use of different therapeutic groups, many of which harbor neurotoxicity as a side-effect, whether central or peripheral. Peripheral neuropathy is a major concern as it tends to be severe and usually irreversible. Anti-tubercular drugs that may contribute to peripheral neuropathy include INH, ethambutol, linezolid, cycloserine and para-amino salicylic acid. This potential adverse effect must be balanced against the intrinsically grave prognosis that drug resistant tuberculosis harbors. We present such a clinically challenging case of a 25 years-old female with extremely drug resistant tuberculosis whose treatment necessitated the use of several neurotoxic anti-tubercular drugs, leading to severe sensory peripheral neuropathy who did not improve despite the withdrawal of culprit drugs. She developed positive and negative sensory symptoms in both lower limbs. Nerve conduction studies were suggestive of sensory neuropathy affecting both lower limbs. Alternate causes of peripheral neuropathy including HIV, vasculitis, B12 deficiency and diabetes were ruled out. Despite drug withdrawal, the patient did not improve significantly. This case emphasizes the irreversibility of anti-tubercular therapy-induced peripheral neuropathy, demanding more rigorous clinical screening for the same while managing such patients.

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Clofazimine; Cycloserine; Deprescriptions; Diarylquinolines; Ethionamide; Extensively Drug-Resistant Tuberculosis; Female; Humans; Kanamycin; Linezolid; Neural Conduction; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Pyrazinamide; Pyridoxine; Tuberculosis, Pulmonary

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

Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB.. To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB.. BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment.. A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%.. Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

Topics: Adult; Antitubercular Agents; Cardiotoxicity; Clofazimine; Cycloserine; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Ethionamide; Female; Humans; India; Linezolid; Male; Moxifloxacin; National Health Programs; Sputum; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Little is known about the metabolic state of

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

The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case.

Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Diarylquinolines; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ethionamide; Fluoroquinolones; Lung; Mice; Moxifloxacin; Mycobacterium tuberculosis; Organ Size; Pyrazinamide; Quinolines; Rifampin; Spleen; Survival Analysis; Tuberculosis