The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities

Mingote, Laia Ruiz; Namutamba, Dorothy; Apina, Francis; Barnabas, Nomampondo; Contreras, Carmen; Elnour, Taharqa; Frick, Mike; Lee, Cynthia; Seaworth, Barbara; Shelly, Debra; Skipper, Natalie; Filho, Ezio Tavora dos Santos

doi:10.1016/s0140-6736(14)60523-7

Cited by 17 publications

(14 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bedaquiline also prolongs the QT interval in patients, which is a measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. In a phase II trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving a placebo, although the causes of mortality were not directly attributable to the drug (4,5). Thus, strategies to reduce the human dose of bedaquiline while retaining antibacterial activity may be valuable.…”

mentioning

confidence: 99%

Verapamil Increases the Bactericidal Activity of Bedaquiline against Mycobacterium tuberculosis in a Mouse Model

Gupta

Tyagi

Bishai

2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bBedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected against the development of resistant mutants in vivo. The adjunctive use of verapamil may permit use of lower doses of bedaquiline to be used and thereby reduce its dose-related toxicities in tuberculosis patients. Bedaquiline (also known as Sirturo, TMC-207, R207910, or the "J" compound) represents the first novel drug class to be approved by the U.S. Food and Drug Administration in the last 40 years for the treatment of multidrug-resistant tuberculosis (MDR-TB) (1, 2). The recommended human dosage of bedaquiline is 400 mg once daily for the first 2 weeks, followed by 200 mg three times per week from weeks 3 to 24 (3). Bedaquiline usage in patients presents several safety concerns, including increased mortality and liver-related adverse drug reactions. Bedaquiline also prolongs the QT interval in patients, which is a measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. In a phase II trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving a placebo, although the causes of mortality were not directly attributable to the drug (4, 5). Thus, strategies to reduce the human dose of bedaquiline while retaining antibacterial activity may be valuable.The active efflux of drugs is known to play a major role in antimicrobial resistance in Mycobacterium tuberculosis (6). Smallmolecule inhibition of efflux pumps improves the activity of several antimycobacterial agents that are subject to efflux. Verapamil is an efflux pump inhibitor that has been shown to have an antimicrobial-potentiating effect in the treatment of M. tuberculosis both in vitro and in vivo (7). Recently, it was shown that inhibition of the efflux pumps of M. tuberculosis by verapamil reduces the bacterial drug tolerance induced in the intracellular compartment within macrophages and in zebrafish granuloma-like lesions (8). The addition of verapamil to standard TB treatment accelerates both the bactericidal and the sterilizing activities of the regimen in a mouse model (9).We recently showed that supplementing bedaquiline with verapamil profoundly decreases the MIC of bedaquiline in the wildtype strain M. tuberculosis H37Rv and also in drug-susceptible and drug-resistant clinical isolates. The MIC of clofazimine against M. tuberculosis H37Rv also decreased significantly in the presence of 50 g/ml verapamil (10). We hypothesized that these results may extend to an in vivo infection model and that verapamil may potentiate the killing of M. tuberculosis by bedaquiline and accelerate the clearance of mycobacteria. Shortening treatment...

show abstract

mentioning

confidence: 99%

Verapamil Increases the Bactericidal Activity of Bedaquiline against Mycobacterium tuberculosis in a Mouse Model

Gupta

Tyagi

Bishai

2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In the only randomized trial (TMC207-C 209), 10 of 79 patients in the bedaquiline group died (13%) compared with 2 of 81 patients in the placebo group (2%). In a separate, single-group, open-label trial, 16 of 233 patients (7%) who received bedaquiline died [47].…”

Section: Bedaquilinementioning

confidence: 99%

Faster drug approval: challenges for safety

Preziosi

2016

Expert Opinion on Drug Safety

View full text Add to dashboard Cite

More rapid drug premarketing procedures pose a challenge for regulatory agencies in terms of innovation and improving real-world safety and effectiveness Areas covered: This review considers the blockbuster drugs used over the previous fifteen years with adverse reactions after marketing, the elements and time span of risk identification and the measures implemented or considered, based on the existing literature and reports from the agencies Expert opinion: Risk prediction is founded on several factors: randomization, sample size, a well-established endpoint for safety, use of a comparator rather than placebo and a longer Phase-III period, in which a serious illness may be identified by early signs of alteration in the primary parenchyma with the latest biochemical, instrumental and imaging techniques. In comparative non-inferiority evaluations, increased safety should be preferred, with the exception of drugs that may be useful in serious or life-threatening diseases for which there are few or no effective existing therapies. A period of restricted use may be required to test and dispense new drugs, as well as to implement specific methods for the early detection of adverse events. It is important not to regard a new medicine axiomatically as the best treatment before it comes into wide use.

show abstract

“…The drug is claimed to inhibit specifically mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme essential for generation of drug-resistance and associates with a disquieting number of dangerous side-effects. These are waved away in view of the urgency of the problem [44].…”

Section: The Efficiency Of Drugsmentioning

confidence: 99%

Can the Triumphant March of TB be Stopped? A Critical Appraisal of the Currently Applied Policy of Eradication

Maes¹

2016

Clin Microbiol

View full text Add to dashboard Cite

The fight against TB is organized by International (WHO, International Union of Tuberculosis and Lung Diseases (UTLD) and National organizations (Ministries of Health). Their strategy is based on a "herd medicine" approach. The vaccine and the massive administration of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide-with streptomycin eventually added for the resistant cases) worldwide during decennia were expected to solve the TB problem. They did not because the means applied to fight the disease were not appropriate. The BCG vaccine is the only vaccine in use, yet it sometimes promotes TB multiplication instead of eradication; only four drugs were imposed by Standard Operating Procedures during decennia, of which some are immunodepressive and may, under some conditions, add to the immunodepressive activity of the pathogen and favour relapse; the diagnosis limited to the detection of the pathogen ignores the immune condition of the patients under treatment.The prognosis, diagnosis and treatment of tuberculosis can be improved. The BCG vaccine is iatrogenic and needs replacement; diagnostic tests based on the detection of the pathogen have their use but need to be completed with the detection of asymptomatic cases and the monitoring of the immune status of the treated patients with a sero-diagnostic test that detects unapparent infections and immune-depressed cases; the drugs used to fight TB must be re-evaluated and complemented by the application of immune-stimulating products to those refractory patients who show a need therefore. The continuing use of an iatrogenic vaccine and of immunodepressive drugs defeats the purpose.

show abstract

The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities

Cited by 17 publications

References 4 publications

Verapamil Increases the Bactericidal Activity of Bedaquiline against Mycobacterium tuberculosis in a Mouse Model

Verapamil Increases the Bactericidal Activity of Bedaquiline against Mycobacterium tuberculosis in a Mouse Model

Faster drug approval: challenges for safety

Can the Triumphant March of TB be Stopped? A Critical Appraisal of the Currently Applied Policy of Eradication

Contact Info

Product

Resources

About