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MINI REVIEW
Year : 2016  |  Volume : 5  |  Issue : 3  |  Page : 172-173

Bedaquiline: A new hope in treatment of tuberculosis


1 Department of Pharmacology, GSVM Medical College, Kanpur, India
2 Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication5-Aug-2016

Correspondence Address:
Dr. Ajay Kumar Verma
Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.187830

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  Abstract 

Multidrug resistant tuberculosis is defined as resistance to at least isoniazid and rifampicin. Multidrug resistant Tuberculosis is one of the most challenging health problem being faced by the medical fraternity. An urgent need for newer and more effective drugs is relies to combat this Drug Resistant Tuberculosis menance. Bedaquiline, first in a new class of drug , has been approved by the US Food and Drug Association, the first time in 40 years that a drug has been approved that attacked Tuberculosis. In phase III trials Bedaquiline was found to bring about faster culture conversion and significantly more culture conversions. Accordingly, the FDA has approved bedaquiline as part of combination therapy to treat adults with MDR pulmonary TB when other alternatives are not available. Bedaquiline has a promising potential and has a favourable outcome in Drug Resistant Tuberculosis.

Keywords: Bedaquiline, multi drug reisitant, tuberculosis


How to cite this article:
Singh A, Prakash V, Kant S, Kumar R, Bhatia A, Verma AK, Srivastava A. Bedaquiline: A new hope in treatment of tuberculosis. Int J Health Allied Sci 2016;5:172-3

How to cite this URL:
Singh A, Prakash V, Kant S, Kumar R, Bhatia A, Verma AK, Srivastava A. Bedaquiline: A new hope in treatment of tuberculosis. Int J Health Allied Sci [serial online] 2016 [cited 2021 Feb 27];5:172-3. Available from: https://www.ijhas.in/text.asp?2016/5/3/172/187830

Resistance to rifampicin with or without resistance to isoniazid is referred to as multidrug-resistant tuberculosis (MDR-TB). They are the two most effective bactericidal agents presently used in therapy of TB. At present, MDR-TB is one of the most challenging health problems being faced by the science of medicine. About 3.5% of all newly diagnosed patients have MDR-TB. [1]

The therapy for MDR-TB is highly toxic and costlier than the treatment regimen used to treat rifampicin sensitive TB. The absence of drugs as effective as isoniazid and rifampicin for therapy leads to reduced chances of treatment success (bacteriologic cure and treatment completion) and increased death rate when compared to patients with rifampicin sensitive TB. The need for newer and more effective drug is thus realized.

Accelerated approval to the drug "Bedaquiline" to treat-resistant TB was granted by the US Food and Drug Administration (FDA) on December 28, 2012. [2] It was for the first time in 40 years that a drug was approved which had a different mechanism of action against tubercle bacilli. It was discovered by scientists at Janssen and was called as Sirturo. It is the first in a new class of drugs that aims to treat resistant TB. Mycobacterial adenosine triphosphate (ATP) synthase is required for the synthesis of ATP by Mycobacterium tuberculosis. Bedaquiline, a diarylquinoline, [3] acts at this step by binding to the oligomeric and proteolipic subunit C of mycobacterial ATP synthase leading to inhibition of ATP synthesis and resulting in bacterial death. "atpE" is the gene encoding the subunit C of the ATP synthase and the amino-acid sequence is conserved even in nonrelated M. tuberculosis. Both replicating, as well as dormant Mycobacterium, are killed. [4]

Safety and efficacy of bedaquiline was established in 440 patients in phase 2 clinical trials. [5] Random allotment of 160 patients with newly diagnosed, smear-positive, MDR to receive either 400 mg of bedaquiline once a day for 2 weeks, followed by 200 mg thrice a week for 22 weeks, or placebo, both in combination with a desired background regimen was done in the first trial. Bedaquiline was administered to 23 out of 47 patients enrolled in the second trial. The dosage was same as in the first trial, but the duration of use of bedaquiline was curtailed to 8 weeks. Safety, tolerability, and efficacy of this novel drug was tested in 233 patients in the third trial with dosage and duration same as used in the first trial. In these phase 2 trials, the end point was taken as median time to culture conversion, which was seen to be statistically significantly reduced, with acceptable adverse effects. Nausea, joint pain, and headache were the common side effects found in the clinical trials. [5] At a dose of 400 mg, early bactericidal activity of bedaquiline was similar to rifampicin and isoniazid from 4 th day onward. [6]

The use should be reserved for patients who do not have any other therapy options as the drug has shown some significant risks of deaths in clinical trials. It can lead to cardiac arrhythmia attributable to QT prolongation.

Hepatic cyp450 enzyme is responsible for its metabolism. Microsomal enzyme induction and inhibition may lead to inconstant serum levels. Plasma concentration is dwindled to half when used concurrently with rifampicin, an enzyme inducer. Even though its serum level waned in mouse model, its activity was not affected when administered with rifampicin. [7] Persons receiving bedaquiline should avoid alcohol and other hepatotoxic drugs. [8] It can be used cautiously in patients with mild to moderate hepatic dysfunction (Child-Pugh A or B), but is contraindicated in patients with severe hepatic dysfunction (Child-Pugh C). [9] Since it is minimally excreted by the kidneys, it is safe in patients with mild to moderate renal impairment (not requiring dialysis), and should be administered with vigilance in patients with severe renal impairment requiring dialysis. [10]

Phase III trials need speedy movement and early completion besides analysis of emerging operational data on the usage of the drug. To accelerate the approval of bedaquiline, the FDA weighed the pros and cons of its therapy. The risks included likely progression of disease and death, and the development of increased antimycobacterial resistance for the patient and the population at risk when improper and inadequate therapy was instituted. Bedaquiline is thus indicated in a patient population for which there is considerable unmet need and a positive benefit-risk balance. In several European countries and South Africa, bedaquiline is now available for use on a limited basis. A study done in Indian settings on five patients of DR-TB showed good improvement with acceptable microbiological conversion rates and without noticeable adverse events. [11]

The available drugs for therapy of MDR-TB have low cure rates. In this scenario, bedaquiline has a promising potential in increasing sputum conversion rate and hence favorable outcome in therapy of this form of TB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
WHO. Global Tuberculosis Report 2014. Vol. 5. Geneva: World Health Organization; 2014. p. 54.  Back to cited text no. 1
    
2.
Walker J, Tadena N. J and J tuberculosis drug gets fast-track clearance. Wall St J 2013. Available from: http://www.online.wsj.com/article/SB10001424127887323320404578213421059138236.html.[Last cited on 2013 Mar 17].  Back to cited text no. 2
    
3.
Goel D. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis. J Pharmacol Pharmacother 2014;5:76-8.  Back to cited text no. 3
[PUBMED]  Medknow Journal  
4.
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 2008;283:25273-80.  Back to cited text no. 4
    
5.
US Food and Drug Administration. FDA news release. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm. [Last cited on 2013 Mar 18].  Back to cited text no. 5
    
6.
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother 2008;52:2831-5.  Back to cited text no. 6
    
7.
Lounis N, Gevers T, Van Den Berg J, Andries K. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother 2008;52:3568-72.  Back to cited text no. 7
    
8.
Food and Drug Administration. SIRTURO (bedaquiline) tablets label. Washington, DC: Food and Drug Administration; 2012.  Back to cited text no. 8
    
9.
Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, Editor. The Liver and Portal Hypertension. Philadelphia, PA: Saunders; 1964. p. 50-64.  Back to cited text no. 9
    
10.
Centers for Disease Control and Prevention. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep 2013;62:1-12.  Back to cited text no. 10
    
11.
Udwadia ZF, Amale RA, Mullerpattan JB. Initial experience of bedaquiline use in a series of drug-resistant tuberculosis patients from India. Int J Tuberc Lung Dis 2014;18:1315-8.  Back to cited text no. 11
    



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