Bedaquiline in Multi Drug Resistant Tuberculosis Management.

Bedaquiline in Multi Drug Resistant Tuberculosis Management. 

Rifampicin revolutionized the treatment of tuberculosis. But the initiation of every new drug led to the selection of mutations conferring resistance to it. Two new Anti TB drugs Bedaquiline and Delamanidwere introduced in 2015.Drug resistance, however, has remained a challenge and still is a challenge.

Bedaquiline belongs to a new class of drugs called Diarylquinolines, and is indicated as part of combination therapy in adult patients (≥18 years) with pulmonary multidrug-resistant tuberculosis (MDR-TB). Over 40 years, Bedaquiline is the first new drug developed specifically to treat tuberculosis.

Treatment success rates among patients with MDR-TB--especially those with resistance to second-line drugs--are poor, and the new drugs offer an opportunity to improve health and decrease transmission.  In order to achieve the best possible outcomes, however, the drugs need to be given in a systematic way so optimal results are achieved for patients, providers, and the TB program.

WHO has recently changed the groupings of the drugs in their new guidelines.  There is no more group 5 (WHO 2016 guidelines).  Now there are Group A, B, C, and D and within group D there are D1 drugs (first line agents), D2 drugs (BDQ and DLM) and D3 drugs (PAS, Imipenem).

Mechanism of Action

It is a bactericidal drug that inhibits the proton pump of mycobacterial ATP synthase, a critical enzyme in the synthesis of ATP for Mycobacterium tuberculosis.

Key Facts about Bedaquiline (Bdq)

• Bedaquiline has a slow terminal elimination profile, having a terminal half-life of approximately 5.5 months.
• It shows better absorption on taking the drug with food versus when taken fasting.
• Risk of death was observed in BdQ group vs placebo, however, no evidence that directly linked the drug to the cause of death was however seen.
• Can cause QT interval prolongationresulting in arrtythmias and can also cause hepatotoxicity
• It is only given for the first 24 weeks of treatment along with WHO background regimen.
• Bedaquiline should not be added alone to a failing regimen or in the middle of treatment.
• Its use currently demands recommended screening and close monitoring of treatment.
• PMDT Sites should meet and practice the WHO 5 conditions for use of new drugs.

Dosage of Bedaquiline

Currently Bdq is provided in 100 mg tablets and following is the dosage as per WHO standard recommendations:

• Week 1–2: Bedaquiline 400 mg daily (seven days per week).
• Week 3–24: Bedaquiline 200 mg, three times per week (with at least 48 hours between doses) for a total dose of 600 mg per week.
• Week 25: End of treatment (start of month 7): Continue other second-line anti-TB drugs only.
• Bedaquiline is not advised to be continued after completion of six months (24 weeks)

Inclusion Criteria

• Confirmed MDR, pre-XDR* and XDR-TB patients
• Where four essential drugs cannot be ensured in the treatment selection
• MDR-TB patients with previous exposure of FQ & Am/Km/Cm for > 1 month and results of repeat DST is not available.
• Patients with two or more Group 4 drugs compromised (Eto, Cs, PAS)
• Intolerance to one of the SLDs.
• Close contacts of patients where index case has resistance to either  FQ, Km/Am/Cm or XDR-TB.
• Failure of standard MDR-TB Treatment as per WHO-2013 definition.
• Long standing MDR-TB cases with extensive bilateral lung damage or advanced disease
• MDR-TB patients on treatment with hearing impairment tested by audiometry.
• Pulmonary disease only.
• Age ≥ 18 years and under 65 years, over 12 years weighing 30 kg or above and up to 68 years can be considered when potential benefit outweighs the risk based on decision in review panel. 
• HIV co-morbid conditions
• Written Informed Consent
• Patients where close monitoring can be ensured and willing to reside in the catchment area of selected PMDT sites

Exclusion Criteria

• Age less than 18 and more than 65 Years ,exceptions can be made as mentioned in inclusion criteria. 
• Pregnancy
• Evidence/history of cardiac disease/event at baseline
• A confirmed prolongation of QTc interval (Fridercia formula) > 500 ms, pathological Q waves in the screening ECG
• Risk factors ( e.g heart failure ,hypokalemia, hypomagnesemia) if cannot be corrected
• Severe Hepatic disorder
• Any patients for which close monitoring cannot be ensured.

Side Effects

• Less commonly but possibly severe adverse effects (QT interval prolongation and hepatotoxicity) and require special attention for screening and management aspects.
• The most frequent and common adverse drug reactions (>10% of patients) during treatment with bedaquiline in the controlled trials were nausea, arthralgia and headache

Absolute Contraindications

For absolute contraindicationsBdq cannot be used. Examples of absolute contraindications are as follows,

• Patient refuses to consent
• Hypersensitivity
• High risk for cardiac complications

Relative contraindications

In the following situations BdQ should be avoided, but can be used on case by case based on consultation outweighing the risks and benefits, when effective treatment cannot be constructed.

• Children or persons under 18 years of age. BdQ use in this group should be avoided until further data/recommendations are available
• Pregnancy. So far recommendations are not to use BdQ in pregnancy until further evidence is available.
• Breast Feeding: This is still not sure that bedaquiline and its metabolites are passed into human breast milk, however, may be used in case by case situations where its use outweighs the benefit.

Cautions

• Use of BdQ in the Children & Elderly: Because of not having sound evidence of safety of use in elderly >65 years and children < 18 years, the use of BdQ should be with special care/caution and proper clinical judgment.
• Renal Impairment:
• Hepatic Impairment: As above, in patients with mild or moderate haptic impairment dose adjustment of BdQ is not required.
• Deranged Serum Potassium: Before starting bedaquiline, potassium levels should be corrected and carefully monitored as hypokalemia is associated with QT prolongation and also risk of arrhythmias due to hypo or hyperkalemia. Therefore ECG should be carefully monitored before starting treatment with BdQ.
• Extra pulmonary disease only: BdQ can be used in such patients and inclusion may be considered when potential benefit outweighs the risk.

 Co-administration with QT-prolonging drugs

 Following drugs may have impact on QT prolongation when co-prescribed with BdQ,

• Haloperidol/Haldol.
• Amitriptyline/tricyclic antidepressants.  
• Moxifloxacin (to a lesser extent with levofloxacin).
• Clofazimine.
• Macrolide drugs (erythromycin, clarithromycin, azithromycin).
• Serotonin 5-HT3 receptor antagonist i.e. Dolasetron, Ondansetron(anti-nausea drugs commonly used in MDR-TB).
• Azole antifungal agents (e.g., ketonazole, itraconzaole, fluconazole), Some antimalarials (quinine sulfate, chloroquine), drugs used for psychiatric disorder (e.g. chlorpromazine, haloperidol, thioridazine).