Bedaquiline in multidrug-resistant pulmonary tuberculosis GENESIS-SEFH drug evaluation report.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a disease affecting pulmonary parenchyma and tracheobronchial tree due to organisms which shows high-level resistance to both isoniazid and rifampicin, with or without resistance to other anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) is characterized for in vitro resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one injectable drug (capreomycin, amikacin or kanamycin). In 2013, among the world reported cases of pulmonary tuberculosis, 450,000 were MDR-TB or XDR-TB. Almost 60% of them were located at India, China and Russian Federation. In Spain, in 2012, 6,046 cases of tuberculosis were reported, with a 3.9-4.3% proportion of MDR-TB; and approximately 6% of them could be XDRTB, a higher ratio than other occidental countries. MDRTB poses special challenges on his treatment. Curation rate is around 62% and mortality reaches 11%. Male gender, alcoholism, quinolone resistance and positive smear at diagnosis are poor prognostic factors. In XDRTB, curation rates falls to 43.7% and mortality reaches 20.8%. Current treatment of MDR-TB needs to be individualized, being guided by antibiogram and including in the first 6 months an injectable drug (amikacin, kanamycin, capreomycin, streptomycin) and a fluoroquinolone (levofloxacin, moxifloxacin or ofloxacin) during the complete course of treatment. Treatment should include at least 4 effective agents and should continue 18 months after obtaining negative cultures2. Bedaquiline (Sirturo®, Lab. Janssen), is a new diarylquinoline approbed by FDA (December 2012) according to the accelerated approval pathway, intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life threatening condition, based on a surrogate endpoint or an intermediate clinical endpoint and clinical benefit that can be verified by post approval studies. Bedaquiline was approved by EMA in March 2014 after an orphan drug designation in 2005. Bedaquiline is available in 100 mg tablets. The recommended dosage is 400 mg once daily during weeks 1 and 2, and 200 mg per day three times per week (with at least 48 hours between doses) weeks 3 to 24. Bedaquiline tablets should be taken with food, in order to increase oral bioavailability (by about 2-fold). Tablets should be swallowed whole with a glass of water. Bedaquiline efficacy and safety in children younger than 18 years and in adults older than 65 years has not been established yet. Dosage adjustment in patients with mild or moderate renal impairment is not needed. In patients with creatinine clearance < 30 ml/min, terminal renal disease requiring hemodialysis, peritoneal dialysis or mild or moderate hepatic impairment bedaquiline should be used with caution. In patients with severe hepatic impairment, bedaquiline is not recommended.