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New, novel treatment of multidrug-resistant Mycobacterium tuberculosis
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In the practice of infectious diseases, the topic of multidrug resistance is an all too common conversation. The conversations trend toward the newest emergent pathogen or the pathogens with the largest threat to public health. Multidrug-resistant Mycobacterium tuberculosis has been added to this ongoing, ever-changing conversation.
According to CDC, in 2011, it was estimated that tuberculosis affected more the 10,000 patients is the United States and nearly 9 million worldwide. WHO reports that 3.7% of new cases of TB are MDR-TB, defined as TB resistant to isoniazid and rifampin. It is speculated this resistance has emerged from improperly treated drug-susceptible TB; improper treatment regimens that do not include three or four drug therapies; and failure to ensure the patient completes the whole treatment course. WHO also notes that approximately 20% of previously treated patients have developed MDR-TB. It is estimated that about 9% of MDR-TB cases also have resistance to two other classes of drugs, or extensively drug-resistant TB (XDR-TB).
By March 2013, WHO reported 84 countries had reported at least one XDR-TB case. Both MDR-TB and XDR-TB continue to be a threat to public health. Further research and drug development must ensue if we want to be armed with treating these pathogens.
Kimberly D. Boeser
Bedaquiline (Sirturo, Janssen Therapeutics) is a novel antimycobacterial for the treatment of MDR-TB. Bedaquiline is a diarylquinoline, which inhibits the proton pump of mycobacterial adenosine 5’-triphosphate synthase 3. This enzyme is essential for the generation of energy in M. tuberculosis. Bedaquiline has been studied and granted accelerated approval by the FDA (December 2012) for those patients aged older than 18 years who have documented resistant pulmonary MDR-TB and for whom an effective treatment regimen cannot otherwise be provided. It is not indicated for the treatment of latent, extrapulmonary or sensitive M. tuberculosis.
This new molecular entity, similar to many other treatments for TB, is most effective when combined with other antimycobacterial drugs (eg, rifampin or pyrazinamide). Bedaquiline should be combined with at least three other drugs to which the isolate is shown to be susceptible. When resistance is suspected but not confirmed by in vitro testing, bedaquiline should be combined with at least four other drugs. This therapy should be administered using a directly observed program.
As with all antimycobacterial treatments, development of resistance is a great concern. It is no different with bedaquiline. Resistance through modification of the atpE target gene is the most notable mechanism of resistance, but other mechanisms may exist. MDR-TB isolates that were resistant to bedaquiline also were resistant to additional antimycobacterial drugs. No cross-resistance was found between bedaquiline and isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide, fluoroquinolones and amikacin.
Study results
Study 1 of TMC 207-C208 evaluated bedaquiline in a randomized, placebo-controlled, double blind study enrolling 160 newly diagnosed patients with pulmonary MDR-TB. Patients were randomly assigned to treatment with bedaquiline plus other antimycobacterial drugs (n=79) or placebo plus other antimycobacterial drugs (n=81) used to treat MDR-TB. The bedaquiline or placebo was given as 400 mg once daily for the first 2 weeks and then as 200 mg three times per week for the remaining 22 weeks. After the bedaquiline/placebo-treatment phase, the patients continued to receive their other antimycobacterial drugs until total treatment duration of 18 to 24 months was achieved or at least 12 months had passed after the first confirmed negative culture. The other treatments consisted of a combination of five other antimycobacterial drugs: ethionamide (Trecator, Wyeth Pharmaceuticals), kanamycin, pyrazinamide, ofloxacin, and cycloserine (Seromycin, Purdue GMP) or terizidone, or available alternative. The primary endpoint of the study was time to sputum culture conversion (interval in days between the first dose of the study drug and the date of the first of two consecutive negative-sputum cultures collected at least 25 days apart during treatment).
The median time to culture conversion was 83 days in the bedaquiline group and 125 days in the placebo group. Overall, bedaquiline had decreased time to culture conversion and improved culture conversion rates compared with placebo at 24 and 72 weeks. In addition, the bedaquiline group experienced less treatment failure compared with placebo group at 24 and 72 weeks, 22.4%/29.9% vs. 42.4%/43.9%, respectively.
Bedaquiline was evaluated in Study 2 of TMC 207-C208, which was a randomized, placebo-controlled, double blind study of 47 newly diagnosed patients with pulmonary MDR-TB in South Africa. The patient population was 74% male, 55% black, and 13% HIV-positive; median age was 33 years. Cavitation was present in one lung in 62% of patients and both lungs in 18% of patients. Patients were randomly assigned to treatment with either bedaquiline plus other antimycobacterial drugs (n=23) or placebo plus other antimycobacterial drugs (n=24) used to treat MDR-TB; confirmed MDR-TB was found in 21 of the bedaquiline group and 23 of the placebo group. The bedaquiline or placebo was given as 400 mg once daily for the first 2 weeks and then as 200 mg three times per week for the remaining 6 weeks.
After the bedaquiline/placebo-treatment phase, the patients continued to receive their other antimycobacterial drugs and were followed up for 96 weeks. The other drugs consisted of a combination of five other antimycobacterial drugs (kanamycin, ofloxacin, ethionamide, ethambutol, and cycloserine or terizidone, or alternative agents). Similarly to Study 1, the bedaquiline group had decreased time to culture conversion and improved culture conversion rates compared with placebo by 8 weeks and also at 24 weeks.
More facts on bedaquiline
Bedaquiline is dosed at 400 mg orally once daily for the first 2 weeks of treatment followed by 200 mg orally three times per week for 22 weeks. Bedaquiline is available as 100-mg tablets, and the entire bottle should be dispensed because it contains the total 24-week course of therapy. This tablet should be taken with water and should not be cut or crushed in any way.
Bedaquiline has primary metabolism via cytochrome P450 (CYP 3A4) to the less active metabolite, which has four to six times less antimycobacterial activity. In addition, bedaquiline undergoes triphasic elimination. Urinary excretion of unchanged drug is less than 0.001%. Dosage adjustments for mild to moderate renal or hepatic impairment are unnecessary. It is recommended to use with caution and weigh risk vs. benefit in those patients with severe renal or hepatic impairment, as it has not been studied sufficiently in these patients.
The most common adverse reactions (at least 10%) reported with bedaquiline included nausea, arthralgia, headache, hemoptysis and chest pain. Only hemoptysis and chest pain occurred at a frequency greater than placebo. Bedaquiline has a black box warning for increase risk for death and QTc prolongations. The risk for death was increased compared with placebo in one of the aforementioned placebo-controlled trials.
Bedaquiline therapy should be limited only to those patients who alternative treatment options are not available or benefit outweighs the risk. All patient receiving therapy should have electrocardiogram monitoring throughout therapy; baseline prior to initiation of therapy and at least 2, 12 and 24 weeks after starting therapy. In addition, hepatic-related adverse drug reactions have been reported; therefore, patients should have liver functions test at baseline and at least monthly during therapy.
Multidrug-resistant M. tuberculosis will continue to be a threat to public health. Similar to many other multidrug-resistant pathogens, we are running out of effective treatments options. Bedaquiline is a new, novel molecular entity that was granted accelerated approval for MDR-TB. In general, studies have shown that bedaquiline plus other antimycobacterial drugs, when compared with placebo plus other antimycobacterial drugs, had shorter time to conversion of sputum cultures. The risk of development of resistance is present with bedaquiline, as it is with all antimycobacterial agents when not combined with drug regimens. Many of the adverse effects reported are significant and will make administration of this medication difficult. Each patient case will need to be closely evaluated based on pathogen susceptibility, the patients other concomitant medications, cardiac risk and underlying liver function before initiation of therapy. When documented resistance is noted, bedaquiline may be an alternative treatment option for patients with pulmonary MDR-TB.
For more information:
CDC. Treatment of TB disease. Available at: www.cdc.gov/ tb/topic/treatment/tbdisease.htm. Published December 2011. Accessed June 2013.
CDC. Drug-resistant TB. Available at: www.cdc.gov/ tb/topic/drtb/default.htm. Published June 2012. Accessed June 2013.
Chhabra N. J Pharmacol Pharmacother. 2012;3:98-104.
Dooley KE. J Infect Dis. 2013;207:1352-1358.
FDA. Janssen Research and Development LLC. FDA Anti-infective Drugs Advisory Committee meeting briefing package: NDA 204-384 and TMC207 (bedaquiline). Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329260.pdf. Published Nov. 28, 2012. Accessed May 2013.
Rustomjee R. Antimicrob Agents Chemother. 2008;52:2831-2835.
Sirturo [package insert]. Raritan, NJ: Janssen Therapeutics; December 2012.
Villemagne B. Eur J Med Chem. 2012;51:1-16.
For more information:
Kimberly D. Boeser, PharmD, is an infectious disease clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-Fairview and the University of Minnesota Amplatz Children’s Hospital.
Disclosure: Boeser reports no relevant financial disclosures.