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A Review of Tuberculosis: Focus on Bedaquiline Bonnie Chan, Tina M

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A Review of Tuberculosis: Focus on Bedaquiline Bonnie Chan, Tina M THERAPY UPDATE Bedaquiline THERAPY UPDATE A review of tuberculosis: Focus on bedaquiline BONNIE CHAN, TINA M. KHADEM, AND JACK BROWN efore the mid-19th century, tuberculosis remained an an- Purpose. The history and prevalence of of resistance. No in vitro cross-resistance be- cient disease about which much tuberculosis and the role of bedaquiline tween bedaquiline and currently available B in multidrug-resistant (MDR) tuberculosis antitubercular agents has been observed was hypothesized but little was are reviewed. thus far. Because bedaquiline targets a com- definitively known. Speculations of Summary. Tuberculosis continues to cause pletely different enzyme, cross-resistance its origins date back nearly 15,000 significant morbidity and mortality world- with other conventional agents remains 1,2 to 20,000 years ago. Tuberculosis wide. Increasing rates of drug-resistant unlikely. Enhanced sterilizing capacity via paleopathological changes have tuberculosis are a significant concern synergistic depletion of ATP further exhibits been found in human remains from and pose serious implications for current the promising potential of bedaquiline with predynastic Egypt (3500–2650 BC), and future treatment of the disease. In pyrazinamide. A course of bedaquiline re- Neolithic Sweden (3200–2300 BC), December 2012, the Food and Drug Ad- quires 24 weeks of therapy in combination ministration approved bedaquiline as part with other antitubercular drugs. and Neolithic Italy (fourth millen- of the treatment regimen for pulmonary Conclusion. The approval of bedaquiline 2-4 nium BC). The earliest human MDR tuberculosis. Bedaquiline’s unique represents a major milestone in MDR cases of tuberculosis thus far were mechanism of action presents an alterna- tuberculosis therapy. Bedaquiline should confirmed in bone lesions from tive approach to current antimycobacte- be considered in patients who have not a 9,000-year-old Neolithic infant rial killing. By directly inhibiting adenosine responded to a regimen containing four and woman in the eastern Mediter- triphosphate (ATP) synthase, bedaquiline second-line drugs and pyrazinamide and ranean.5 It was not until 1720 that is effective against both replicating and patients with documented evidence of dormant mycobacteria. Pulmonary cavitary MDR tuberculosis resistant to fluoroquino- English physician Benjamin Marten lesions can contain heterogeneous popula- lones. The exact role of bedaquiline cannot first proposed the transmission of tions. This potential mix of semireplicating be determined until further efficacy and small living organisms as the culprit and hypometabolic mycobacteria is more safety data are obtained through ongoing for pulmonary tuberculosis, referred difficult to eliminate with conventional an- Phase III trials. to then as “consumption.” In 1882, titubercular drugs, thus increasing the risk Am J Health-Syst Pharm. 2013; 70:1984-94 German physician Robert Koch suc- cessfully visualized and identified this causative microbe as Mycobac- terium tuberculosis. Koch went on to Modern era of tuberculosis people—one third of the world’s earn the Nobel Prize in Physiology or Tuberculosis continues to cause population—are thought to be in- Medicine in 1905 for his tuberculin significant morbidity and mortality fected with tuberculosis.7 The high- skin test.2,6 worldwide. Approximately 2 billion est rates for tuberculosis are among BONNIE CHAN, PHARM.D., is Assistant Professor of Pharmacy, College, and Adjunct Research Assistant Professor, Department of School of Pharmacy, Philadelphia College of Osteopathic Medicine, Social and Preventative Medicine, URMC. Suwanee, GA; at the time of writing she was Postgraduate Year 2 Address correspondence to Dr. Brown at the Department of Infectious Diseases Pharmacy Resident, Department of Pharmacy, Pharmacy Practice and Administration, Wegmans School of Phar- University of Rochester Medical Center (URMC), Rochester, NY. macy, St. John Fisher College, 3690 East Avenue, Rochester, NY TINA M. KHADEM, PHARM.D., is Postdoctoral Research Fellow, De- 14618 ([email protected]). partment of Pharmacy Practice, Wegmans School of Pharmacy, St. The authors have declared no potential conflicts of interest. John Fisher College, Rochester, and Postdoctoral Research Fellow, Department of Pharmacy, URMC. JAck BROWN, PHARM.D., M.S., Copyright © 2013, American Society of Health-System Pharma- is Associate Professor and Chair, Department of Pharmacy Practice cists, Inc. All rights reserved. 1079-2082/13/1102-1984$06.00. and Administration, Wegmans School of Pharmacy, St. John Fisher DOI 10.2146/ajhp130199 1984 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 THERAPY UPDATE Bedaquiline developing countries, where societal decreased by 2.2%. Tuberculosis- or capreomycin).9 The incidence factors, such as rapid urbanization related mortality rates dropped 41% of drug-resistant tuberculosis may and migration, pose special chal- between 1990 and 2011.9 further rise as accessibility to anti- lenges in tuberculosis prevention microbial susceptibility testing for and control.7,8 Urbanization, migra- Burden of tuberculosis and isoniazid and rifampicin increases. tion, and poverty remain invariably multidrug-resistant tuberculosis linked to tuberculosis transmission. In 2011, tuberculosis ranked as Tuberculosis microbiology and Lower socioeconomic groups are the second leading worldwide cause drug resistance at increased risk due to higher ex- of death among infectious diseases. M. tuberculosis is inherently resis- posure in overcrowded living and An estimated 8.7 million new tuber- tant to many antimicrobials. Classi- working conditions, malnutrition, culosis cases (125 cases per 100,000 fied as acid-fast bacilli, the virulence poor health awareness, and limited persons) and 1.4 million tuberculosis- and slow growth of M. tuberculosis access to quality health care.7 These related deaths occurred in 2011.9 have been attributed to its unique cell circumstances, along with human In the United States, the number of wall structure.12 Covalently linked to immunodeficiency virus (HIV) and reported tuberculosis cases declines underlying arabinogalactan and pep- drug resistance, remain major con- each year. People infected with HIV tidoglycan macromolecules, mycolic tributors to global tuberculosis rates. as well as people who have come from acids and free lipids create a tight, In 1993, the World Health Organi- countries with endemic tuberculosis closely packed hydrophobic barrier. zation (WHO) declared tuberculosis represent a significant number of tu- This barrier is approximately 1000- a global public health emergency.9 berculosis cases in the United States. fold less permeable to hydrophilic National and international efforts to Across all age groups, 6% of people molecules, such as water-soluble an- treat and control tuberculosis were with tuberculosis have reported be- tibiotics, than the cell wall of Esch- reinvigorated with strategies such ing infected with HIV, a percentage erichia coli.13 The inner saccharide as DOTS (Directly Observed Treat- that has remained unchanged since layer further inhibits lipophilic ment, Short-Course) and Stop TB.9 2008.9 substances from entering, making Introduced in the mid-1990s, DOTS Although global tuberculosis rates the cell wall remarkably difficult to was an international strategy focus- are on the decline, concerns regard- penetrate. Besides being covalently ing on five key elements of action, ing multidrug-resistant (MDR) attached to the cell wall, mycolic which were further expanded in the tuberculosis and extensively drug- acids form trehalose 6,6´-dimycolate Stop TB strategy (appendix). The resistant (XDR) tuberculosis are (TDM), a toxic glycolipid found in implementation of DOTS programs growing. MDR tuberculosis, defined the cell envelope. TDM has been im- in 182 countries was met with posi- as tuberculosis resistant to both iso- plicated in the intracellular survival tive results as countries were able to niazid and rifampin, emerged during of M. tuberculosis. By preventing improve national tuberculosis con- the 1970s. Of the 12 million cases of phagosome–lysosome fusion and trol programs. By 2004, more than tuberculosis, approximately 630,000 thus arresting the biogenesis of ma- 20 million tuberculosis cases were are estimated to be MDR tubercu- ture phagolysosomes, TDM allows treated through DOTS programs, losis.9 Tuberculosis surveillance pro- M. tuberculosis to remain latent in and more than 16 million of these grams were notified of nearly 60,000 host macrophages for years.14 cases were cured.9,10 The Stop TB cases of MDR tuberculosis globally in The resistance of M. tuberculosis strategy was launched by WHO 2011.11 More than half of these cases to antitubercular drugs is likely the in 2006 as an evidenced-based ap- occurred in patients living in India, result of a spontaneous genetic event; proach to reducing the burden of China, the Russian Federation, and at worst, it is a “man-made amplifica- tuberculosis. Targets set by the STOP South Africa. Approximately 4% of tion of the natural phenomenon.”15 TB Partnership endeavor toward new cases (primary drug resistance) The likelihood of spontaneous muta- a 2015 goal to reduce tuberculosis and 20% of previously treated cases tions to isoniazid and rifampin are prevalence and related mortality (acquired drug resistance) qualified 3.5 × 10–6 and 3.1 × 10–8, respec- rates by 50% compared with the rates as MDR tuberculosis.9 Of these MDR tively.16,17 Given that pulmonary in 1990. The ultimate
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