《学术英语（医学）》拓展阅读资料：a review of tuberculosis focus on badaquiline

THERAPY UPDATE A review of tuberculosis: focus on bedaquiline BONNIE CHAN, TINA M. KHADEM, AND JACK BROWN efore the mid-19th century, cient disease about which much tuberculosis and th y and prevalence of of resistance. No in vitro cross-resistance be uberculosis remained anan Purpose. The histor ole of bedaquiline tween bedaquiline and currently availab was hypothesized but little was in multidrug-resistant(MDR) tuberculosis antitubercular agents has been observed definitively known. Speculations of thus far. Because bedaquiline targets a com- Summary Tuberculosis continues to cause pletely different enzyme, cross-resistance its origins date back nearly 15,000 cant morbidity and mortality orld- with other conventional agents remains 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 een 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 nd Neolithic Italy(fourth millen ministration approved bedaquiline as part with other antitubercular drugs. of the treatment regimen for pulmonary Conclusion. The approval of bedaquilin nium BC).2- 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 respond a regimen containing four and woman in the eastern Mediter- triphosphate(ATP) synthase, bedaquiline second-line drugs and pyrazinamide and ranean 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 ll trials to then as consumption. In 1882 tubercular drugs, thus increasing the risk Am J Heaith-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 worlds 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. The high kin 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. Address correspondence to Dr. Brown at the Department of Infectious Diseases Pharmacy Resident, De Pharmacy Practice and Administration, Wegmans School of Pha 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 Gjebkac artment of Pharmacy Practice, Wegmans School of Pharmacy, St The authors have declared no potential conflicts of interest hn Fisher College, Rochester, and Postdoctoral Research Fellor Department of Pharmacy, URMC. JACK BROWN, PHARM. D, MS Copyright o 2013, American Society of Health-System Pharma- is Associate Professor and Chair, Department of Pharmacy Practice ists, Inc. All rights reserved. 1079-2082/13/1102-1984$06.00. and Administration, Wegmans School of Pharmacy, St John Fisher DOI0.2146/aihp130199 1984 Am JHealth-Syst Pharm-Vol 70 Nov 15, 2013

THERAPY UPDATE Bedaquiline 1984 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 THERAPY UPDATE A review of tuberculosis: Focus on bedaquiline Bonnie Chan, Tina M. Khadem, and Jack Brown Bonnie Chan, Pharm.D., is Assistant Professor of Pharmacy, School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA; at the time of writing she was Postgraduate Year 2 Infectious Diseases Pharmacy Resident, Department of Pharmacy, University of Rochester Medical Center (URMC), Rochester, NY. Tina M. Khadem, Pharm.D., is Postdoctoral Research Fellow, De￾partment of Pharmacy Practice, Wegmans School of Pharmacy, St. John Fisher College, Rochester, and Postdoctoral Research Fellow, Department of Pharmacy, URMC. Jack Brown, Pharm.D., M.S., is Associate Professor and Chair, Department of Pharmacy Practice and Administration, Wegmans School of Pharmacy, St. John Fisher College, and Adjunct Research Assistant Professor, Department of Social and Preventative Medicine, URMC. Address correspondence to Dr. Brown at the Department of Pharmacy Practice and Administration, Wegmans School of Phar￾macy, St. John Fisher College, 3690 East Avenue, Rochester, NY 14618 (jebkac@gmail.com). The authors have declared no potential conflicts of interest. Copyright © 2013, American Society of Health-System Pharma￾cists, Inc. All rights reserved. 1079-2082/13/1102-1984$06.00. DOI 10.2146/ajhp130199 Purpose. The history and prevalence of tuberculosis and the role of bedaquiline in multidrug-resistant (MDR) tuberculosis are reviewed. Summary. Tuberculosis continues to cause significant morbidity and mortality world￾wide. Increasing rates of drug-resistant tuberculosis are a significant concern and pose serious implications for current and future treatment of the disease. In December 2012, the Food and Drug Ad￾ministration approved bedaquiline as part of the treatment regimen for pulmonary MDR tuberculosis. Bedaquiline’s unique mechanism of action presents an alterna￾tive approach to current antimycobacte￾rial killing. By directly inhibiting adenosine triphosphate (ATP) synthase, bedaquiline is effective against both replicating and dormant mycobacteria. Pulmonary cavitary lesions can contain heterogeneous popula￾tions. This potential mix of semireplicating and hypometabolic mycobacteria is more difficult to eliminate with conventional an￾titubercular drugs, thus increasing the risk of resistance. No in vitro cross-resistance be￾tween bedaquiline and currently available antitubercular agents has been observed thus far. Because bedaquiline targets a com￾pletely different enzyme, cross-resistance with other conventional agents remains unlikely. Enhanced sterilizing capacity via synergistic depletion of ATP further exhibits the promising potential of bedaquiline with pyrazinamide. A course of bedaquiline re￾quires 24 weeks of therapy in combination with other antitubercular drugs. Conclusion. The approval of bedaquiline represents a major milestone in MDR tuberculosis therapy. Bedaquiline should be considered in patients who have not responded to a regimen containing four second-line drugs and pyrazinamide and patients with documented evidence of MDR tuberculosis resistant to fluoroquino￾lones. The exact role of bedaquiline cannot be determined until further efficacy and safety data are obtained through ongoing Phase III trials. Am J Health-Syst Pharm. 2013; 70:1984-94 B efore the mid-19th century, tuberculosis remained an an￾cient disease about which much was hypothesized but little was definitively known. Speculations of its origins date back nearly 15,000 to 20,000 years ago.1,2 Tuberculosis paleopathological changes have been found in human remains from predynastic Egypt (3500–2650 BC), Neolithic Sweden (3200–2300 BC), and Neolithic Italy (fourth millen￾nium BC).2-4 The earliest human cases of tuberculosis thus far were confirmed in bone lesions from a 9,000-year-old Neolithic infant and woman in the eastern Mediter￾ranean.5 It was not until 1720 that English physician Benjamin Marten first proposed the transmission of small living organisms as the culprit for pulmonary tuberculosis, referred to then as “consumption.” In 1882, German physician Robert Koch suc￾cessfully visualized and identified this causative microbe as Mycobac￾terium tuberculosis. Koch went on to earn the Nobel Prize in Physiology or Medicine in 1905 for his tuberculin skin test.2,6 Modern era of tuberculosis Tuberculosis continues to cause significant morbidity and mortality worldwide. Approximately 2 billion people—one third of the world’s population—are thought to be in￾fected with tuberculosis.7 The high￾est rates for tuberculosis are among

THERAPY UPDATE Bedaquiline developing countries, where societal decreased by 2.2%. Tuberculosis- or capreomycin). 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. further rise as accessibility to anti- microbial susceptibility testing fo 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. These related deaths occurred in 2011. have been attributed to its unique cell circumstances, along with human In the United States, the number of wall structure. 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. 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 ayer further inhibits lipophilic ment, Short-Course)and Stop TB. 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 ng 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. 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. I4 cases were cured. o The Stop Tb cases of MDR tuberculosis globally in The resistance of M. tuberculosis strategy was launched by WHo 2011. 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 x 10- and 3.1 x 10-, respec rates by 50% compared with the rates as MDR tuberculosis. Of these MDr tively. 6. 17 Given that pulmonary in 1990. The ultimate goal is to elimi- tuberculosis cases, approximately 9% cavities often contain high bacterial nate tuberculosis as a public health are thought to be XDR tuberculo- loads(10-10% organisms),concern problem by 2050. According to the XDR tuberculosis is defined as regarding spontaneous dual muta 2012 WHO Global Tuberculosis Re- tuberculosis resistant to isoniazid, tions has been noted. However, as port, progress toward attaining the rifampin, fluoroquinolones, and at the chromosomal loci responsible 2015 goal is being made. From 2010 least one of three injectable second- for resistance are not linked, the risk to 2011, new cases of tuberculosis line drugs(amikacin, kanamycin, of dual spontaneous mutations to Am J Health-Syst Pharm-Vol 70 Nov 15, 2013 1985

THERAPY UPDATE Bedaquiline Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 1985 developing countries, where societal factors, such as rapid urbanization and migration, pose special chal￾lenges in tuberculosis prevention and control.7,8 Urbanization, migra￾tion, and poverty remain invariably linked to tuberculosis transmission. Lower socioeconomic groups are at increased risk due to higher ex￾posure in overcrowded living and working conditions, malnutrition, poor health awareness, and limited access to quality health care.7 These circumstances, along with human immunodeficiency virus (HIV) and drug resistance, remain major con￾tributors to global tuberculosis rates. In 1993, the World Health Organi￾zation (WHO) declared tuberculosis a global public health emergency.9 National and international efforts to treat and control tuberculosis were reinvigorated with strategies such as DOTS (Directly Observed Treat￾ment, Short-Course) and Stop TB.9 Introduced in the mid-1990s, DOTS was an international strategy focus￾ing on five key elements of action, which were further expanded in the Stop TB strategy (appendix). The implementation of DOTS programs in 182 countries was met with posi￾tive results as countries were able to improve national tuberculosis con￾trol programs. By 2004, more than 20 million tuberculosis cases were treated through DOTS programs, and more than 16 million of these cases were cured.9,10 The Stop TB strategy was launched by WHO in 2006 as an evidenced-based ap￾proach to reducing the burden of tuberculosis. Targets set by the STOP TB Partnership endeavor toward a 2015 goal to reduce tuberculosis prevalence and related mortality rates by 50% compared with the rates in 1990. The ultimate goal is to elimi￾nate tuberculosis as a public health problem by 2050.10 According to the 2012 WHO Global Tuberculosis Re￾port, progress toward attaining the 2015 goal is being made. From 2010 to 2011, new cases of tuberculosis decreased by 2.2%. Tuberculosis￾related mortality rates dropped 41% between 1990 and 2011.9 Burden of tuberculosis and multidrug-resistant tuberculosis In 2011, tuberculosis ranked as the second leading worldwide cause of death among infectious diseases. An estimated 8.7 million new tuber￾culosis cases (125 cases per 100,000 persons) and 1.4 million tuberculosis￾related deaths occurred in 2011.9 In the United States, the number of reported tuberculosis cases declines each year. People infected with HIV as well as people who have come from countries with endemic tuberculosis represent a significant number of tu￾berculosis cases in the United States. Across all age groups, 6% of people with tuberculosis have reported be￾ing infected with HIV, a percentage that has remained unchanged since 2008.9 Although global tuberculosis rates are on the decline, concerns regard￾ing multidrug-resistant (MDR) tuberculosis and extensively drug￾resistant (XDR) tuberculosis are growing. MDR tuberculosis, defined as tuberculosis resistant to both iso￾niazid and rifampin, emerged during the 1970s. Of the 12 million cases of tuberculosis, approximately 630,000 are estimated to be MDR tubercu￾losis.9 Tuberculosis surveillance pro￾grams were notified of nearly 60,000 cases of MDR tuberculosis globally in 2011.11 More than half of these cases occurred in patients living in India, China, the Russian Federation, and South Africa. Approximately 4% of new cases (primary drug resistance) and 20% of previously treated cases (acquired drug resistance) qualified as MDR tuberculosis.9 Of these MDR tuberculosis cases, approximately 9% are thought to be XDR tuberculo￾sis. XDR tuberculosis is defined as tuberculosis resistant to isoniazid, rifampin, fluoroquinolones, and at least one of three injectable second￾line drugs (amikacin, kanamycin, or capreomycin).9 The incidence of drug-resistant tuberculosis may further rise as accessibility to anti￾microbial susceptibility testing for isoniazid and rifampicin increases. Tuberculosis microbiology and drug resistance M. tuberculosis is inherently resis￾tant to many antimicrobials. Classi￾fied as acid-fast bacilli, the virulence and slow growth of M. tuberculosis have been attributed to its unique cell wall structure.12 Covalently linked to underlying arabinogalactan and pep￾tidoglycan macromolecules, mycolic acids and free lipids create a tight, closely packed hydrophobic barrier. This barrier is approximately 1000- fold less permeable to hydrophilic molecules, such as water-soluble an￾tibiotics, than the cell wall of Esch￾erichia coli. 13 The inner saccharide layer further inhibits lipophilic substances from entering, making the cell wall remarkably difficult to penetrate. Besides being covalently attached to the cell wall, mycolic acids form trehalose 6,6´-dimycolate (TDM), a toxic glycolipid found in the cell envelope. TDM has been im￾plicated in the intracellular survival of M. tuberculosis. By preventing phagosome–lysosome fusion and thus arresting the biogenesis of ma￾ture phagolysosomes, TDM allows M. tuberculosis to remain latent in host macrophages for years.14 The resistance of M. tuberculosis to antitubercular drugs is likely the result of a spontaneous genetic event; at worst, it is a “man-made amplifica￾tion of the natural phenomenon.”15 The likelihood of spontaneous muta￾tions to isoniazid and rifampin are 3.5 × 10–6 and 3.1 × 10–8, respec￾tively.16,17 Given that pulmonary cavities often contain high bacterial loads (107 –109 organisms), concern regarding spontaneous dual muta￾tions has been noted.18 However, as the chromosomal loci responsible for resistance are not linked, the risk of dual spontaneous mutations to

THERAPY UPDATE Bedaquiline both isoniazid and rifampin is quite tional testing or no testing at the time mented background of resistance in low(9 x 10- ) MDR tuberculosis of diagnosis. 2 Rifampin resistance the setting. 229.30 isolates may arise via sequential ac- is a marker for MDR tuberculosis Antitubercular drugs for the treat- cumulations of mutations in target in over 90% of cases. The results ment for MDR tuberculosis have genes for specific antibiotics due to of conventional testing of cultured been grouped by WHO according to subtherapeutic drug levels, such as mycobacteria and drug-susceptibility efficacy, experience of use, and drug from treatment errors or poor adher- testing may not become available class( Table 1).1. Group l drugs are ence. Resistance to first-line agents for months. Studies have found that considered the most potent and best has been linked to mutations in at rapid drug-susceptibility testing tolerated agents. Drugs in groups least 10 genes. -20 The transfer of with molecular techniques allows 2-5, apart from streptomycin,are these resistant mutations from one for a shorter time to diagnosis and considered second-line or reserve agent to another has been demon- earlier treatment of MDR tuberculo- drugs for treating MDR tuberculosis. strated through the evolution of two sis. 4 Depending on the molecular Treatment of MDR tuberculosis with closely related subclones of MDr test(line probe assays versus Xpert more than one injectable agent is tuberculosis, W and Wl, responsible MTB/RIF [ Cepheid, Sunnyvale, unnecessary. Fluoroquinolones are for widespread disease in New York CA]the M. tuberculosis complex used extensively in the treatment of City and elsewhere. 21 as well as mutations in the rpob MDR tuberculosis. Like the inject- (rifampin resistance)or katG(high- able agents, only one fluoroquino Drug-susceptibility testing for level isoniazid resistance) gene re- lone should be used per regimen resistant tuberculosis gions may be simultaneously detect- as they all share the same genetic The lack of laboratory diagnos- ed. However, conventional culture target, gyr A Newer-generation fluor tic capacity has been identified as a and drug-susceptibility testing still quinolones are recommended over critical barrier in preventing early should be used to rule out resistance earlier-generation fluoroquinolones. and appropriate identification of to second-line agents, which cannot Given the cost and toxicity profiles of and subsequent therapy for MDr be detected by molecular tests. each agent, high-dose levofloxacin tuberculosis. According to WHO, the (1000 mg daily) and moxifloxacin documented cases of mdr tuber- Current treatment for MDR are considered the fluoroquino culosis in 2011 represented 19% of tuberculosis lones of choice. Ciprofloxacin is no the estimated 310,000 cases of MDr Lengthy therapy with multiple longer recommended to treat drug tuberculosis in patients with pulmo- antitubercular drugs is necessary susceptible or drug-resistant tuber Overall, the numbers of MDR tu- and slow growth of M. tuberculosis of resistance. 22.33 Tapid development nary tuberculosis for that same year. due to the intracellular location culosis due to the berculosis cases diagnosed and sub- and the decreased likelihood of Among the oral bacteriostatic sequently treated with second-line resistant mutation to persist during agents, thioamides followed by agents remain below the Global Plan combination therapy. b ,7At least four closerine and then p-aminosalicylic to Stop TB targets, which established antitubercular drugs are to be used in acid are recommended in the follow that by 2015(1)over 50% of esti- combination for MDR tuberculosis. ing order based on efficacy, adverse mated MDR tuberculosis cases will As a conditional recommendation events, and cost. Thioamides, spe- be detected and notified, (2)100% of by WHO, treatment regimens should cifically ethionamide, are associated atients with confirmed MDR tuber- include at least pyrazinamide, a with higher cure rates than cyclo- culosis will receive treatment, and(3) fluoroquinolone, a parenteral agent, serine and p-aminosalicylic acid. over 75% of MDR tuberculosis cases ethionamide (or protionamide), and Ethionamide inhibits the activity of will be successfully treated. cycloserine(or p-aminosalicylic acid the inha gene product, enoyl-acyl In response to this growing crisis, if cycloserine cannot be used ) These carrier protein reductase. This is WHO has published guidelines for second-line agents are not as effec- the same enzyme by which acti- the programmatic management of tive as isoniazid and rifampin, and vated isoniazid inhibits mycolic acid drug-resistant tuberculosis. The 2011 there have been no randomized tri- biosynthesis and may account for update provided further focus on als to help optimize their use against cross-resistance between isoniazid the detection and treatment of drug- MDR tuberculosis. 8 Consequently, resistant isolates and ethionamide asistant tuberculosis in resource- the choice of drug primarily de- When two oral bacteriostatic agents limited settings. Specifically, rapid pends on drug-susceptibility testing are warranted, cycloserine, which in drug-susceptibility testing of iso- of the isolated resistant strain, prior hibits the incorporation of D-alanine niazid and rifampin or of rifampin tuberculosis treatment, and the into mycobacterial cell wall synthesis, alone is recommended over conven- frequency of the drugs use or docu- may be added Cycloserine is associ- 1986 Am JHealth-Syst Pharm-Vol 70 Nov 15, 2013

THERAPY UPDATE Bedaquiline 1986 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 both isoniazid and rifampin is quite low (9 × 10–14).16 MDR tuberculosis isolates may arise via sequential ac￾cumulations of mutations in target genes for specific antibiotics due to subtherapeutic drug levels, such as from treatment errors or poor adher￾ence. Resistance to first-line agents has been linked to mutations in at least 10 genes.18-20 The transfer of these resistant mutations from one agent to another has been demon￾strated through the evolution of two closely related subclones of MDR tuberculosis, W and W1, responsible for widespread disease in New York City and elsewhere.21 Drug-susceptibility testing for resistant tuberculosis The lack of laboratory diagnos￾tic capacity has been identified as a critical barrier in preventing early and appropriate identification of and subsequent therapy for MDR tuberculosis. According to WHO, the documented cases of MDR tuber￾culosis in 2011 represented 19% of the estimated 310,000 cases of MDR tuberculosis in patients with pulmo￾nary tuberculosis for that same year.9 Overall, the numbers of MDR tu￾berculosis cases diagnosed and sub￾sequently treated with second-line agents remain below the Global Plan to Stop TB targets, which established that by 2015 (1) over 50% of esti￾mated MDR tuberculosis cases will be detected and notified, (2) 100% of patients with confirmed MDR tuber￾culosis will receive treatment, and (3) over 75% of MDR tuberculosis cases will be successfully treated.10 In response to this growing crisis, WHO has published guidelines for the programmatic management of drug-resistant tuberculosis. The 2011 update provided further focus on the detection and treatment of drug￾resistant tuberculosis in resource￾limited settings. Specifically, rapid drug-susceptibility testing of iso￾niazid and rifampin or of rifampin alone is recommended over conven￾tional testing or no testing at the time of diagnosis.22 Rifampin resistance is a marker for MDR tuberculosis in over 90% of cases.23 The results of conventional testing of cultured mycobacteria and drug-susceptibility testing may not become available for months. Studies have found that rapid drug-susceptibility testing with molecular techniques allows for a shorter time to diagnosis and earlier treatment of MDR tuberculo￾sis.22,24 Depending on the molecular test (line probe assays versus Xpert MTB/RIF [Cepheid, Sunnyvale, CA]) the M. tuberculosis complex as well as mutations in the rpoB (rifampin resistance) or katG (high￾level isoniazid resistance) gene re￾gions may be simultaneously detect￾ed.25 However, conventional culture and drug-susceptibility testing still should be used to rule out resistance to second-line agents, which cannot be detected by molecular tests. Current treatment for MDR tuberculosis Lengthy therapy with multiple antitubercular drugs is necessary due to the intracellular location and slow growth of M. tuberculosis and the decreased likelihood of a resistant mutation to persist during combination therapy.26,27 At least four antitubercular drugs are to be used in combination for MDR tuberculosis. As a conditional recommendation by WHO, treatment regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or protionamide), and cycloserine (or p-aminosalicylic acid if cycloserine cannot be used). These second-line agents are not as effec￾tive as isoniazid and rifampin, and there have been no randomized tri￾als to help optimize their use against MDR tuberculosis.28 Consequently, the choice of drug primarily de￾pends on drug-susceptibility testing of the isolated resistant strain, prior tuberculosis treatment, and the frequency of the drug’s use or docu￾mented background of resistance in the setting.22,29,30 Antitubercular drugs for the treat￾ment for MDR tuberculosis have been grouped by WHO according to efficacy, experience of use, and drug class (Table 1).31,32 Group 1 drugs are considered the most potent and best tolerated agents. Drugs in groups 2–5, apart from streptomycin, are considered second-line or reserve drugs for treating MDR tuberculosis. Treatment of MDR tuberculosis with more than one injectable agent is unnecessary.31 Fluoroquinolones are used extensively in the treatment of MDR tuberculosis. Like the inject￾able agents, only one fluoroquino￾lone should be used per regimen, as they all share the same genetic target, gyrA. Newer-generation fluor￾oquinolones are recommended over earlier-generation fluoroquinolones. Given the cost and toxicity profiles of each agent, high-dose levofloxacin (1000 mg daily) and moxifloxacin are considered the fluoroquino￾lones of choice. Ciprofloxacin is no longer recommended to treat drug￾susceptible or drug-resistant tuber￾culosis due to the rapid development of resistance.22,33 Among the oral bacteriostatic agents, thioamides followed by cy￾closerine and then p-aminosalicylic acid are recommended in the follow￾ing order based on efficacy, adverse events, and cost. Thioamides, spe￾cifically ethionamide, are associated with higher cure rates than cyclo￾serine and p-aminosalicylic acid.22 Ethionamide inhibits the activity of the inhA gene product, enoyl–acyl carrier protein reductase. This is the same enzyme by which acti￾vated isoniazid inhibits mycolic acid biosynthesis and may account for cross-resistance between isoniazid￾resistant isolates and ethionamide. When two oral bacteriostatic agents are warranted, cycloserine, which in￾hibits the incorporation of d-alanine into mycobacterial cell wall synthesis, may be added. Cycloserine is associ-

THERAPY UPDATE Bedaquiline Table 1 Antitubercular Agents for the Treatment of Multidrug-Resistant Tuberculosis27 3132 Adult Daily Dose Major Adverse Effects First-line oral agents Pyrazinamide 20-30mg/kg Nausea, vomiting, hepatotoxicity Ethambutol 15-25mg/kg Rifabutin 5 mg/kg Injectable agents 15-20mg/kg Renal, auditory, and vestibular toxicities Amikacin 5-20 mg/kg Renal, auditory, and vestibular toxicities aureomycin 15-20mg/kg Renal, auditory, and vestibular toxicities 15-20mg/kg Vestibular, renal, and auditory toxicities nes Levofloxacin 1000m Gastrointestinal symptoms, insomnia, dizziness, Q-T interval prolongation, tendon rupture Moxifloxacin 400mg Gastrointestinal symptoms, insomnia, dizziness, Q-T 800m interval prolongation, tendon rupture Ofloxacin Gastrointestinal symptoms, insomnia, dizziness, Q-T interval prolongation, tendon rupture Oral, bacteriostatic second-line agents 150 mg/kg ntestinal intolerance 15-20mg/kg ral neuropathy, central nervous s dysfunction Terizidone 15-20mg/kg Neurologic and psychiatric disturbances Ethionamide 15-20mg/kg Gastrointestinal intolerance, peripheral neuropathy, psychiatric disturbanc 15-20mg/kg Gastrointestinal intolerance, peripheral neuropathy, psychiatric disturbances Agents with unclear role in treatment of drug-resistant tuberculosis Clofazimine Gastrointestinal intoler Linezolid 00 mg amoxicillin/clavulanate 875 mg/125 mg every 12 hr Diarrhea, rash Thiacetazone Imipenem/cilastatin 500-1000 mg every 6 hr Seizures h-dose isoniazid 16-20mg/kg Hepatotoxicity, peripheral neuropathy 500 mg every 12 hr Gastrointestinal intolerance, Q-T interval prolongation isoniazid and rifampin are not included as first-line oral agents for multidrug-resistant tuberculosis due to resistance. lot available in the United States ated with a high rate of neuropsy- due to confounding results makes it by appropriate and supervised treat- chiatric symptoms, ranging from difficult to provide definitive recom- ment, and a strong commitment to somnolence to severe psychosis and mendations for these agents. For tuberculosis control and research suicidal ideation. Greater than 50% the most part, these agents are used have been heavily emphasized in the of patients who receive cycloserine 1 in difficult-to-treat drug-resistant tu- fight against resistance. However, g daily may experience these adverse berculosis against which agents from many resource-limited countries effects. Finally, p-aminosalicylic acid groups 1-4 are inadequate may lack adequate laboratories and remains a last-line agent because of tools to detect and resources to treat its low effectiveness, poor tolerability Focus on bedaquiline MDR tuberculosis. The treatment in the gastrointestinal tract, and high The emergence and rise of drug- of MDR tuberculosis presents seri- cost. 34 resistant tuberculosis are direct ous challenges. Treatment of MDR Group 5 agents are not recom- consequences of the shortcomings tuberculosis is lengthy, costly, and mended for routine use in drug- of current tuberculosis manage gh rates of se resistant tuberculosis treatment regi- ment strategies. The need for early ous drug-related toxicity. Protracted mens Inconclusive clinical evidence and accurate diagnosis, supported therapy with complex regimens is Am J Health-Syst Pharm--Vol 70 Nov 15, 2013 1987

THERAPY UPDATE Bedaquiline Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 1987 ated with a high rate of neuropsy￾chiatric symptoms, ranging from somnolence to severe psychosis and suicidal ideation. Greater than 50% of patients who receive cycloserine 1 g daily may experience these adverse effects. Finally, p-aminosalicylic acid remains a last-line agent because of its low effectiveness, poor tolerability in the gastrointestinal tract, and high cost.34 Group 5 agents are not recom￾mended for routine use in drug￾resistant tuberculosis treatment regi￾mens. Inconclusive clinical evidence a Isoniazid and rifampin are not included as first-line oral agents for multidrug-resistant tuberculosis due to resistance. b Not available in the United States. Table 1. Antitubercular Agents for the Treatment of Multidrug-Resistant Tuberculosis27,31,32 Drug(s) Adult Daily Dose Major Adverse Effects First-line oral agentsa Pyrazinamide Ethambutol Rifabutin Injectable agents Kanamycin Amikacin Capreomycin Streptomycin Fluoroquinolones Levofloxacin Moxifloxacin Ofloxacin Oral, bacteriostatic second-line agents p-aminosalicylic acid Cycloserine Terizidoneb Ethionamide Protionamideb Agents with unclear role in treatment of drug-resistant tuberculosis Clofazimineb Linezolid Amoxicillin/clavulanate Thiacetazoneb Imipenem/cilastatin High-dose isoniazid Clarithromycin 20–30 mg/kg 15–25 mg/kg 5 mg/kg 15–20 mg/kg 15–20 mg/kg 15–20 mg/kg 15–20 mg/kg 1000 mg 400 mg 800 mg 150 mg/kg 15–20 mg/kg 15–20 mg/kg 15–20 mg/kg 15–20 mg/kg 100 mg 600 mg 875 mg/125 mg every 12 hr 150 mg 500–1000 mg every 6 hr 16–20 mg/kg 500 mg every 12 hr Nausea, vomiting, hepatotoxicity Neuropathy (optic neuritis) Rash, discoloration of body fluids, neutropenia Renal, auditory, and vestibular toxicities Renal, auditory, and vestibular toxicities Renal, auditory, and vestibular toxicities Vestibular, renal, and auditory toxicities Gastrointestinal symptoms, insomnia, dizziness, Q-T interval prolongation, tendon rupture Gastrointestinal symptoms, insomnia, dizziness, Q-T interval prolongation, tendon rupture Gastrointestinal symptoms, insomnia, dizziness, Q-T interval prolongation, tendon rupture Gastrointestinal intolerance Peripheral neuropathy, central nervous system dysfunction Neurologic and psychiatric disturbances Gastrointestinal intolerance, peripheral neuropathy, psychiatric disturbances Gastrointestinal intolerance, peripheral neuropathy, psychiatric disturbances Gastrointestinal intolerance, skin pigmentation Myelosuppression, peripheral neuropathy Diarrhea, rash Cutaneous hypersensitivity Seizures Hepatotoxicity, peripheral neuropathy Gastrointestinal intolerance, Q-T interval prolongation due to confounding results makes it difficult to provide definitive recom￾mendations for these agents.31 For the most part, these agents are used in difficult-to-treat drug-resistant tu￾berculosis against which agents from groups 1–4 are inadequate. Focus on bedaquiline The emergence and rise of drug￾resistant tuberculosis are direct consequences of the shortcomings of current tuberculosis manage￾ment strategies. The need for early and accurate diagnosis, supported by appropriate and supervised treat￾ment, and a strong commitment to tuberculosis control and research have been heavily emphasized in the fight against resistance. However, many resource-limited countries may lack adequate laboratories and tools to detect and resources to treat MDR tuberculosis. The treatment of MDR tuberculosis presents seri￾ous challenges. Treatment of MDR tuberculosis is lengthy, costly, and associated with high rates of seri￾ous drug-related toxicity. Protracted therapy with complex regimens is

THERAPY UPDATE Bedaquiline a significant barrier to adherence. In December 2012, the Food and l-phenyl-butan-2-ol, and the mo- Costs associated with these regimens Drug Administration(FDA)ap- lecular formula is C3H3BrN, O further complicate an already dif- proved bedaquiline as part of the bedaquiline has a molecular weight ficult situation. A standard course of treatment regimen for pulmonary of 555.51 daltons. 20,while drugs to treat MDR tuber- use of bedaquiline should be reserved Although derived from quinolone antitubercular drugs may cost about MDR tuberculosis. Specifically, the Target and mechanism of acti culosis may cost as much as S5000, for patients for whom effective treat- bedaquiline exhibits no nhBy depending on the agents used and ment regimens cannot otherwise be tory effects on dNa gyrase. Instead, the duration of therapy. Costs from provided. This constraint stemmed bedaquiline inhibits mycobacterial dditional diagnostic tests, labora- from FDAs accelerated approval adenosine triphosphate(ATP)syn tory tests, and office visits may fur- program in which bedaquiline was thase, an essential enzyme in the ther augment expenses in an already granted approval based on efficacy generation of energy for M. tuber- prolonged and extensive treatment and safety data from Phase II stud- culosis. s Bedaquiline binds to the regimen. ies. Below, the available data for and oligomeric and proteolipid subunit The need for new drugs to combat clinical implications of bedaquiline c of the proton pump of mycobacte- MDR tuberculosis is critical. current are discussed rial ATP synthase and is assumed to therapies primarily consist of older Drug discovery. The develop- mimic a conserved basic residue in second-line agents that have been re- ment of bedaquiline is an important the proton transfer chain, arginine purposed for the treatment of MDr advance against tuberculosis and 186. Subsequently, conformational tuberculosis. The available evidence involved the screening of over 70,000 changes occur in mycobacterial to guide the dosing and combination compounds for inhibition against ATP synthase by blocking the ro- of these agents remains limited and Mycobacterium smegmatis, a rapidly tary movement of subunit c, whick of low quality Without new drugs, growing, nonpathogenic mycobac- is necessary for proton flow. Al the dilemma of treating progres- terium used as a model for tuber- though bedaquiline is highly active sively more-resistant tuberculosis culosis. From these prototypes, against both replicating and dor- with potentially nonsusceptible or Andries et al. identified bedaquiline mant mycobacteria, M. tuberculosis less-effective regimens will escalate. ( initially known as R207910, then in a dormant state may be especially Moreover, there is a profound need TMC207) as the lead compound sensitive to ATP depletion. Thus, for for newer agents that may shorten among a series of diarylquinolines. an organism that already exists in r simplify current treatment regi- Bedaquiline was the most active low-energystates, further deple mens for drug-sensitive, MDR, and among three compounds with in tion of low ATP stores results in an XDR tuberculosis. To date, the target vivo antimycobacterial activity. Their effective method of antimycobacte treatment success rate of at least 75% results, which were seven years in rial killing for MDR tuberculosis was achieved the making, were first described at The novel mechanism of action by only 30 of 107 countries that re- the 2004 Interscience Conference on of diarylquinolines was initially ported treatment outcomes. Antimicrobial Agents and Chemo- identified in an analysis of mutant For over 40 years, no new agents therapy meeting. strains resistant to bedaquiline Point for the treatment of tuberculosis Chemistry Diarylquinolines con- mutations in the genome sequences had been approved. In light of re- tain a quinolinic central heterocyclic of M. tuberculosis and M. smegmatis sistance and cross-resistance among nucleus with side chains of tertiary target the atpE gene responsible for antitubercular agents, bedaquiline alcohol and tertiary amine groups. encoding subunit c of ATP synthase represents a much-needed treatment A pure enantiomer with two chiral Further findings indicate bedaqui strategy when all other routes have centers, bedaquiline was isolated line's highly selective inhibition of been exhausted. Bedaquiline is the from a mixture of four isomers. Us- M. tuberculosis ATP synthase. 42 first novel antitubercular drug to be ing high-performance liquid chro- Haagsma et al. observed a 20,000- approved since rifampin in 1970. matography(HPLC), Andries et al. fold lower sensitivity for bedaquiline New chemical entities, such as bed- purified and separated two diastereo- by human mitochondrial ATP syn aquiline, account for a minority of isomers with an A: B ratio of 40: 60. thase compared with mycobacterial compounds in the antitubercular The active diastereoisomer was fur- ATP synthase In their study, mito- drug pipeline. Furthermore, bedag. ther separated by chiral HPLC; be- chondria from human cells, uiline's novel mechanism of action aquiline was the active R, S-isomer. liver, and bovine heart all showed sets it apart from analogs of known The chemical name of bedaquiline is very low sensitivity for bedaquiline antitubercular drugs and existing 1-(6-bromo-2-methoxy-quinolin-3-yl)- indicating unlikely target-based tox- ntibiotics under investigation 4-dimethylamino-2-naphthalen-1-yl- icity in mammalian cells 1988 Am JHealth-Syst Pharm-Vol 70 Nov 15, 2013

THERAPY UPDATE Bedaquiline 1988 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 a significant barrier to adherence. Costs associated with these regimens further complicate an already dif￾ficult situation. A standard course of antitubercular drugs may cost about $20, while drugs to treat MDR tuber￾culosis may cost as much as $5000, depending on the agents used and the duration of therapy.35 Costs from additional diagnostic tests, labora￾tory tests, and office visits may fur￾ther augment expenses in an already prolonged and extensive treatment regimen. The need for new drugs to combat MDR tuberculosis is critical. Current therapies primarily consist of older second-line agents that have been re￾purposed for the treatment of MDR tuberculosis.36 The available evidence to guide the dosing and combination of these agents remains limited and of low quality. Without new drugs, the dilemma of treating progres￾sively more-resistant tuberculosis with potentially nonsusceptible or less-effective regimens will escalate. Moreover, there is a profound need for newer agents that may shorten or simplify current treatment regi￾mens for drug-sensitive, MDR, and XDR tuberculosis. To date, the target treatment success rate of at least 75% for MDR tuberculosis was achieved by only 30 of 107 countries that re￾ported treatment outcomes.9 For over 40 years, no new agents for the treatment of tuberculosis had been approved. In light of re￾sistance and cross-resistance among antitubercular agents, bedaquiline represents a much-needed treatment strategy when all other routes have been exhausted. Bedaquiline is the first novel antitubercular drug to be approved since rifampin in 1970.37 New chemical entities, such as bed￾aquiline, account for a minority of compounds in the antitubercular drug pipeline. Furthermore, bedaq￾uiline’s novel mechanism of action sets it apart from analogs of known antitubercular drugs and existing antibiotics under investigation. In December 2012, the Food and Drug Administration (FDA) ap￾proved bedaquiline as part of the treatment regimen for pulmonary MDR tuberculosis. Specifically, the use of bedaquiline should be reserved for patients for whom effective treat￾ment regimens cannot otherwise be provided.38 This constraint stemmed from FDA’s accelerated approval program in which bedaquiline was granted approval based on efficacy and safety data from Phase II stud￾ies.39 Below, the available data for and clinical implications of bedaquiline are discussed. Drug discovery. The develop￾ment of bedaquiline is an important advance against tuberculosis and involved the screening of over 70,000 compounds for inhibition against Mycobacterium smegmatis, a rapidly growing, nonpathogenic mycobac￾terium used as a model for tuber￾culosis.40,41 From these prototypes, Andries et al.42 identified bedaquiline (initially known as R207910, then TMC207) as the lead compound among a series of diarylquinolines. Bedaquiline was the most active among three compounds with in vivo antimycobacterial activity. Their results, which were seven years in the making, were first described at the 2004 Interscience Conference on Antimicrobial Agents and Chemo￾therapy meeting.43 Chemistry. Diarylquinolines con￾tain a quinolinic central heterocyclic nucleus with side chains of tertiary alcohol and tertiary amine groups.44 A pure enantiomer with two chiral centers, bedaquiline was isolated from a mixture of four isomers. Us￾ing high-performance liquid chro￾matography (HPLC), Andries et al.42 purified and separated two diastereo￾isomers with an A:B ratio of 40:60. The active diastereoisomer was fur￾ther separated by chiral HPLC; be￾daquiline was the active R,S-isomer. The chemical name of bedaquiline is 1-(6-bromo-2-methoxy-quinolin-3-yl)- 4-dimethylamino-2-naphthalen-1-yl- 1-phenyl-butan-2-ol, and the mo￾lecular formula is C32H31BrN2 O2 . Bedaquiline has a molecular weight of 555.51 daltons.42 Target and mechanism of action. Although derived from quinolones, bedaquiline exhibits no inhibi￾tory effects on DNA gyrase. Instead, bedaquiline inhibits mycobacterial adenosine triphosphate (ATP) syn￾thase, an essential enzyme in the generation of energy for M. tuber￾culosis. 42,45 Bedaquiline binds to the oligomeric and proteolipic subunit c of the proton pump of mycobacte￾rial ATP synthase and is assumed to mimic a conserved basic residue in the proton transfer chain, arginine 186. Subsequently, conformational changes occur in mycobacterial ATP synthase by blocking the ro￾tary movement of subunit c, which is necessary for proton flow.45 Al￾though bedaquiline is highly active against both replicating and dor￾mant mycobacteria, M. tuberculosis in a dormant state may be especially sensitive to ATP depletion. Thus, for an organism that already exists in “low-energy” states, further deple￾tion of low ATP stores results in an effective method of antimycobacte￾rial killing. The novel mechanism of action of diarylquinolines was initially identified in an analysis of mutant strains resistant to bedaquiline. Point mutations in the genome sequences of M. tuberculosis and M. smegmatis target the atpE gene responsible for encoding subunit c of ATP synthase. Further findings indicate bedaqui￾line’s highly selective inhibition of M. tuberculosis ATP synthase.42 Haagsma et al.46 observed a 20,000- fold lower sensitivity for bedaquiline by human mitochondrial ATP syn￾thase compared with mycobacterial ATP synthase. In their study, mito￾chondria from human cells, murine liver, and bovine heart all showed very low sensitivity for bedaquiline, indicating unlikely target-based tox￾icity in mammalian cells

THERAPY UPDATE Bedaquiline Antimicrobial spectra. Bedaquiline the results from cultures using this followed by 200 mg three times a has demonstrated potent antimyco- medium are finalized within four to week for six weeks correlated with bacterial activity against replicating five weeks. Instead, recommended mean peak and steady-state concen- bacilli both in vitro and in vivo. susceptibility-testing methods in- trations of 1.659 and 0.902 ng/mL The activity of bedaquiline seems to clude the Middlebrook 7H10/7Hll at week 8, respectively. Steady-state be limited to mycobacteria. For in Agar method and the resazurin plasma concentrations for most vitro antimycobacterial activity, the microtiter assay(REMA). 48.49 Both patients remained above the target median minimum inhibitory con- methods assess a range of concentra- level of 0.6 ug/mL throughout the centrations(MICs)of bedaquiline tions from 0.008 to 1.0 ug/mL With eight-week study period. A term against M. tuberculosis H37Rv and the Middlebrook 7H10/7HIl Agar nal elimination half-life of approxi six susceptible isolates of M. tuber- method, the MIC is determined as mately 5.5 months was observed with culosis were 0.03 and 0.06 ug/mL, the lowest concentration of bedaqui- bedaquiline and its major metabolite, respectively. The median MIC of line with 99% inhibition of growth. N-monodesmethyl(M2). In fact, bedaquiline against M. tuberculosis The MIC for the REMa is deter- plasma concentrations of bedaqui strains resistant to both isoniazid mined by the lowest concentration line and M2 were still quantifiable and rifampin was 0.03 ug/mL. Over- of bedaquiline that prevents a visible week 96. 2 all, these MICs were much lower change of resazurin color from blue Long half-lives and prolonged ef- than the MICs of gram-positive and to pink. fects of single-dose administrations gram-negative bacteria. MICs ex Pharmacokinetics and phar- in mice provided the initial rationale ceeding 32 ug/mL were observed for macodynamics. Pharmacokinetic for less-frequent administration. Ir Staphylococcus aureus, Streptococcu ies in healthy male volunteers murine models, bedaquiline exhib pneumoniae, Haemophilus influenzae, showed a linear relationship between ited half-lives ranging up to 64 and and e. coli, 42 bedaquiline doses and the maximum 92 hours in plasma and tissue, re- No cross-resistance between plasma concentration(Cm )and area spectively. Diacon et al. attributed bedaquiline and other antituber- under the concentration-time curve prolonged half-lives in their study cular drugs has been detected. Be- (AUC). In both single and multiple patients with the slow distribution daquiline demonstrated similar in ascending-dose studies, C and of bedaquiline and M2 from tissues. vitro activity against M. tuberculosis AUC increased proportionally up Both compounds have cationic am clinical isolates resistant to isoniazid, to the highest doses tested-a single phiphilic characteristics, which may rifampin, streptomycin, ethambutol, dose of 700 mg and multiple daily cause intracellular accumulation of yrazinamide, and moxifloxacin. doses reaching 400 mg. After admin- phospholipids and lead to drug ac For susceptibility testing, Andries et istration of a single dose, bedaquiline cumulation. Excess accumulation of al. 2 included a total of 50 strains of concentrations peaked at 5 hours and phospholipids in tissues is reversible M. tuberculosis, of which 30 clini- declined triexponentially once the on drug termination and subsequent al isolates were mdR tuberculo- C was reached. An"effective half- elimination sis. Strains were subcultured on life" of approximately 24 hours was These prolonged effects from a Lowenstein-Jensen media at 37C. deduced from a twofold increase in single dose supported the potential The radiometric BACTEC 460 meth- the AUC from administration to 24 for less-frequent dosing regimens od(bd, franklin Lakes, ND) was used hours later. 42 Once-weekly doses of 12.5 mg/kg to determine the susceptibility of Comparable pharmacokinetic for four weeks resulted in signifi bedaquiline and other conventional parameters were observed in Phase cantly lower bacterial loads per organ tuberculosis agents at their stan- II studies. In an early bactericidal(spleen and lung)(p<0.0014). This dard breakpoint concentrations activity study of 75 treatment-naive regimen demonstrated comparable (rifampin 2.0 ug/mL, isoniazid 0. 2 patients with smear-positive pulmo- efficacy to the minimum effective ug/mL, streptomycin 4.0 ug/mL, and nary tuberculosis, a regimen of 400 dosage of 6.5 mg/kg administered ethambutol 5.0 ug/mL). All MDR mg daily for seven days resulted in a five times per week for four weeks tuberculosis isolates tested were sus- C of 5.5 ug/mL, an AUC of 64.75 The minimum effective dosage was ceptible to bedaquiline at 0.1 ug/mL ug. hr/mL, and a time to maximum defined as the minimum dosage nec- with 57% of these isolates(17 of 30) concentration of four hours. 0 Mean essary to prevent mortality, spleen susceptible at 0.01 ug/mL. plasma concentration-time profiles enlargement, and gross lung lesions Susceptibility testing. Current were described by Diacon et al. in a in the mice. Dosages of 12.5 and 25 recommendations for suscepti- study of 47 patients with pulmonary mg/kg further resulted in signifi- bility testing do not include the MDR tuberculosis. a treatment re cantly greater reductions in bacterial Lowenstein-Jensen medium, since men of 400 mg daily for two weeks loads(p<0.0014)than isoniazid 25 Am J Health-Syst Pharm-Vol 70 Nov 15, 2013 1989

THERAPY UPDATE Bedaquiline Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 1989 Antimicrobial spectra. Bedaquiline has demonstrated potent antimyco￾bacterial activity against replicating bacilli both in vitro and in vivo. The activity of bedaquiline seems to be limited to mycobacteria. For in vitro antimycobacterial activity, the median minimum inhibitory con￾centrations (MICs) of bedaquiline against M. tuberculosis H37Rv and six susceptible isolates of M. tuber￾culosis were 0.03 and 0.06 mg/mL, respectively. The median MIC of bedaquiline against M. tuberculosis strains resistant to both isoniazid and rifampin was 0.03 mg/mL. Over￾all, these MICs were much lower than the MICs of gram-positive and gram-negative bacteria. MICs ex￾ceeding 32 mg/mL were observed for Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and E. coli. 42 No cross-resistance between bedaquiline and other antituber￾cular drugs has been detected. Be￾daquiline demonstrated similar in vitro activity against M. tuberculosis clinical isolates resistant to isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide, and moxifloxacin.42 For susceptibility testing, Andries et al.42 included a total of 50 strains of M. tuberculosis, of which 30 clini￾cal isolates were MDR tuberculo￾sis. Strains were subcultured on Löwenstein–Jensen media at 37 °C. The radiometric BACTEC 460 meth￾od (BD, Franklin Lakes, NJ) was used to determine the susceptibility of bedaquiline and other conventional tuberculosis agents at their stan￾dard breakpoint concentrations (rifampin 2.0 mg/mL, isoniazid 0.2 mg/mL, streptomycin 4.0 mg/mL, and ethambutol 5.0 mg/mL). All MDR tuberculosis isolates tested were sus￾ceptible to bedaquiline at 0.1 mg/mL with 57% of these isolates (17 of 30) susceptible at 0.01 mg/mL.42 Susceptibility testing. Current recommendations for suscepti￾bility testing do not include the Löwenstein–Jensen medium, since the results from cultures using this medium are finalized within four to five weeks.47 Instead, recommended susceptibility-testing methods in￾clude the Middlebrook 7H10/7H11 Agar method and the resazurin microtiter assay (REMA).48,49 Both methods assess a range of concentra￾tions from 0.008 to 1.0 mg/mL. With the Middlebrook 7H10/7H11 Agar method, the MIC is determined as the lowest concentration of bedaqui￾line with 99% inhibition of growth. The MIC for the REMA is deter￾mined by the lowest concentration of bedaquiline that prevents a visible change of resazurin color from blue to pink.38 Pharmacokinetics and phar￾macodynamics. Pharmacokinetic studies in healthy male volunteers showed a linear relationship between bedaquiline doses and the maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC). In both single and multiple ascending-dose studies, Cmax and AUC increased proportionally up to the highest doses tested—a single dose of 700 mg and multiple daily doses reaching 400 mg. After admin￾istration of a single dose, bedaquiline concentrations peaked at 5 hours and declined triexponentially once the Cmax was reached. An “effective half￾life” of approximately 24 hours was deduced from a twofold increase in the AUC from administration to 24 hours later.42 Comparable pharmacokinetic parameters were observed in Phase II studies. In an early bactericidal activity study of 75 treatment-naive patients with smear-positive pulmo￾nary tuberculosis, a regimen of 400 mg daily for seven days resulted in a Cmax of 5.5 mg/mL, an AUC of 64.75 mg ·hr/mL, and a time to maximum concentration of four hours.50 Mean plasma concentration–time profiles were described by Diacon et al.51 in a study of 47 patients with pulmonary MDR tuberculosis. A treatment regi￾men of 400 mg daily for two weeks followed by 200 mg three times a week for six weeks correlated with mean peak and steady-state concen￾trations of 1.659 and 0.902 ng/mL at week 8, respectively. Steady-state plasma concentrations for most patients remained above the target level of 0.6 mg/mL throughout the eight-week study period.51 A termi￾nal elimination half-life of approxi￾mately 5.5 months was observed with bedaquiline and its major metabolite, N-monodesmethyl (M2). In fact, plasma concentrations of bedaqui￾line and M2 were still quantifiable at week 96.52 Long half-lives and prolonged ef￾fects of single-dose administrations in mice provided the initial rationale for less-frequent administration. In murine models, bedaquiline exhib￾ited half-lives ranging up to 64 and 92 hours in plasma and tissue, re￾spectively.42 Diacon et al.52 attributed prolonged half-lives in their study patients with the slow distribution of bedaquiline and M2 from tissues. Both compounds have cationic am￾phiphilic characteristics, which may cause intracellular accumulation of phospholipids and lead to drug ac￾cumulation. Excess accumulation of phospholipids in tissues is reversible on drug termination and subsequent elimination. These prolonged effects from a single dose supported the potential for less-frequent dosing regimens. Once-weekly doses of 12.5 mg/kg for four weeks resulted in signifi￾cantly lower bacterial loads per organ (spleen and lung) (p < 0.0014). This regimen demonstrated comparable efficacy to the minimum effective dosage of 6.5 mg/kg administered five times per week for four weeks. The minimum effective dosage was defined as the minimum dosage nec￾essary to prevent mortality, spleen enlargement, and gross lung lesions in the mice. Dosages of 12.5 and 25 mg/kg further resulted in signifi￾cantly greater reductions in bacterial loads (p < 0.0014) than isoniazid 25

THERAPY UPDATE Bedaquiline mg/kg, which has potent antimyco- cations for bedaquiline; however, in this review, the following section bacterial activity. When bedaquiline bedaquiline is not indicated in pa- will focus on the Phase II studies that tion regimen of isoniazid, rifampin, or drug-sensitive tuberculosis. The approval by FD, quiline's accelerated 25 mg/kg was added to the combina- tients with latent, extrapulmonary, resulted in bedac and pyrazinamide, a significantly safety and efficacy of bedaquiline in Rustomjee et al. assessed the bac- greater decrease in pulmonary bacte- the aforementioned settings have not tericidal activity of bedaquiline in 75 rial load was seen(p<0.0018). 2 been established treatment-naive patients with smear- The bioavailability of bedaquiline FDa granted bedaquiline acceler- positive pulmonary tuberculosis. Pa is significantly affected by food. a ated approval based on the surrogate tients were randomized to one of five standard meal with approximately 22 endpoint of time to sputum conver- groups: once-daily bedaquiline(25 g of fat increased the bioavailability sion. 51,52 This surrogate endpoint was 100, or 400 mg), rifampin 600 mg, or bedaquiline by twofold compared defined as the time between study isoniazid 300 mg for seven days. Spu- with fasting conditions. Current drug initiation and the date of the tum samples were collected at base- dosing recommendations include first of two consecutive negative line and after each dose. Bedaquiline the administration of bedaquiline sputum cultures, taken at least 25 at 25 and 100 mg did not exhibit bac with meals in order to enhance oral days apart with no confirmed posi- tericidal effect. The 400-mg dose of bioavailability tive intermediate cultures. Phase I bedaquiline correlated with greater Bedaquiline is primarily metabo- trials assessing this surrogate end- bactericidal activity, thus displaying lized by cytochrome P-450 isoen- point showed greater sputum culture a linear relationship between dosage zyme 3A4(CYP3A4). Therefore, conversion up to week 24 for the and effect. Specifically in patients its metabolism can be affected bedaquiline group. This evidence who received 400-mg daily doses by CYP3A4 inducers and inhibi- suggests that bedaquiline provides of bedaquiline, Rustomjee et al. so tors. The major metabolite, M2, an advantage over existing therapy noted comparable decreases in bacte- is threefold to sixfold less active for MDR tuberculosis. However, rial load with isoniazid and rifampin against M. tuberculosis than beda- bedaquiline's accelerated approval on days 4 through 7. From days 0 to bedaquiline is 1: 4 compared with Phase Ill trial sent on confirmatory through 7, decreases in bacterial load quinine. In humans, the ratio for M2 remains conting were 0.77 log CFU/mL for bedaqui ice, in which 80% of bedaquiline converted to m2. 53 c Approved dosing and administra- line at 400 mg, 1.88 log CFU/mL for tion A course of bedaquiline requires isoniazid, and 1.70 log CFU/mL for Results from in vitro studies by 24 weeks of therapy in combination rifampin. This delayed bactericidal Andreis et al. suggest that bedaqui- with other antitubercular drugs. The activity may potentially be attributed ne has time-dependent, bactericidal dosing of bedaquiline is 400 mg once to bedaquiline's mechanism of action activity. M. tuberculosis in log-phase daily for 2 weeks followed by 200 mg as ATP depletion and pH disruption growth was exposed to bedaquiline thrice weekly for 22 weeks. Bedaqui- usually take days to impact mycobac oncentrations 10 and 100 times the line is available as 100-mg tablets, terial viability MIC. Despite higher concentrations, which must be taken with food and A two-stage Phase II multicenter, samples exposed to bedaquiline swallowed whole with water. The placebo-controlled study was con concentrations at 100 times the MIC manufacturer recommends dispens- ducted, comprising of an explor- resulted in similar reductions of ing bedaquiline in its original con- atory stage( 8 weeks) followed by a bacterial loads as 10 times the MIc tainer. If tablets are dispensed outside separate proof of efficacy stage(24 on days 2, 6, and 12 when cultures the original container, they should be weeks) to assess the safety, pharma were serially diluted and plated. At placed in a light-resistant container cokinetics, and antibacterial activity 6 and 12 days, bacterial loads were with a maximum expiration date of bedaquiline. In stage I, Diacon et reduced by approximately 1 and 3 of three months. Tablets should be al 5152 randomized 47 newly diag log colony-forming units(CFU)/mL, stored at room temperature(25C nosed pulmonary MDr tuberculosis respectively. or 77F)with excursions permitted patients from South Africa to re- Current FDA-approved indica- to 15-30C (59-86F) ceive bedaquiline (n= 23)(400 mg tion. bedaquiline dicated in Clinical studies. Eleven Phase daily for 2 weeks followed by 200 combination with at least three I studies have been conducted in mg three times a week for 6 weeks) other antitubercular drugs in adults which pharmacokinetic and pharma- or placebo(n= 24)in combination (age 2 18 years) with pulmonary codynamic parameters, dosing strat- with a background regimen that MDR tuberculosis and when no egies, and drug-drug interactions of consisted of five second-line agents other effective regimen is available. bedaquiline were assessed. As these (kanamycin, ofloxacin, ethionamide, Currently, there are no contraindi- subjects were previously discussed pyrazinamide, and cycloserine or 1990 Am JHealth-Syst Pharm-Vol 70 Nov 15, 2013

THERAPY UPDATE Bedaquiline 1990 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 mg/kg, which has potent antimyco￾bacterial activity. When bedaquiline 25 mg/kg was added to the combina￾tion regimen of isoniazid, rifampin, and pyrazinamide, a significantly greater decrease in pulmonary bacte￾rial load was seen (p < 0.0018).42 The bioavailability of bedaquiline is significantly affected by food. A standard meal with approximately 22 g of fat increased the bioavailability of bedaquiline by twofold compared with fasting conditions.38 Current dosing recommendations include the administration of bedaquiline with meals in order to enhance oral bioavailability. Bedaquiline is primarily metabo￾lized by cytochrome P-450 isoen￾zyme 3A4 (CYP3A4).53 Therefore, its metabolism can be affected by CYP3A4 inducers and inhibi￾tors. The major metabolite, M2, is threefold to sixfold less active against M. tuberculosis than beda￾quiline. In humans, the ratio for M2 to bedaquiline is 1:4 compared with mice, in which 80% of bedaquiline is converted to M2. 53 Results from in vitro studies by Andreis et al.42 suggest that bedaqui￾line has time-dependent, bactericidal activity. M. tuberculosis in log-phase growth was exposed to bedaquiline concentrations 10 and 100 times the MIC. Despite higher concentrations, samples exposed to bedaquiline concentrations at 100 times the MIC resulted in similar reductions of bacterial loads as 10 times the MIC on days 2, 6, and 12 when cultures were serially diluted and plated. At 6 and 12 days, bacterial loads were reduced by approximately 1 and 3 log colony-forming units (CFU)/mL, respectively. Current FDA-approved indica￾tion. Bedaquiline is indicated in combination with at least three other antitubercular drugs in adults (age ≥ 18 years) with pulmonary MDR tuberculosis and when no other effective regimen is available.38 Currently, there are no contraindi￾cations for bedaquiline; however, bedaquiline is not indicated in pa￾tients with latent, extrapulmonary, or drug-sensitive tuberculosis. The safety and efficacy of bedaquiline in the aforementioned settings have not been established. FDA granted bedaquiline acceler￾ated approval based on the surrogate endpoint of time to sputum conver￾sion.51,52 This surrogate endpoint was defined as the time between study drug initiation and the date of the first of two consecutive negative sputum cultures, taken at least 25 days apart with no confirmed posi￾tive intermediate cultures. Phase II trials assessing this surrogate end￾point showed greater sputum culture conversion up to week 24 for the bedaquiline group. This evidence suggests that bedaquiline provides an advantage over existing therapy for MDR tuberculosis. However, bedaquiline’s accelerated approval remains contingent on confirmatory Phase III trials. Approved dosing and administra￾tion. A course of bedaquiline requires 24 weeks of therapy in combination with other antitubercular drugs. The dosing of bedaquiline is 400 mg once daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks. Bedaqui￾line is available as 100-mg tablets, which must be taken with food and swallowed whole with water.38 The manufacturer recommends dispens￾ing bedaquiline in its original con￾tainer. If tablets are dispensed outside the original container, they should be placed in a light-resistant container with a maximum expiration date of three months. Tablets should be stored at room temperature (25 °C or 77 °F) with excursions permitted to 15–30 °C (59–86 °F).38 Clinical studies. Eleven Phase I studies have been conducted in which pharmacokinetic and pharma￾codynamic parameters, dosing strat￾egies, and drug–drug interactions of bedaquiline were assessed.54 As these subjects were previously discussed in this review, the following section will focus on the Phase II studies that resulted in bedaquiline’s accelerated approval by FDA. Rustomjee et al.50 assessed the bac￾tericidal activity of bedaquiline in 75 treatment-naive patients with smear￾positive pulmonary tuberculosis. Pa￾tients were randomized to one of five groups: once-daily bedaquiline (25, 100, or 400 mg), rifampin 600 mg, or isoniazid 300 mg for seven days. Spu￾tum samples were collected at base￾line and after each dose. Bedaquiline at 25 and 100 mg did not exhibit bac￾tericidal effect. The 400-mg dose of bedaquiline correlated with greater bactericidal activity, thus displaying a linear relationship between dosage and effect. Specifically in patients who received 400-mg daily doses of bedaquiline, Rustomjee et al.50 noted comparable decreases in bacte￾rial load with isoniazid and rifampin on days 4 through 7. From days 0 through 7, decreases in bacterial load were 0.77 log CFU/mL for bedaqui￾line at 400 mg, 1.88 log CFU/mL for isoniazid, and 1.70 log CFU/mL for rifampin. This delayed bactericidal activity may potentially be attributed to bedaquiline’s mechanism of action as ATP depletion and pH disruption usually take days to impact mycobac￾terial viability.44 A two-stage Phase II multicenter, placebo-controlled study was con￾ducted, comprising of an explor￾atory stage (8 weeks) followed by a separate proof of efficacy stage (24 weeks) to assess the safety, pharma￾cokinetics, and antibacterial activity of bedaquiline. In stage I, Diacon et al.51,52 randomized 47 newly diag￾nosed pulmonary MDR tuberculosis patients from South Africa to re￾ceive bedaquiline (n = 23) (400 mg daily for 2 weeks followed by 200 mg three times a week for 6 weeks) or placebo (n = 24) in combination with a background regimen that consisted of five second-line agents (kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or

THERAPY UPDATE Bedaquiline terizidone). After 8 weeks of double- placebo group(p=0.069). In both predose time point occurred during blind treatment, bedaquiline was stages of the study, fewer patients the second stage of the study at week discontinued, and patients continued receiving bedaquiline developed 18(15.7 and 6.2 milliseconds in the with their initial background regi- pre-XDR tuberculosis or XDR tuber- bedaquiline and placebo groups, men for 18-24 months. Final follow- culosis when compared with those respectively)(p not reported). The up was at week 104. The addition of receiving placebo(I patient versus 4 highest risk for Q-TcF prolongation bedaquiline, as compared to placebo, patients in stage 1; 0 patient versus 7 correlated with the initial 24 weeks resulted in reduced time to sputum patients in stage 2). Thus, the addi- of bedaquiline treatment, after which culture conversion(hazard ratio, tion of bedaquiline may potentially Q-TcF prolongation persisted but 11.8; 95% confidence interval, 2.3- decrease the risk of acquiring resis- increases became less prominent in 61.3; P=0.003)and significantly in- tance to other background agents. the bedaquiline group. No Q-TcF creased proportions of patients with A total of 233 patients with con- absolute values exceeded 500 mil egative sputum cultures(47. 6%[10 firmed pulmonary MDR tuberculo- liseconds, and no adverse events of 21] versus 8.7%[2 of 23])after sis(newly diagnosed and previously were associated with electrocardio- 8 weeks. Time to culture conver- treated) were enrolled in a single- graphic changes in both stages of the sion at 24 weeks was significantly group, open-label, uncontrolled study. 51.52.54 However, Q-TcF values reduced in the bedaquiline group Phase II trial. 54 Patients with XDR over 500 milliseconds were reported (hazard ratio, 2.25; 95% confidence tuberculosis taking at least three in the single-group, open-label interval, 1.08-4.71;P=0.031). Nega- susceptible antitubercular agents uncontrolled Phase II trial. Con tive sputum cultures at week 24 were were also included. Patients received comitant administration with the observed in 17(81%)of 21 patients bedaquiline for up to 24 weeks in antimycobacterial agent clofazimine versus 15(65. 2%)of 23 patients in combination with background MDR resulted in mean Q-TcF increases the bedaquiline and placebo groups, tuberculosis regimens. The two-year of approximately 30 milliseconds respectively Accordingly, the 38.9% follow-up period consisting solely of and values over 500 milliseconds. and 15.8%difference at weeks 8 and background regimens for MDR tu- Hence, additive effects of medica- 24 in the percentage of culture con- berculosis is currently ongoing tions that can prolong the Q-TCF version demonstrated reliably bet- Adverse effects. Pooled safety interval must be considered ter microbiological responses with data from the two-stage Phase II Of greatest concern is the bedaquiline trial revealed more hepatic disorders creased risk of mortality reported Similar to the first stage of the in patients receiving bedaquiline with bedaquiline. In stage 2 of the study, newly diagnosed MDR tu-(9 of 102 patients[8.8%])versus Phase III, multicenter, placebo berculosis patients in stage 2 were placebo(2 of 105 patients [1.9%]) controlled study, an increased risk randomized in a 1: I ratio to receive (p not reported). Increases in liver of death was seen in the bedaquiline edaquiline or placebo for 8 weeks function test values resolved in all group(9 of 79 patients [11.4%) in combination with a background but 2 patients. A Hy's law analysis compared with the placebo group regimen of other second-line tuber- identified elevated serum aspartate (2 of 81 patients [2.5%1) within a culosis agents. 2 Patients continued transaminase(greater than threefold 120-week window(p=0.03).3.One on their background regimens for the upper limit of normal)and total death occurred during bedaquiline 18-24 months, and final follow-up bilirubin (greater than twofold the administration. Five deaths in the occurred at week 120. A total of 160 upper limit of normal) as risk fac- bedaquiline group and all deaths in patients from seven countries were tors for drug-related liver injury. the placebo group appeared to be enrolled in the study: 79 were treated Currently, no dosage adjustments tuberculosis related. 5 In stage 1 with bedaquiline, and 81 received for hepatic dysfunction are provided. none of the deaths due to hemoptysis placebo. At week 24, a significantly However, increased laboratory test secondary to tuberculosis, complica greater percentage of patients in the value monitoring, viral hepatitis tions of tuberculosis, and acquired bedaquiline group had culture con- testing, and discontinuation of con- immune deficiency syndrome were version(78.8%[52 of 66 patients comitant hepatotoxic medications considered to be bedaquiline relat- ersus 57.6%[38 of 66 patients],p= are recommended for patients with ed51 However, no clear relationship 0.008). Durable microbiological re- impaired liver function.38 between these deaths and treatment sponses continued to be observed at Increases in mean Q-T interval, response or underlying disease sever- week 72. The percentage of respond- corrected using Fridericia's formula ity was found. The reason for the dif- ers at week 72 was 71.2%(47 of 66 (Q-TcF), were more pronounced in ference in mortality rates between the patients)in the bedaquiline group the bedaquiline group. The larg- two study groups remains unclear. and 56.1%(37 of 66 patients) in the est mean increase in Q-TcF at a Nonetheless, the FDA-approved indi Am J Health-Syst Pharm--Vol 70 Nov 15, 2013 1991

THERAPY UPDATE Bedaquiline Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 1991 terizidone). After 8 weeks of double￾blind treatment, bedaquiline was discontinued, and patients continued with their initial background regi￾men for 18–24 months. Final follow￾up was at week 104. The addition of bedaquiline, as compared to placebo, resulted in reduced time to sputum culture conversion (hazard ratio, 11.8; 95% confidence interval, 2.3– 61.3; p = 0.003) and significantly in￾creased proportions of patients with negative sputum cultures (47.6% [10 of 21] versus 8.7% [2 of 23]) after 8 weeks.51 Time to culture conver￾sion at 24 weeks was significantly reduced in the bedaquiline group (hazard ratio, 2.25; 95% confidence interval, 1.08–4.71; p = 0.031). Nega￾tive sputum cultures at week 24 were observed in 17 (81%) of 21 patients versus 15 (65.2%) of 23 patients in the bedaquiline and placebo groups, respectively.52 Accordingly, the 38.9% and 15.8% difference at weeks 8 and 24 in the percentage of culture con￾version demonstrated reliably bet￾ter microbiological responses with bedaquiline. Similar to the first stage of the study, newly diagnosed MDR tu￾berculosis patients in stage 2 were randomized in a 1:1 ratio to receive bedaquiline or placebo for 8 weeks in combination with a background regimen of other second-line tuber￾culosis agents.52 Patients continued on their background regimens for 18–24 months, and final follow-up occurred at week 120. A total of 160 patients from seven countries were enrolled in the study; 79 were treated with bedaquiline, and 81 received placebo. At week 24, a significantly greater percentage of patients in the bedaquiline group had culture con￾version (78.8% [52 of 66 patients] versus 57.6% [38 of 66 patients], p = 0.008). Durable microbiological re￾sponses continued to be observed at week 72. The percentage of respond￾ers at week 72 was 71.2% (47 of 66 patients) in the bedaquiline group and 56.1% (37 of 66 patients) in the placebo group (p = 0.069). In both stages of the study, fewer patients receiving bedaquiline developed pre-XDR tuberculosis or XDR tuber￾culosis when compared with those receiving placebo (1 patient versus 4 patients in stage 1; 0 patient versus 7 patients in stage 2). Thus, the addi￾tion of bedaquiline may potentially decrease the risk of acquiring resis￾tance to other background agents.54 A total of 233 patients with con￾firmed pulmonary MDR tuberculo￾sis (newly diagnosed and previously treated) were enrolled in a single￾group, open-label, uncontrolled Phase II trial.54 Patients with XDR tuberculosis taking at least three susceptible antitubercular agents were also included. Patients received bedaquiline for up to 24 weeks in combination with background MDR tuberculosis regimens. The two-year follow-up period consisting solely of background regimens for MDR tu￾berculosis is currently ongoing. Adverse effects. Pooled safety data from the two-stage Phase II trial revealed more hepatic disorders in patients receiving bedaquiline (9 of 102 patients [8.8%]) versus placebo (2 of 105 patients [1.9%]) (p not reported). Increases in liver function test values resolved in all but 2 patients. A Hy’s law analysis identified elevated serum aspartate transaminase (greater than threefold the upper limit of normal) and total bilirubin (greater than twofold the upper limit of normal) as risk fac￾tors for drug-related liver injury.54 Currently, no dosage adjustments for hepatic dysfunction are provided. However, increased laboratory test value monitoring, viral hepatitis testing, and discontinuation of con￾comitant hepatotoxic medications are recommended for patients with impaired liver function.38 Increases in mean Q-T interval, corrected using Fridericia’s formula (Q-TcF), were more pronounced in the bedaquiline group.51 The larg￾est mean increase in Q-TcF at a predose time point occurred during the second stage of the study at week 18 (15.7 and 6.2 milliseconds in the bedaquiline and placebo groups, respectively) (p not reported).54 The highest risk for Q-TcF prolongation correlated with the initial 24 weeks of bedaquiline treatment, after which Q-TcF prolongation persisted but increases became less prominent in the bedaquiline group. No Q-TcF absolute values exceeded 500 mil￾liseconds, and no adverse events were associated with electrocardio￾graphic changes in both stages of the study.51,52,54 However, Q-TcF values over 500 milliseconds were reported in the single-group, open-label, uncontrolled Phase II trial.54 Con￾comitant administration with the antimycobacterial agent clofazimine resulted in mean Q-TcF increases of approximately 30 milliseconds and values over 500 milliseconds.54 Hence, additive effects of medica￾tions that can prolong the Q-TcF interval must be considered. Of greatest concern is the in￾creased risk of mortality reported with bedaquiline. In stage 2 of the Phase III, multicenter, placebo￾controlled study, an increased risk of death was seen in the bedaquiline group (9 of 79 patients [11.4%]) compared with the placebo group (2 of 81 patients [2.5%]) within a 120-week window (p = 0.03).38,55 One death occurred during bedaquiline administration. Five deaths in the bedaquiline group and all deaths in the placebo group appeared to be tuberculosis related.54,55 In stage 1, none of the deaths due to hemoptysis secondary to tuberculosis, complica￾tions of tuberculosis, and acquired immune deficiency syndrome were considered to be bedaquiline relat￾ed.51 However, no clear relationship between these deaths and treatment response or underlying disease sever￾ity was found. The reason for the dif￾ference in mortality rates between the two study groups remains unclear. Nonetheless, the FDA-approved indi-

THERAPY UPDATE Bedaquiline cation recommends bedaquiline use Place in therapy. Continual emer- in complicated multidrug regimens in patients with MDR tuberculosis gence of more-resistant tuberculo- Shortening current therapy durations who have not responded to effective sis, such as XDR and totally-drug. while improving efficacy can poten first-line treatment regimens. resistant tuberculosis, raises serious tially improve patient outcomes Drug intera actions Patients receiv- concerns regarding current prac- Significant adverse effects are seen ing multidrug regimens for the treat- tices for control and management of with MDR tuberculosis regimens ment of tuberculosis and Hiv are at MDR tuberculosis. as the first novel that contain at least four antituber significant risk for drug-drug inter- antitubercular drug approved in over cular agents, none of which are be- actions that may require dosage ad- four decades, bedaquiline represents nign. Bedaquiline was relatively well justments or increased monitoring. an important milestone in tubercu- tolerated, with most adverse events dministr'garding the concomitant losis treatment thought to be associated with stan- administration of antiretrovirals Bedaquiline's unique mechanism dard MDR tuberculosis agents. How and bedaquiline are substantial. of action presents a much-needed ever, serious adverse events with be- Efavirenz, as a CYP3A4 inducer, alternative approach to current anti- aquiline therapy have culminated in may decrease levels of bedaquiline, a mycobacterial killing. By directly in- black-box warnings for Q-T interval CYP3A4 substrate hibiting ATP synthase, bedaquiline is prolongation and an increased risk Dooley et al. 3 conducted a Phase effective against both replicating and of mortality. The exact relationship I pharmacokinetic study to assess dormant mycobacteria. Pulmonary between bedaquiline and increased the potential for drug interactions cavitary lesions can contain hetero- risk of mortality are unknown in 33 healthy volunteers receiv- geneous populations. This potential Considerable concern regarding the ing bedaquiline and efavirenz. Two mix of semireplicating and hypo- quality of the drug s safety data exists 400-mg doses of bedaquiline were metabolic mycobacteria is more dif- due to the risks of bias and impreci given to each volunteer--the first ficult to eliminate with conventional sion(e. g, small sample size, use of dose alone and the second dose with antitubercular drugs, thus increasing modified intent-to-treat analysis, efavirenz. Plasma sampling for bed- the risk of resistance. No in vitro and the lack of quality evidence for aquiline and its metabolite, M2, was cross-resistance between bedaquiline the background regimens used in the performed over 14 days following and currently available antituber- trials). 57 Phase Ill studies that focus each dose. Efavirenz, at steady-state cular agents has been observed thus on safety data will have a significant concentrations, did reduce the AUC far. Because bedaquiline targets a impact on bedaquiline use in MDR of bedaquiline by 20% but the aUc completely different enzyme, cross- tuberculosis f M2 remained unchanged, sug- resistance with other conventional Plans for a Phase III trial of 600 gesting more rapid clearance. The agents remains unlikely. Enhanced patients with sputum smear-positive clinical consequences of diminished sterilizing capacity via synergistic pulmonary MDR or pre-XDR tu- bedaquiline concentrations in MDr depletion of ATP further exhibits the berculosis are underway. Pre-XDR tuberculosis are unknown promising potential of bedaquiline tuberculosis is defined as MDR tu As a CYP3A4 substrate, bedaqui- with pyrazinamide. Thus, bedaqui- berculosis resistant to either a fluoro- line is susceptible to both CYP3A4 line represents an important addi- quinolone or a second-line injectable inducers and inhibitors. Dosage tion to the limited range of agents agent but not both. The objective of recommendations for bedaquiline currently available against drug. the trial is to confirm the efficacy of are unchanged despite potential resistant tuberculosis bedaquiline by comparing treatment interactions. However, the manufac- A major critique of MDR tubercu- outcomes at week 60 in patient turers recommendations state that losis treatment is the significantly pro- randomized to receive bedaquiline administration of bedaquiline longed duration of therapy required or placebo added to a background with strong CYP3A4 inducers(e. g, in these patients. In Phase II studies, regimen. The secondary endpoint rifamycin)should be avoided. Co- regimens containing bedaquiline re- will assess relapse-free cure at week administration with strong CYP3A4 sulted in greater reductions in bacterial 84. The total treatment duration of inhibitors(e.g, ketoconazole) for load and greater proportions of spu- 36 weeks with 48 weeks of treatment- more than two weeks should be tum culture conversions Of specific free follow-up will provide add avoided unless the benefits outweigh interest, 24 weeks of treatment with tional insight into patient outcomes the risks. Further in vivo evaluations bedaquiline resulted in faster culture associated with a shorter duration of with prolonged coadministration of conversion and higher sputum con- MDR tuberculosis treatment while bedaquiline need to be conducted version rates than those with placebo. on bedaquiline. Moreover, safety data before specific dosing recommenda- The propagation of resistance through will provide additional focus on pre tions can be made noncompliance is a major concern viously identified adverse events. s 1992 Am JHealth-Syst Pharm-Vol 70 Nov 15, 2013

THERAPY UPDATE Bedaquiline 1992 Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 cation recommends bedaquiline use in patients with MDR tuberculosis who have not responded to effective first-line treatment regimens. Drug interactions. Patients receiv￾ing multidrug regimens for the treat￾ment of tuberculosis and HIV are at significant risk for drug–drug inter￾actions that may require dosage ad￾justments or increased monitoring. Concerns regarding the concomitant administration of antiretrovirals and bedaquiline are substantial. Efavirenz, as a CYP3A4 inducer, may decrease levels of bedaquiline, a CYP3A4 substrate. Dooley et al.53 conducted a Phase I pharmacokinetic study to assess the potential for drug interactions in 33 healthy volunteers receiv￾ing bedaquiline and efavirenz. Two 400-mg doses of bedaquiline were given to each volunteer––the first dose alone and the second dose with efavirenz. Plasma sampling for bed￾aquiline and its metabolite, M2, was performed over 14 days following each dose. Efavirenz, at steady-state concentrations, did reduce the AUC of bedaquiline by 20% but the AUC of M2 remained unchanged, sug￾gesting more rapid clearance. The clinical consequences of diminished bedaquiline concentrations in MDR tuberculosis are unknown. As a CYP3A4 substrate, bedaqui￾line is susceptible to both CYP3A4 inducers and inhibitors. Dosage recommendations for bedaquiline are unchanged despite potential interactions. However, the manufac￾turer’s recommendations state that coadministration of bedaquiline with strong CYP3A4 inducers (e.g., rifamycin) should be avoided.38 Co￾administration with strong CYP3A4 inhibitors (e.g., ketoconazole) for more than two weeks should be avoided unless the benefits outweigh the risks. Further in vivo evaluations with prolonged coadministration of bedaquiline need to be conducted before specific dosing recommenda￾tions can be made. Place in therapy. Continual emer￾gence of more-resistant tuberculo￾sis, such as XDR and totally-drug￾resistant tuberculosis, raises serious concerns regarding current prac￾tices for control and management of MDR tuberculosis. As the first novel antitubercular drug approved in over four decades, bedaquiline represents an important milestone in tubercu￾losis treatment. Bedaquiline’s unique mechanism of action presents a much-needed alternative approach to current anti￾mycobacterial killing. By directly in￾hibiting ATP synthase, bedaquiline is effective against both replicating and dormant mycobacteria. Pulmonary cavitary lesions can contain hetero￾geneous populations. This potential mix of semireplicating and hypo￾metabolic mycobacteria is more dif￾ficult to eliminate with conventional antitubercular drugs, thus increasing the risk of resistance.56 No in vitro cross-resistance between bedaquiline and currently available antituber￾cular agents has been observed thus far. Because bedaquiline targets a completely different enzyme, cross￾resistance with other conventional agents remains unlikely. Enhanced sterilizing capacity via synergistic depletion of ATP further exhibits the promising potential of bedaquiline with pyrazinamide. Thus, bedaqui￾line represents an important addi￾tion to the limited range of agents currently available against drug￾resistant tuberculosis. A major critique of MDR tubercu￾losis treatment is the significantly pro￾longed duration of therapy required in these patients. In Phase II studies, regimens containing bedaquiline re￾sulted in greater reductions in bacterial load and greater proportions of spu￾tum culture conversions. Of specific interest, 24 weeks of treatment with bedaquiline resulted in faster culture conversion and higher sputum con￾version rates than those with placebo. The propagation of resistance through noncompliance is a major concern in complicated multidrug regimens. Shortening current therapy durations while improving efficacy can poten￾tially improve patient outcomes. Significant adverse effects are seen with MDR tuberculosis regimens that contain at least four antituber￾cular agents, none of which are be￾nign. Bedaquiline was relatively well tolerated, with most adverse events thought to be associated with stan￾dard MDR tuberculosis agents. How￾ever, serious adverse events with be￾daquiline therapy have culminated in black-box warnings for Q-T interval prolongation and an increased risk of mortality. The exact relationship between bedaquiline and increased risk of mortality are unknown. Considerable concern regarding the quality of the drug’s safety data exists due to the risks of bias and impreci￾sion (e.g., small sample size, use of modified intent-to-treat analysis, and the lack of quality evidence for the background regimens used in the trials).57 Phase III studies that focus on safety data will have a significant impact on bedaquiline use in MDR tuberculosis. Plans for a Phase III trial of 600 patients with sputum smear-positive pulmonary MDR or pre-XDR tu￾berculosis are underway. Pre-XDR tuberculosis is defined as MDR tu￾berculosis resistant to either a fluoro￾quinolone or a second-line injectable agent but not both. The objective of the trial is to confirm the efficacy of bedaquiline by comparing treatment outcomes at week 60 in patients randomized to receive bedaquiline or placebo added to a background regimen. The secondary endpoint will assess relapse-free cure at week 84. The total treatment duration of 36 weeks with 48 weeks of treatment￾free follow-up will provide addi￾tional insight into patient outcomes associated with a shorter duration of MDR tuberculosis treatment while on bedaquiline. Moreover, safety data will provide additional focus on pre￾viously identified adverse events.54

THERAPY UPDATE Bedaquiline Compared with older agents documented evidence of MDR tu- xperience. In: Dooley Sw, Simone PM repurposed for the treatment of berculosis resistant to fluoroquino- ds. Clinical tuberculosis. New york: and Hall:1994:171-89 drug-resistant tuberculosis, bedaqui- lones. The exact role of bedaquiline 17. Johnson R, Streicher EM, Louw ge et line has been shown to be effective cannot be determined until further al. Drug resistance in Mycobacterium against MDR tuberculosis in mul- efficacy and safety data are obtained tuberculosis. Curr Issues Mol BioL. 2006 8:97-111. tiple randomized controlled stud- through ongoing Phase III trials 18. Pfyffer GE. Drug-resistant tuberculosis: ies. However, the overall evidence resistance mechanisms and rapid sus- that led to bedaquiline's approval references eptibility testing. Scheiz Med wock remains limited. An interim policy 1. Kapur V,Whittam TS, Musser JM Is My: 19. Zignol M, Hosseini MS, Wright A et al sch:.2000;130:1909-13 guidance recently compiled by WHo fomfet is 1994 170:1548-9. years Global incidence of multidrug-resistant ranked the current evidence for 2. Daniel TM. The history of tuberculosis uberculosis. J Infect Dis. 2006; 194: 479. bedaquiline use in adults with pul- 3. Formicola v, Milanesi Q, Scarsini C. Evi- 20. Zhang Y, Young D. Molecular dence of spinal tuberculosis at the be low. 7 Contributing to this grade of ng of the fourth millennium BC fror berculosi evidence was the low confidence in Arene Candide cave(Liguria, Italy). Am J 34:313.9./Antimicrob Chemothe Phys Anthropol. 1987; 72: 1-6 1. Ramaswamy S, Musser JM. Molecular bedaquiline's efficacy and safety (i.e, 4. Canci A, Minozzi S, Borgognini Tarli SM netic basis of antimicrobial agent resis- adverse events, mortality, emergence New evidence of tuberculous spondyliti tance in Mycobacterium tuberculosis: 1998 of resistance, and generalizability to from Neolithic Liguria(Italy). IntJOsteo- update. Tuber Lung Dis. 1998; 79: 3-29 archaeol.1996;6:497-501 22. Falzon D, Jaramillo E, Schunemann H]et other patient populations). Expert 5.Her al WHO guidelines for the programmat opinions emphasize bedaquiline DE et al. Detection and molecular char- ic management of drug-resistant tuber- use when an effective regimen con- acterization of 9, 000-year-old Mycobact culosis: 2011 update. Eur Respir J. 2011; rium tuberculosis from a Neolithic settle. aining four second-line drugs and ment in the Eastern Mediterranean. PLos 23. Drobniewski FA, Pozniak AL. Molecular pyrazinamide cannot be designed ne.2008;3:e3426. diagnosis, detection of drug resistand per WHO recommendations and 6. Herzog H. History of tuberculosis. Respi and epidemiology of tuberculosis. Br J Hosp Med.1996;8:204-8 when there is documented evidence 7. Lonnroth K, Castro KG, Chakaya JM et 24. Scott LE, McCarthy K, Gous n et al f MDR tuberculosis with fluoroqu al. Tuberculosis control and elimination omparison of Xpert MTB/RIF with clone resistance. a maximum dura C010-50: cure, care, and social develop- other nudeic acid technologies for diag ment. Lancet.2010;375:1814-29 ng pulmonary tuberculosis in a high tion of six months of bedaquiline HIV prevalence setting: a prospective treatment in conjunction with MDR tudy. PLoS Med. 2011; 8:e100106 tuberculosis background regimens is 9xmm体35mhp recommended. 7 Preferred adjunct 9. World Health Organization. Global tu tic test: technical agents have yet to be indicated. berculosisreport2012.www.who.int/tb/ practical Current who interim recom- publications/global_report/en/(accessed ations.http://whqlibdoc.whoint/ publications/2011/9789241501569 mendations are riddled with ca- 10. Stop TB Partnership/World Health eng-pdf (accessed 2013 Aug 1) meats for bedaquiline therapy Organization. The global plan to 26. Connolly LE, Edelstein PH, Ramakrishnan MdrtuberculosisWithoutmorestopTb2011-2015.www.stoptb.org/ L. Why is long-term therapy required to cure tuberculosis? plos med. 2007 comprehensive data from Phase Ill B_GlobalPlan ToStopTB2011-2015pdf 4:e120. studies,provisions for the safe and 27. Caminero JA, Sotgiu G, Zumla A et al ective use of bedaquiline must be World Health Organization. Glob- altuberculosiscontrol2011.http:// resistant and extensively drug-resistant implemented with special attention whqlibdoc who int/publications/2011 to pharmacovigilance. Due to the 9789241564380engp limited data in patients with HIV and 12. Barry ci 28. Mitnick CD, Castro KG, Harrington M terpreting cell wall'virulence al. Randomized trials to optimize treat the elderly(age 65 years or older), factorsof Mycobacterium tuberculosis. ment of multidrug-resistant tuberculo- Trends MicrobioL. 2001: 9: 237-41 sis. PLoS Med. 2007: 4: e292. Particular caution should be em- 13. Barry MC, Mdluli K Drug sensitivity and 29. Esp dard shor A, Kim Sh, Suarez PG et al. ployed with these populations environmental adaptation of mycobacte hemotherapy for rial cell wall components. Trends Micro- treatment Conclusion iol.1996;4:275 outcomes in 6 countries. JAMA. 2000; V, Singh S, Master S et al. My 283:2537-45 The approval of bedaquiline rep- ium tuberculosis inhibition of 30. Aziz MA, Wright A, Laszlo A et al. resents a major milestone in mdr agygas a sost defence mie chan. pe resistance ( the globalt project osis dntig Microbiol.2006;8:719-27 tuberculosis Drug Resistance Surveil hould be considered in patients who 15. Rusch-Gerdes S. Epidemiology of resis- ce): an updated analysis. Lancet. 2006; have not responded to a regime 19997( suppl2):S17-8 containing four second-line drugs 16. The extent and management of drug. 31. World Health Organization. Treat ment of tuberculosis: guidelines- and pyra acidamide and patients with resistant tuberculosis: the america 4thed.http://whqlibdoc.whoint/ Am J Health-Syst Pharm--Vol 70 Nov 15, 20131993

THERAPY UPDATE Bedaquiline Am J Health-Syst Pharm—Vol 70 Nov 15, 2013 1993 Compared with older agents repurposed for the treatment of drug-resistant tuberculosis, bedaqui￾line has been shown to be effective against MDR tuberculosis in mul￾tiple randomized controlled stud￾ies. However, the overall evidence that led to bedaquiline’s approval remains limited. An interim policy guidance recently compiled by WHO ranked the current evidence for bedaquiline use in adults with pul￾monary MDR tuberculosis as “very low.”57 Contributing to this grade of evidence was the low confidence in bedaquiline’s efficacy and safety (i.e., adverse events, mortality, emergence of resistance, and generalizability to other patient populations). Expert opinions emphasize bedaquiline use when an effective regimen con￾taining four second-line drugs and pyrazinamide cannot be designed per WHO recommendations and when there is documented evidence of MDR tuberculosis with fluoroqui￾nolone resistance. A maximum dura￾tion of six months of bedaquiline treatment in conjunction with MDR tuberculosis background regimens is recommended.57 Preferred adjunct agents have yet to be indicated. Current WHO interim recom￾mendations are riddled with ca￾veats for bedaquiline therapy in MDR tuberculosis. Without more comprehensive data from Phase III studies, provisions for the safe and effective use of bedaquiline must be implemented with special attention to pharmacovigilance.57 Due to the limited data in patients with HIV and the elderly (age 65 years or older), particular caution should be em￾ployed with these populations. Conclusion The approval of bedaquiline rep￾resents a major milestone in MDR tuberculosis therapy. Bedaquiline should be considered in patients who have not responded to a regimen containing four second-line drugs and pyrazinamide and patients with documented evidence of MDR tu￾berculosis resistant to fluoroquino￾lones. The exact role of bedaquiline cannot be determined until further efficacy and safety data are obtained through ongoing Phase III trials. References 1. Kapur V, Whittam TS, Musser JM. Is My￾cobacterium tuberculosis 15,000 years old? J Infect Dis. 1994; 170:1348-9. 2. Daniel TM. The history of tuberculosis. Respir Med. 2006; 100:1862-70. 3. Formicola V, Milanesi Q, Scarsini C. Evi￾dence of spinal tuberculosis at the begin￾ning of the fourth millennium BC from Arene Candide cave (Liguria, Italy). Am J Phys Anthropol. 1987; 72:1-6. 4. Canci A, Minozzi S, Borgognini Tarli SM. New evidence of tuberculous spondylitis from Neolithic Liguria (Italy). Int J Osteo￾archaeol. 1996; 6:497-501. 5. Hershkovitz I, Donoghue HD, Minnikin DE et al. Detection and molecular char￾acterization of 9,000-year-old Mycobacte￾rium tuberculosis from a Neolithic settle￾ment in the Eastern Mediterranean. PLoS One. 2008; 3:e3426. 6. Herzog H. History of tuberculosis. Respi￾ration. 1998; 65:5-15. 7. Lonnroth K, Castro KG, Chakaya JM et al. Tuberculosis control and elimination 2010–50: cure, care, and social develop￾ment. Lancet. 2010; 375:1814-29. 8. Vynnycky E, Fine PE. Interpreting the decline in tuberculosis: the role of secular trends in effective contact. Int J Epide￾miol. 1999; 28:327-34. 9. World Health Organization. Global tu￾berculosis report 2012. www.who.int/tb/ publications/global_report/en/ (accessed 2013 Aug 12). 10. Stop TB Partnership/World Health Organization. The global plan to stop TB 2011–2015. www.stoptb.org/ assets/documents/global/plan/ TB_GlobalPlanToStopTB2011-2015.pdf (accessed 2013 Aug 12). 11. World Health Organization. Glob￾al tuberculosis control 2011. http:// whqlibdoc.who.int/publications/2011/ 9789241564380_eng.pdf (accessed 2013 Aug 12). 12. Barry CE. Interpreting cell wall ‘virulence factors’ of Mycobacterium tuberculosis. Trends Microbiol. 2001; 9:237-41. 13. Barry MC, Mdluli K. Drug sensitivity and environmental adaptation of mycobacte￾rial cell wall components. Trends Micro￾biol. 1996; 4:275-8. 14. Deretic V, Singh S, Master S et al. My￾cobacterium tuberculosis inhibition of phagolysosome biogenesis and autoph￾agy as a host defence mechanism. Cell Microbiol. 2006; 8:719-27. 15. Rüsch-Gerdes S. Epidemiology of resis￾tant tuberculosis in Europe. Infection. 1999; 7(suppl 2):S17-8. 16. The extent and management of drug￾resistant tuberculosis: the American experience. In: Dooley SW, Simone PM, eds. Clinical tuberculosis. New York: Chapman and Hall; 1994:171-89. 17. Johnson R, Streicher EM, Louw GE et al. Drug resistance in Mycobacterium tuberculosis. Curr Issues Mol Biol. 2006; 8:97-111. 18. Pfyffer GE. Drug-resistant tuberculosis: resistance mechanisms and rapid sus￾ceptibility testing. Schweiz Med Wochen￾schr. 2000; 130:1909-13. 19. Zignol M, Hosseini MS, Wright A et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006; 194:479- 85. 20. Zhang Y, Young D. Molecular genetics of drug resistance in Mycobacterium tu￾berculosis. J Antimicrob Chemother. 1994; 34:313-9. 21. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resis￾tance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998; 79:3-29. 22. Falzon D, Jaramillo E, Schünemann HJ et al. WHO guidelines for the programmat￾ic management of drug-resistant tuber￾culosis: 2011 update. Eur Respir J. 2011; 38:516-28. 23. Drobniewski FA, Pozniak AL. Molecular diagnosis, detection of drug resistance and epidemiology of tuberculosis. Br J Hosp Med. 1996; 8:204-8. 24. Scott LE, McCarthy K, Gous N et al. Comparison of Xpert MTB/RIF with other nucleic acid technologies for diag￾nosing pulmonary tuberculosis in a high HIV prevalence setting: a prospective study. PLoS Med. 2011; 8:e1001061. 25. World Health Organization. Rapid implementation of the Xpert MTB/ RIF diagnostic test: technical and op￾erational “how-to” practical consid￾erations. http://whqlibdoc.who.int/ publications/2011/9789241501569_ eng.pdf (accessed 2013 Aug 1). 26. Connolly LE, Edelstein PH, Ramakrishnan L. Why is long-term therapy required to cure tuberculosis? PLoS Med. 2007; 4:e120. 27. Caminero JA, Sotgiu G, Zumla A et al. Best drug treatment for multidrug￾resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010; 10:621-9. 28. Mitnick CD, Castro KG, Harrington M et al. Randomized trials to optimize treat￾ment of multidrug-resistant tuberculo￾sis. PLoS Med. 2007; 4:e292. 29. Espinal MA, Kim SJ, Suarez PG et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA. 2000; 283:2537-45. 30. Aziz MA, Wright A, Laszlo A et al. Epidemiology of antituberculosis drug resistance (the Global Project on Anti￾tuberculosis Drug Resistance Surveil￾lance): an updated analysis. Lancet. 2006; 368:2142-54. 31. World Health Organization. Treat￾ment of tuberculosis: guidelines— 4th ed. http://whqlibdoc.who.int/