《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