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DOI: 10.1055/s-0028-1085706
Emerging Drugs for Active Tuberculosis
Publikationsverlauf
Publikationsdatum:
22. September 2008 (online)
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ABSTRACT
Tuberculosis (TB) drug research and development lay largely fallow from the 1960s to the turn of the century. A realization that current treatments for this major public health epidemic are proving inadequate to control the disease and prevent development and spread of drug resistance has stimulated renewed activity during the past 5 to 10 years. As a result, there are now seven drugs in clinical development for TB and many groups working on discovery-stage projects. This article summarizes the published information available on the seven clinical candidates and describes some of the challenges faced by those pursuing research and development of novel TB therapies.
KEYWORDS
Tuberculosis - treatment - clinical development - drug resistance
REFERENCES
- 1 Mitchison D A. Antimicrobial therapy of tuberculosis: justification for currently recommended treatment regimens. Semin Respir Crit Care Med. 2004; 25(3) 307-315
- 2 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America . Treatment of tuberculosis. Am J Respir Crit Care Med. 2003; 167 603-662
- 3 Fox W, Ellard G A, Mitchison D A. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999; 3(10 Suppl 2) S231-S279
- 4 World Health Organization .Global Tuberculosis Control: Surveillance, Planning, Financing: WHO Report 2008. Geneva, Switzerland; WHO 2008
- 5 World Health Organization Cluster on Communicable Diseases .What Is DOTS? A Guide to Understanding the WHO-Recommended TB Control Strategy Known as DOTS. Geneva, Switzerland; WHO 1999
- 6 Raviglione M C, Smith I. XDR Tuberculosis: implications for global public health. N Engl J Med. 2007; 356 656-659
- 7 World Health Organization .Anti-tuberculosis Drug Resistance in the World: Fourth Global Report. Geneva, Switzerland; WHO 2008
- 8 American Thoracic Society: CDC: Infectious Disease Society of America . Treatment of tuberculosis. MMWR Recomm Rep. 2003; 52(RR-11) 1-77
- 9 Granich R M, Oh P, Lewis B, Porco T C, Flood J. Multidrug resistance among persons with tuberculosis in California, 1994–2003. JAMA. 2005; 293 2732-2739
- 10 Sensi P, Margalith P, Timbal M T. Rifamycin, a new antibiotic: preliminary report. Farmaco Ed Sci. 1959; 14 146-147
- 11 Nwaka S, Ridley R. Virtual drug discovery and development for neglected diseases through public-private partnerships. Nat Rev Drug Discov. 2003; 2 919-928
- 12 Department of Health and Human Services, FDA .The CDER Handbook. Revised March 16, 1998. Available at: http://www.fda.gov/cder/handbook/ Accessed August 21, 2008
- 13 Glossary of Clinical Trial Terms. 2008. (Accessed 26 March 2008) at http://www.clinicaltrials.gov/ct2/info/glossary
- 14 Mitnick C D, Castro K G, Harrington M, Sacks L V, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med. 2007; 4 e292
- 15 Gatifloxacin (marketed as TEQUIN). Information for Healthcare Professionals. Accessed March 20, 2008 at http://www.fda.gov/CDER/Drug/InfoSheets/HCP/gatifloxacinHCP.pdf
- 16 Avelox product label. Accessed March 20, 2008 at http://www.fda.gov/cder/foi/label/2005/021085s027,029,021277s024,025lbl.pdf
- 17 Christian Lienhardt, IUATLD. Paris, France; March 17, 2008 Personal communication
- 18 Aubry A, Fisher L M, Jarlier V, Cambau E. First functional characterization of a singly expressed bacterial type II topoisomerase: the enzyme from Mycobacterium tuberculosis . Biochem Biophys Res Commun. 2006; 348 158-165
- 19 Aubry A, Veziris N, Cambau E, Truffot-Pernot C, Jarlier V, Fisher L M. Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother. 2006; 50 104-112
- 20 Rodríguez J C, Ruiz M, Climent A, Royo G. In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis . Int J Antimicrob Agents. 2001; 17 229-231
- 21 Lu T, Drlica K. In vitro activity of C-8-methoxy fluoroquinolones against mycobacteria when combined with anti-tuberculosis agents. J Antimicrob Chemother. 2003; 52 1025-1028
- 22 Alvirez-Freites E J, Carter J L, Cynamon M H. In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis . Antimicrob Agents Chemother. 2002; 46 1022-1025
- 23 Nuermberger E L, Yoshimatsu T, Tyagi S et al.. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med. 2004; 169 421-426
- 24 Rosenthal I M, Williams K, Tyagi S et al.. Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med. 2006; 174 94-101
- 25 Yoshimatsu T, Nuermberger E, Tyagi S, Chaisson R, Bishai W, Grosset J. Bactericidal activity of increasing daily and weekly doses of moxifloxacin in murine tuberculosis. Antimicrob Agents Chemother. 2002; 46 1875-1879
- 26 Cynamon M, Sklaney M R, Shoen C. Gatifloxacin in combination with rifampicin in a murine tuberculosis model. J Antimicrob Chemother. 2007; 60 429-432
- 27 Cynamon M H, Sklaney M. Gatifloxacin and ethionamide as the foundation for therapy of tuberculosis. Antimicrob Agents Chemother. 2003; 47 2442-2444
-
28 Drlica K, Lu T, Malik M, Zhao X.
Fluoroquinolones as antituberculosis agents . In: Rom WN, Garay SM Tuberculosis. 2nd ed. Philadelphia, PA; Lippincott Williams & Wilkins 2004: 791-807 - 29 Fish D N, North D S. Gatifloxacin, an advanced 8-methoxy fluoroquinolone. Pharmacotherapy. 2001; 21 35-59
- 30 Falagas M E, Rafailidis P I, Rosmarakis E S. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents. 2007; 29 374-379
- 31 Owens Jr R C, Ambrose P G. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005; 41(Suppl 2) S144-S157
- 32 Park-Wyllie L Y, Juurlink D N, Kopp A et al.. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med. 2006; 354 1352-1361
- 33 Saukkonen J J, Cohn D L, Jasmer R M et al.. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006; 174 935-952
- 34 Gosling R D, Uiso L O, Sam N E et al.. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med. 2003; 168 1342-1345
- 35 Johnson J L, Hadad D J, Boom W H et al.. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006; 10 605-612
- 36 Rustomjee R, Lienhardt C, Kanyok T et al.. A phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008; 12 128-138
- 37 Burman W J, Goldberg S, Johnson J L et al.. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006; 174 331-338
- 38 Chaisson R E, Conde M, Efron A et al.. A randomized, placebo-controlled trial of moxifloxacin versus ethambutol in the initial phase of tuberculosis therapy in Brazil. Presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy September 17–20, 2007 Chicago, IL;
- 39 Dorman S, Johnson J, Padayatchi N et al.. Moxifloxacin vs. isoniazid in the first 2 months of treatment for pulmonary tuberculosis. Presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy September 17–20, 2007 Chicago, IL;
- 40 Andries K, Verhasselt P, Guillemont J et al.. A diarylquinoline drug active on the ATP Synthase of Mycobacterium tuberculosis . Science. 2005; 307 223-227
- 41 Koul A, Dendouga N, Vergauwen K et al.. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007; 3 323-324
- 42 Lounis N, Veziris N, Chauffour A, Truffot-Pernot C, Andries K, Jarlier V. Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration. Antimicrob Agents Chemother. 2006; 50 3543-3547
- 43 McNeeley D. Update on the clinical development program of TMC207 (R207910). 2nd Open Forum on Key Issues in TB Drug Development. Accessed December 12–13, 2006 at: http://www.kaisernetwork.org/health_cast/uploaded_files/McNeeley,_David_(12-12)_TMC207.pdf
-
44 McNeeley D D. Yardley, PA; 2008 Personal communication
- 45 Stover C K, Warrener P, VanDevanter D R et al.. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000; 405 962-966
- 46 Matsumoto M, Hashizume H, Tomishige T et al.. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 2006; 3 e466
- 47 Kawasaki M, Yamamoto K, Matsumoto M. Mechanism of action of OPC-67683 against M. tuberculosis . Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) December 16–19, 2005 Washington, DC;
- 48 Manjunatha U H, Boshoff H, Dowd C S et al.. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis . Proc Natl Acad Sci U S A. 2006; 103 431-436
- 49 Lenaerts A J, Gruppo V, Marietta K S et al.. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005; 49 2294-2301
- 50 Tyagi S, Nuermberger E, Yoshimatsu T et al.. Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents Chemother. 2005; 49 2289-2293
- 51 Nuermberger E, Tyagi S, Tasneen R et al.. Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 52 1522-1524
- 52 Lee R E, Protopopova M, Crooks E, Slayden R A, Terrot M, Barry III C E. Combinatorial lead optimization of [1,2]-diamines based on ETH as potential anti-tuberculosis preclinical candidates. J Comb Chem. 2003; 5 172-187
- 53 Protopopova M, Hanrahan C, Nikonenko B et al.. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother. 2005; 56 968-974
- 54 Jia L, Coward L, Gorman G S, Noker P E, Tomaszewski J E. Pharmacoproteomic effects of isoniazid, ethambutol, and N-geranyl-N-(2-adamantyl)ethane-1,2-diamine (SQ109) on Mycobacterium tuberculosis H37Rv. J Pharmacol Exp Ther. 2005; 315 905-911
- 55 Boshoff H I, Myers T G, Copp B R, McNeil M R, Wilson M A, Barry III C E. The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem. 2004; 279 40174-40184
- 56 Chen P, Gearhart J, Protopopova M, Einck L, Nacy C A. Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro. J Antimicrob Chemother. 2006; 58 332-337
- 57 Jia L, Noker P E, Coward L, Gorman G S, Protopopova M, Tomaszewski J E. Interspecies pharmacokinetics and in vitro metabolism of SQ109. Br J Pharmacol. 2006; 147 476-485
- 58 Nikonenko B V, Protopopova M N, Samala R, Einck L, Nacy C A. Drug therapy of experimental TB: improved outcome by combining SQ109, new diamine antibiotic, with existing TB drugs. Antimicrob Agents Chemother. 2007; 51 1563-1565
-
59 Horwith G, Einck L, Protopopova M, Nacy C. Presented at: 45th Annual Infectious Diseases Society of America (IDSA) Meeting October 4–7, 2007 San Diego, CA;
-
60 Horwith G. Chief Medical Officer, Sequella, Inc .Rockville, MD; 2008 Personal communication
- 61 Arora S K, Sinha N, Sinha R K, Uppadhayaya R S, Modak V M, Tilekar A. Synthesis and in vitro anti-mycobacterial activity of a novel anti-TB composition LL4858. Presented at: 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) October 30–November 2, 2004 Washington, DC;
- 62 Stop T B. Working Group on New Drugs. Global TB Research and Development Projects. 2007. Accessed March 22, 2008 at http://www.stoptb.org/wg/new_drugs/assets/documents/2007GlobalPipeline.pdf
- 63 Payne D J, Gwynn M N, Holmes D J, Pompliano D L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007; 6 29-40
- 64 Dhar N, McKinney J D. Microbial phenotypic heterogeneity and antibiotic tolerance. Curr Opin Microbiol. 2007; 10 30-38
- 65 Bryk R, Gold B, Venugopal A et al.. Selective killing of nonreplicating mycobacteria. Cell Host Microbe. 2008; 3 137-145
- 66 Waddell S J, Laing K, Senner C, Butcher P D. Microarray analysis of defined Mycobacterium tuberculosis populations using RNA amplification strategies. BMC Genomics. 2008; 9 94
- 67 Pandey A K, Sassetti C M. Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A. 2008; 105 4376-4380
- 68 Sacks L V, Burmen R E. Developing new drugs for the treatment of drug-resistant tuberculosis: a regulatory perspective. Special Issue on TB Drug Research and Discovery. Tuberculosis. 2008; 88 (suppl 1)
- 69 van Niekerk C, Ginsberg A M. Assessment of global capacity to conduct TB drug development trials: do we have what it takes?. Manuscript submitted
- 70 Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson R. Building clinical trials capacity for tuberculosis drugs in high-burden countries. PLoS Med. 2007; 4 e302
1 Conducted by the OFLOTUB Consortium and its partners: the World Health Organization–based Special Program for Research and Training in Tropical Diseases (TDR), the European Commission (EU), the French Institut de Recherche pour le Dévelopement (IRD), and Lupin Pharmaceuticals, Ltd
2 Sponsored by University College London and conducted with its partners: the Bayer Healthcare/TB Alliance partnership, the British Medical Research Council, and clinical trial sites in several high-burden countries.
Ann M GinsbergM.D. Ph.D.
Clinical Development, Global Alliance for TB Drug Development
40 Wall St., 24th Fl., New York, NY 10005
eMail: ann.ginsberg@tballiance.org