New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENT

[1]  D. Mitchison.  Rifabutin in the treatment of newly diagnosed pulmonary tuberculosis. , 1995, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[2]  K. Andries,et al.  Genetic Basis for Natural and Acquired Resistance to the Diarylquinoline R207910 in Mycobacteria , 2006, Antimicrobial Agents and Chemotherapy.

[3]  D. Mitchison.  Shortening the treatment of tuberculosis , 2005, Nature Biotechnology.

[4]  N. Lounis,et al.  In Vitro and In Vivo Activities of Moxifloxacin and Clinafloxacin against Mycobacterium tuberculosis , 1998, Antimicrobial Agents and Chemotherapy.

[5]  D. Mitchison,et al.  A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. , 2008, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[6]  P. Venkatesan,et al.  Bactericidal Action of Gatifloxacin, Rifampin, and Isoniazid on Logarithmic- and Stationary-Phase Cultures of Mycobacterium tuberculosis , 2005, Antimicrobial Agents and Chemotherapy.

[7]  H. Lode,et al.  Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: a Prospective, Randomized Study , 2004, Antimicrobial Agents and Chemotherapy.

[8]  G. Stein,et al.  Pharmacokinetics and pharmacodynamics of newer fluoroquinolones. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  J. Caylà,et al.  Is the combination of pyrazinamide plus rifampicin safe for treating latent tuberculosis infection in persons not infected by the human immunodeficiency virus? , 2005, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[10]  L. Daniels,et al.  Use of Transposon Tn5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F420 Biosynthesis by Mycobacterium bovis BCG , 2001, Journal of bacteriology.

[11]  H. McIlleron,et al.  Elevated gatifloxacin and reduced rifampicin concentrations in a single-dose interaction study amongst healthy volunteers. , 2007, The Journal of antimicrobial chemotherapy.

[12]  R. Chaisson,et al.  Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. , 2004, American journal of respiratory and critical care medicine.

[13]  Carolyn Shoen,et al.  Gatifloxacin in combination with rifampicin in a murine tuberculosis model. , 2007, The Journal of antimicrobial chemotherapy.

[14]  P. Garner,et al.  Directly observed therapy for treating tuberculosis. , 2015, The Cochrane database of systematic reviews.

[15]  R. Chaisson,et al.  Daily Dosing of Rifapentine Cures Tuberculosis in Three Months or Less in the Murine Model , 2007, PLoS medicine.

[16]  J. Musser,et al.  Comparative antimycobacterial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations , 1996, Antimicrobial agents and chemotherapy.

[17]  A. R. Somner.  A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24 months after the end of chemotherapy. British Thoracic Association. , 1981, The American review of respiratory disease.

[18]  M. Narita,et al.  Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. , 1998, American journal of respiratory and critical care medicine.

[19]  K. Andries,et al.  A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis. , 2009, American journal of respiratory and critical care medicine.

[20]  M. Spigelman,et al.  New tuberculosis therapeutics: a growing pipeline. , 2007, The Journal of infectious diseases.

[21]  L. Soto-Ramírez,et al.  [Treatment of tuberculosis]. , 1997, Gaceta medica de Mexico.

[22]  I. Morrissey,et al.  A comparison of the bactericidal activity of quinolone antibiotics in a Mycobacterium fortuitum model. , 2001, Journal of medical microbiology.

[23]  C. Hamilton,et al.  A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment. , 2002, American journal of respiratory and critical care medicine.

[24]  C. Nacy,et al.  In search of new cures for tuberculosis. , 2007, Medicinal chemistry (Shariqah (United Arab Emirates)).

[25]  D. Mitchison,et al.  Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Initial report. , 1998, American journal of respiratory and critical care medicine.

[26]  R. Owens,et al.  Pharmacokinetics of Rifapentine in Subjects Seropositive for the Human Immunodeficiency Virus: a Phase I Study , 1999, Antimicrobial Agents and Chemotherapy.

[27]  A. Vernon,et al.  Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid , 1999, The Lancet.

[28]  N. Lounis,et al.  Effectiveness of Once-Weekly Rifapentine and Moxifloxacin Regimens against Mycobacterium tuberculosis in Mice , 2001, Antimicrobial Agents and Chemotherapy.

[29]  L. Jia,et al.  Pharmacodynamics and pharmacokinetics of SQ109, a new diamine‐based antitubercular drug , 2005, British journal of pharmacology.

[30]  D. Mitchison.  Modern methods for assessing the drugs used in the chemotherapy of mycobacterial disease. , 1996, Society for Applied Bacteriology symposium series.

[31]  V. Jarlier,et al.  Efficient Intermittent Rifapentine-Moxifloxacin-Containing Short-Course Regimen for Treatment of Tuberculosis in Mice , 2005, Antimicrobial Agents and Chemotherapy.

[32]  N. Cozzarelli.  DNA gyrase and the supercoiling of DNA. , 1980, Science.

[33]  R. Chaisson,et al.  Bactericidal Activity of Increasing Daily and Weekly Doses of Moxifloxacin in Murine Tuberculosis , 2002, Antimicrobial Agents and Chemotherapy.

[34]  Clifton E. Barry,et al.  A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis , 2000, Nature.

[35]  N. Bergamini,et al.  Rifampicin in Free Combination with Other Antimicrobial Drugs in Non-Tb Infections (Part 1 of 2) , 1981 .

[36]  J. Grosset,et al.  Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis , 2008, Antimicrobial Agents and Chemotherapy.

[37]  K. Drlica,et al.  In vitro activity of C-8-methoxy fluoroquinolones against mycobacteria when combined with anti-tuberculosis agents. , 2003, The Journal of antimicrobial chemotherapy.

[38]  M. Spigelman,et al.  Challenges in tuberculosis drug research and development , 2007, Nature Medicine.

[39]  A. Mccarthy,et al.  Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa , 2006, BMC infectious diseases.

[40]  T. O'connor,et al.  Novel agents in the management of Mycobacterium tuberculosis disease. , 2007, Current medicinal chemistry.

[41]  D. Mitchison,et al.  Sterilizing Activities of Fluoroquinolones against Rifampin-Tolerant Populations of Mycobacterium tuberculosis , 2003, Antimicrobial Agents and Chemotherapy.

[42]  S. Gillespie,et al.  Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective , 2002, Antimicrobial Agents and Chemotherapy.

[43]  G L Drusano,et al.  Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. , 1998, JAMA.

[44]  J. Grosset,et al.  Enhanced Bactericidal Activity of Rifampin and/or Pyrazinamide When Combined with PA-824 in a Murine Model of Tuberculosis , 2008, Antimicrobial Agents and Chemotherapy.

[45]  D. Mitchison.  Role of individual drugs in the chemotherapy of tuberculosis. , 2000, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[46]  C. Nacy,et al.  Drug Therapy of Experimental Tuberculosis (TB): Improved Outcome by Combining SQ109, a New Diamine Antibiotic, with Existing TB Drugs , 2007, Antimicrobial Agents and Chemotherapy.

[47]  C. Chan,et al.  In Vitro Postantibiotic Effects of Rifapentine, Isoniazid, and Moxifloxacin against Mycobacterium tuberculosis , 2004, Antimicrobial Agents and Chemotherapy.

[48]  C. Kunin,et al.  Trends in fluoroquinolone resistance of Mycobacterium tuberculosis complex in a Taiwanese medical centre: 1995-2003. , 2005, The Journal of antimicrobial chemotherapy.

[49]  M. Iseman,et al.  Rifabutine: minimal inhibitory and bactericidal concentrations for Mycobacterium tuberculosis. , 1988, The American review of respiratory disease.

[50]  D. Mitchison,et al.  Moxifloxacin and Gatifloxacin in an Acid Model of Persistent Mycobacterium tuberculosis , 2006, Journal of chemotherapy.

[51]  A. V. Shindikar,et al.  Novel fluoroquinolones: design, synthesis, and in vivo activity in mice against Mycobacterium tuberculosis H37Rv. , 2005, Bioorganic & medicinal chemistry letters.

[52]  K. Andries,et al.  Synergistic Activity of R207910 Combined with Pyrazinamide against Murine Tuberculosis , 2006, Antimicrobial Agents and Chemotherapy.

[53]  R. Slayden,et al.  Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs. , 2000, Biochemical pharmacology.

[54]  G. Alangaden,et al.  The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[55]  S. Ehlers,et al.  Location of Persisting Mycobacteria in a Guinea Pig Model of Tuberculosis Revealed by R207910 , 2007, Antimicrobial Agents and Chemotherapy.

[56]  G. Legari,et al.  Long-Term Tolerance and Effectiveness of Moxifloxacin Therapy for Tuberculosis: Preliminary Results , 2003, Journal of chemotherapy.

[57]  D. Cohn.  Treatment of multidrug-resistant tuberculosis. , 1995, The Journal of hospital infection.

[58]  W. Burman,et al.  Comparative Pharmacokinetics and Pharmacodynamics of the Rifamycin Antibacterials , 2001, Clinical pharmacokinetics.

[59]  H. Drugeon,et al.  Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium tuberculosis complex. , 2000, The Journal of antimicrobial chemotherapy.

[60]  C. Luo,et al.  Effects of Rifampin and Multidrug Resistance Gene Polymorphism on Concentrations of Moxifloxacin , 2007, Antimicrobial Agents and Chemotherapy.

[61]  K. Dooley,et al.  Repeated Administration of High-Dose Intermittent Rifapentine Reduces Rifapentine and Moxifloxacin Plasma Concentrations , 2008, Antimicrobial Agents and Chemotherapy.

[62]  Barry Pj,et al.  Novel agents in the management of Mycobacterium tuberculosis disease. , 2007 .

[63]  T. Nukiwa,et al.  In vitro antimicrobial activity and penetration rate into sputum of gatifloxacin, a novel 6-fluoro-8-methoxy quinolone, and its therapeutic efficacy in respiratory infections , 1999, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[64]  P. Verhasselt,et al.  In Vitro Antimycobacterial Spectrum of a Diarylquinoline ATP Synthase Inhibitor , 2007, Antimicrobial Agents and Chemotherapy.

[65]  G. Drusano,et al.  Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis , 1993, Antimicrobial Agents and Chemotherapy.

[66]  S. Munsiff,et al.  Rifapentine for the treatment of pulmonary tuberculosis. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[67]  M. T. Ruiz,et al.  In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. , 2002, International journal of antimicrobial agents.

[68]  Lacy Daniels,et al.  Demonstration that fbiC Is Required by Mycobacterium bovis BCG for Coenzyme F420 and FO Biosynthesis , 2002, Journal of bacteriology.

[69]  Jerome J. Schentag.  Clinical pharmacology of the fluoroquinolones: studies in human dynamic/kinetic models. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[70]  R. N. Brogden,et al.  Rifabutin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. , 1994, Drugs.

[71]  S. Gillespie,et al.  Fluoroquinolones: a new treatment for tuberculosis? , 1998, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[72]  M. Matsumoto,et al.  Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. , 2006, Journal of medicinal chemistry.

[73]  D. Kochar,et al.  The role of rifampicin in the management of cutaneous leishmaniasis. , 2000, QJM : monthly journal of the Association of Physicians.

[74]  L. Heifets,et al.  Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages , 1995, Antimicrobial agents and chemotherapy.

[75]  J. Rotschafer,et al.  Application of fluoroquinolone pharmacodynamics. , 2000, The Journal of antimicrobial chemotherapy.

[76]  M. Matsumoto,et al.  OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice , 2006, PLoS medicine.

[77]  R. Chaisson,et al.  Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial , 2002, The Lancet.

[78]  D. Wilkinson.  Anti-tuberculosis drug resistance in the world: The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva: World Health Organization, 1997. 228pp. Price Sw. fr 25/US$22.50 (in developing countries Sw. fir 17.50). (Reference WHO/TB/97.229) , 1998 .

[79]  John L. Johnson,et al.  Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. , 2006, American journal of respiratory and critical care medicine.

[80]  H. Stass,et al.  Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. , 1999, The Journal of antimicrobial chemotherapy.

[81]  P. Gangadharam,et al.  Contribution of rpoB Mutations to Development of Rifamycin Cross-Resistance in Mycobacterium tuberculosis , 1998, Antimicrobial Agents and Chemotherapy.

[82]  H. Tomioka,et al.  Comparative In Vitro Antimicrobial Activities of the Newly Synthesized Quinolone HSR-903, Sitafloxacin (DU-6859a), Gatifloxacin (AM-1155), and Levofloxacin againstMycobacterium tuberculosis and Mycobacterium avium Complex , 1999, Antimicrobial Agents and Chemotherapy.

[83]  D. Mitchison,et al.  Comparison of the sterilising activities of the nitroimidazopyran PA-824 and moxifloxacin against persisting Mycobacterium tuberculosis. , 2008, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[84]  M. Iseman,et al.  Tuberculosis therapy: past, present and future , 2002, European Respiratory Journal.

[85]  B. Alisjahbana,et al.  Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis Patients , 2007, Antimicrobial Agents and Chemotherapy.

[86]  Ying Zhang,et al.  Persistent and dormant tubercle bacilli and latent tuberculosis. , 2004, Frontiers in bioscience : a journal and virtual library.

[87]  H. Lode,et al.  Comparative Pharmacokinetics of Ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Trovafloxacin, and Moxifloxacin after Single Oral Administration in Healthy Volunteers , 2000, Antimicrobial Agents and Chemotherapy.

[88]  W. Bishai,et al.  Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. , 2006, American journal of respiratory and critical care medicine.

[89]  P. Yogeeswari,et al.  Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase. , 2006, Bioorganic & medicinal chemistry letters.

[90]  S. Gillespie,et al.  Activity of moxifloxacin against mycobacteria. , 1999, The Journal of antimicrobial chemotherapy.

[91]  Hinrich W. H. Göhlmann,et al.  A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis , 2005, Science.

[92]  A. Pablos-Mendez,et al.  The global alliance for tuberculosis drug development--accomplishments and future directions. , 2005, Clinics in chest medicine.

[93]  R. O'brien,et al.  The need for new drugs against tuberculosis. Obstacles, opportunities, and next steps. , 2001, American journal of respiratory and critical care medicine.

[94]  K. Andries,et al.  Impact of the Interaction of R207910 with Rifampin on the Treatment of Tuberculosis Studied in the Mouse Model , 2008, Antimicrobial Agents and Chemotherapy.

[95]  S. Dorman,et al.  The rapid development of fluoroquinolone resistance in M. tuberculosis. , 2003, The New England journal of medicine.

[96]  M. Cynamon,et al.  In Vitro and In Vivo Activities of Gatifloxacin against Mycobacterium tuberculosis , 2002, Antimicrobial Agents and Chemotherapy.

[97]  P. de Rijk,et al.  Limited fluoroquinolone resistance among Mycobacterium tuberculosis isolates from Rwanda: results of a national survey. , 2007, Journal of Antimicrobial Chemotherapy.

[98]  B. Strates,et al.  Metabolism and pharmacokinetics of the antibiotic rifampin. , 1981, Drug metabolism reviews.

[99]  A. Mwinga,et al.  Prospects for new tuberculosis treatment in Africa , 2004, Tropical medicine & international health : TM & IH.

[100]  Lung Disease,et al.  Anti-tuberculosis drug resistance in the world : the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance , 1997 .

[101]  D. Mitchison,et al.  The search for new sterilizing anti-tuberculosis drugs. , 2004, Frontiers in bioscience : a journal and virtual library.

[102]  B. Kreiswirth,et al.  Minimising moxifloxacin resistance with tuberculosis. , 2008, The Lancet. Infectious diseases.

[103]  J. Grosset,et al.  Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. G.E.T.I.M. (Group for the Study and Treatment of Resistant Mycobacterial Infection). , 1992, The European respiratory journal.

[104]  L. Aarons,et al.  Use of Nonlinear Mixed-Effects Analysis for Improved Precision of Early Pharmacodynamic Measures in Tuberculosis Treatment , 2006, Antimicrobial Agents and Chemotherapy.

[105]  L. Jia,et al.  Pharmacoproteomic Effects of Isoniazid, Ethambutol, and N-Geranyl-N′-(2-adamantyl)ethane-1,2-diamine (SQ109) on Mycobacterium tuberculosis H37Rv , 2005, Journal of Pharmacology and Experimental Therapeutics.

[106]  D. Snider,et al.  U.S. Public Health Service Cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis. , 2015, The American review of respiratory disease.

[107]  T. Sterling,et al.  Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. , 2004, American journal of respiratory and critical care medicine.

[108]  W. Bishai,et al.  Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis , 2005, Antimicrobial Agents and Chemotherapy.

[109]  J. Norton,et al.  Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[110]  W. Bishai,et al.  Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis , 2006, Antimicrobial Agents and Chemotherapy.

[111]  Robert C. Reynolds,et al.  Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models , 2005, Antimicrobial Agents and Chemotherapy.

[112]  D. Peters,et al.  Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. , 1992, Drugs.

[113]  W. Bishai,et al.  Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. , 2005, American journal of respiratory and critical care medicine.

[114]  Ping Chen,et al.  Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro. , 2006, The Journal of antimicrobial chemotherapy.

[115]  C. Dolea,et al.  World Health Organization , 1949, International Organization.

[116]  C. Barry,et al.  Mycobacterium leprae Is Naturally Resistant to PA-824 , 2006, Antimicrobial Agents and Chemotherapy.

[117]  D. Maher,et al.  A research agenda to promote the management of childhood tuberculosis within national tuberculosis programmes. , 2007, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[118]  K. Dooley,et al.  Fluoroquinolone resistance in patients with newly diagnosed tuberculosis. , 2003, Clinical Infectious Diseases.

[119]  Charles L Daley,et al.  American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. , 2003, American journal of respiratory and critical care medicine.

[120]  P. Olliaro,et al.  Rifabutin-containing regimens for pulmonary tuberculosis: early assessment of treatment effectiveness. , 1996, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[121]  L. Jia,et al.  Simultaneous estimation of pharmacokinetic properties in mice of three anti-tubercular ethambutol analogs obtained from combinatorial lead optimization. , 2005, Journal of pharmaceutical and biomedical analysis.

[122]  Saranjit Singh,et al.  Study of the interaction between rifapentine and isoniazid under acid conditions. , 2006, Journal of pharmaceutical and biomedical analysis.

[123]  D. Mitchison,et al.  In vitro activity of new rifamycins against rifampicin-resistant M. tuberculosis and MAIS-complex mycobacteria. , 1987, Tubercle.

[124]  K. Kam,et al.  Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. , 2006, Microbial drug resistance.

[125]  D. Mitchison,et al.  Bioavailability of Chinese rifapentine during a clinical trial in Hong Kong. , 1997, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[126]  S. Gillespie,et al.  The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. , 2003, American journal of respiratory and critical care medicine.

[127]  S. Niemann,et al.  Frequency of rpoB Mutations Inside and Outside the Cluster I Region in Rifampin-Resistant Clinical Mycobacterium tuberculosis Isolates , 2001, Journal of Clinical Microbiology.

[128]  Richard D Moore,et al.  Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. , 2006, American journal of respiratory and critical care medicine.

[129]  D. Bonner,et al.  In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin. , 2000, The Journal of antimicrobial chemotherapy.

[130]  B. Kreis,et al.  Two three-month treatment regimens for pulmonary tuberculosis. , 1976, Bulletin of the International Union against Tuberculosis.

[131]  M. Eller,et al.  Single-dose Pharmacokinetics of Rifapentine in Elderly Men , 1998, Pharmaceutical Research.

[132]  G. Acocella.  Clinical Pharmacokinetics of Rifampicin , 1978, Clinical pharmacokinetics.

[133]  B. Alisjahbana,et al.  Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[134]  E. Vittinghoff,et al.  Short-Course Rifampin and Pyrazinamide Compared with Isoniazid for Latent Tuberculosis Infection: A Multicenter Clinical Trial , 2002, Annals of Internal Medicine.

[135]  B. Metchock,et al.  Fluoroquinolone susceptibility among Mycobacterium tuberculosis isolates from the United States and Canada. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[136]  C. Truffot-Pernot,et al.  [Study of the minimal inhibitory concentration of rifabutine (Ansamycin LM 427) for Mycobacterium tuberculosis, Mycobacterium xenopi and Mycobacterium avium-intracellulare]. , 1988, Revue des maladies respiratoires.

[137]  Alexander Kopp,et al.  Outpatient gatifloxacin therapy and dysglycemia in older adults. , 2006, The New England journal of medicine.

[138]  M. Eller,et al.  Disposition and metabolism of 14C-rifapentine in healthy volunteers. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[139]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[140]  V. Nandi,et al.  Moxifloxacin, Ofloxacin, Sparfloxacin, and Ciprofloxacin against Mycobacterium tuberculosis: Evaluation of In Vitro and Pharmacodynamic Indices That Best Predict In Vivo Efficacy , 2006, Antimicrobial Agents and Chemotherapy.

[141]  A. Laszlo,et al.  Anti-tuberculosis drug resistance in the world. Fourth global report. The WHO / IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007. , 2003 .

[142]  H. Stass,et al.  Pharmacokinetics, Safety, and Tolerability of Ascending Single Doses of Moxifloxacin, a New 8-Methoxy Quinolone, Administered to Healthy Subjects , 1998, Antimicrobial Agents and Chemotherapy.

[143]  L. Jia,et al.  Interspecies pharmacokinetics and in vitro metabolism of SQ109 , 2006, British journal of pharmacology.

[144]  L. Koymans,et al.  A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910 , 2007, Proteins.

[145]  A. Diacon,et al.  Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis , 2008, Antimicrobial Agents and Chemotherapy.

[146]  R. Wallis,et al.  Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis. , 2007, The Journal of antimicrobial chemotherapy.

[147]  W. Bishai,et al.  Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis. , 2005, American journal of respiratory and critical care medicine.

[148]  S. Gillespie,et al.  Early bactericidal activity of a moxifloxacin and isoniazid combination in smear-positive pulmonary tuberculosis. , 2005, The Journal of antimicrobial chemotherapy.

[149]  C. Dye,et al.  Anti-tuberculosis drug resistance in the world: The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva: World Health Organization, 1997. 228pp. Price Sw. fr 25/US$22.50 (in developing countries Sw. fir 17.50). (Reference WHO/TB/97.229) , 1998 .

[150]  M. Uplekar,et al.  An expanded DOTS framework for effective tuberculosis control. , 2002, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[151]  J. Solera,et al.  Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. The GECMEI Group. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas , 1995, Antimicrobial agents and chemotherapy.

[152]  M. McNeil,et al.  NLCQ-1 and NLCQ-2, two new agents with activity against dormant Mycobacterium tuberculosis. , 2007, International journal of antimicrobial agents.

[153]  A. Diacon,et al.  Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears , 2007, Antimicrobial Agents and Chemotherapy.

[154]  Anthony D. Harries,et al.  Treatment of tuberculosis: guidelines for national programmes. Second edition. , 1997 .

[155]  S. Gillespie,et al.  Biomarkers of treatment response in clinical trials of novel antituberculosis agents. , 2007, The Lancet. Infectious diseases.

[156]  R. Chaisson,et al.  Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. , 2004, American journal of respiratory and critical care medicine.

[157]  R. Chaisson,et al.  Moxifloxacin (BAY12-8039), a New 8-Methoxyquinolone, Is Active in a Mouse Model of Tuberculosis , 1999, Antimicrobial Agents and Chemotherapy.

[158]  E. Kantharaj,et al.  Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis , 2003, Antimicrobial Agents and Chemotherapy.

[159]  W. Bishai,et al.  Fluoroquinolones, tuberculosis, and resistance. , 2003, The Lancet. Infectious diseases.

[160]  M. Eller,et al.  Single and multiple dose pharmacokinetics of rifapentine in man: part II. , 1999, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[161]  M. Cynamon,et al.  Gatifloxacin and Ethionamide as the Foundation for Therapy of Tuberculosis , 2003, Antimicrobial Agents and Chemotherapy.

[162]  John L. Johnson,et al.  Population Pharmacokinetics of Levofloxacin, Gatifloxacin, and Moxifloxacin in Adults with Pulmonary Tuberculosis , 2007, Antimicrobial Agents and Chemotherapy.

[163]  D. Mitchison,et al.  In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis. , 1987, Tubercle.

[164]  H. Tomioka,et al.  Comparative antimycobacterial activities of the newly synthesized quinolone AM-1155, sparfloxacin, and ofloxacin , 1993, Antimicrobial Agents and Chemotherapy.

[165]  T. Blaschke,et al.  Clinical pharmacokinetics of rifabutin. , 1996, Clinical pharmacokinetics.

[166]  G. Migliori,et al.  Long-term moxifloxacin in complicated tuberculosis patients with adverse reactions or resistance to first line drugs. , 2006, Respiratory medicine.

[167]  J. Grosset,et al.  Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Mycobacterial Infections , 2004, European Journal of Clinical Microbiology and Infectious Diseases.

[168]  L. Heifets,et al.  Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. , 1990, The American review of respiratory disease.

[169]  A. Maxwell.  DNA gyrase as a drug target. , 1997, Trends in microbiology.