1. NEW TB DRUGS Jacques Choucair MD Infectious Diseases specialist, Hotel Dieu de France Lecturer at the Saint Joseph University School of Medicine

2. History of TB Treatment The development of treatment for TB can be roughly classified into 3 stages: Classical approach – beliefs such as letting out of blood, avoidance of taking meat and alcohol. Sanatorium – In the 1850's, sanatoria were built in Western Europe and America in high attitude, fresh air and nutritious food for the TB patients (artificial pneumothorax, lobectomy, and pneumonectomy)

3. History of TB Treatment Chemotherapy – Various agents were tried for the treatment of TB: mercury, iodine, creosote, etc. – In 1890, Dr. Robert Koch discovered tuberculin and tried it for treatment of TB. – In 1938, Rich & Follis reported that sulfanilamide could inhibit the growth of TB germs in guinea pigs.

4. In 1945, streptomycin was discovered but initial response was soon followed by deterioration and development of drug resistance. Other drugs were also discovered subsequently: para-aminosalicylic acid, isoniazid, pyrazinamide, cycloserine and kanamycine. The advent of rifampicin in the late 1970's marked the beginning of the era of short course therapy; from more than 2 years to a period of 6 months. History of TB Treatment

7. Epidemiology Tuberculosis, a scourge since prehistoric times, affects more than 9 million people and causes death in 1.5 million people each year. Effective treatment has been available for 60 years, but generally takes 6 months, and resistance to the drugs, which is increasing throughout the world, threatens the effectiveness of treatment.

8. What is the standard regimen for drug-susceptible tuberculosis? The standard treatment regimen for presumably drug-susceptible tuberculosis – rifampin, isoniazid, and pyrazinamide, to which ethambutol is added as protection against resistance. Once susceptibility to isoniazid, rifampin, and pyrazinamide has been confirmed, ethambutol can be discontinued. The induction phase is followed by a consolidation phase consisting of rifampin and isoniazid for an additional 4 months of treatment.

9. What challenges are associated with the relatively lengthy course of treatment for tuberculosis? Managing drug toxicity and ensuring adherence to the full course of treatment. Drug toxicity is substantial; – 3 to 13% of patients have hepatotoxic effects. – 15% incidence of interruption or discontinuation. – Of these adverse reactions, 7.7% resulted in hospitalization, disability, or death. Overall, 16 to 49% of patients do not complete the regimen. – adverse drug reactions, cost of treatment, stigma, and the patient’s belief that cure has been achieved when symptoms have resolved and bacteria can no longer be recovered from the sputum.

10. What factors might explain the poor response of some patients to antimycobacterial therapy? Mycobacterium tuberculosis bacteria are sequestered in compartments that are inaccessible to antibiotic action; the interior of granulomas, abscesses, and cavities. Another potential explanation for the poor clinical responses in some patients is inadequate serum antimycobacterial drug levels, since low serum levels further impede the ability of drugs to penetrate infectious foci. inadequate absorption Genetically determined metabolic pathways can also influence serum drug levels. this slow-acetylator genotype is present in more than 50% of white populations.

11. What new antimycobacterial drugs are on the horizon? Several new classes of antimycobacterial drugs have been developed in the past 15 years. Two of these agents, the diarylquinoline bedaquiline and the nitroimidazooxazole delamanid, have received accelerated regulatory approval Other new drug classes (benzothiazinones and imidazopyridines) show promise in preclinical studies but have not yet progressed to clinical trials.

12. beta-Lactamase activity in mycobacteria including Mycobacterium avium and suppression of their growth by a beta-lactamase-stable antibiotic. All the mycobacteria tested possess the enzyme, which explains their resistance to beta-lactam antibiotics. Growth of the mycobacteria was suppressed by novel combinations of the beta- lactam/beta-lactamase-inhibitors, and by a new beta-lactamase-stable cephalosporin, Cefepime (aminothiazolyl methoxyimino cephalosporin). Microbios.1995;81(328):177-85.Prabhakaran K 1, Harris EB, Randhawa B, Hastings RC.

13. In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against the virulent H37Rv strain in human macrophages. isoniazid (0. 02-0.04), rifampin (0.2-0.4), ethambutol and streptomycin (0.5-2.0), ethionamide (0.25-0.5), D-cycloserine (25-75), capreomycin (1-2), kanamycin (2-4), amikacin (0.5- 1.0), clofazimine (0.1-0.4), ofloxacin (0.5-1.0), ciprofloxacin (0.25-1.0), and sparfloxacin (0.1-0.4). among the first-line drugs, rifampin > ethionamide = isoniazid > ethambutol > streptomycin > D-cycloserine; among second-line drugs, clofazimine = amikacin > kanamycin = capreomycin; among fluoroquinolones, sparfloxacin > ofloxacin > ciprofloxacin. Curr Microbiol. 1996 Sep;33(3):167-75.Rastogi N, Labrousse V, Goh KS

14. Suppression of the growth of six potentially- pathogenic mycobacteria by beta-lactam/beta- lactamase-inhibitors. More than 50-80% inhibition of the mycobacterial growth was observed at drug levels of 40-100 micrograms/ml in the medium Amp-sulb, amox-clav and pip-tazo were active even when the detergent was omitted. Against four of the mycobacteria, ampicillin/sulbactam proved to be the most active. The beta-lactam/beta-lactamase-inhibitor combinations may be of use as rational therapeutic agents against mycobacterial infections Microbios. 1997;91(366):7-14. Prabhakaran K 1, Harris EB, Randhawa B

15. Imipenem for Treatment of Tuberculosis in Mice and Humans Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis. Antimicrob Agents Chemother. 2005 Jul; 49(7): 2816–2821. Henry F. Chambers, * Joan Turner, Gisela F. Schecter, Masae Kawamura, and Philip C. Hopewell

16. TMC207 (bedaquiline): the first compound of a new class of potent anti-tuberculosis drugs.. TMC207 is a first-in-class diarylquinoline compound which inhibit bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species. In patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy. Future Microbiol. 2010 Jun;5(6):849-58. Matteelli A1, Carvalho AC, Dooley KE, Kritski A TMC207 use to shorter first-line regimens or using it in second-line regimens for drug-resistant M. tuberculosis infections are both being pursued. Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive drug in the strategy of TB elimination

17. Present and future in the use of anti- tubercular drugs. Time to approval as a antiTB drug is 10-15 years, consisting of phases of preclinical and clinical research. TMC207, a diarylquinoline with a unique way to address Mycobacterial ATP synthetase, shows high activity in vitro against Mycobacterial strains sensitive or resistant to all drugs in the first and second line including quinolones. TMC207 was added to a basic standard regimen in a study of MDR-TB patients. After two months and satisfactory tolerability, sputum conversion rate in culture was 48% (versus 9% in the placebo group). Pneumologia. 2011 Oct-Dec;60(4):198-201. Didilescu C 1, Craiova UM.

18. Present and future in the use of anti- tubercular drugs. Two nitroimidazole (PA-824 and OPC-67683) are currently in clinical development. PA-824 demonstrated good safety and tolerability in adult patients with pulmonary TB in South Africa, when given once daily for 7 days. Associating isoniazid, would prevent the selection of mutants resistant to Isoniazid. Linezolid 600 mg is currently being tested in a Phase II for treatment of XDR-TB in the Republic of Korea. PNU-100480, analogous to the previous one, has the potential to significantly shorten the treatment in cases where there is sensitivity and in those with resistance to drugs. 300 mg dose is under investigation in a phase II pilot study in MDR-TB in South Africa. Pneumologia. 2011 Oct-Dec;60(4):198-201. Didilescu C 1, Craiova UM.

19. New drugs for the treatment of tuberculosis: hope and reality. Rifapentine, a rifamycin with low MIC, long half-life did not confirm its potential in a recent short-term clinical trial and is being extensively re-evaluated. Moxifloxacin, a fluoroquinolone, improved the activity of the standard drug regimen when substituted for ethambutol (EMB). It is being studied to shorten the duration of treatment for fully drug-susceptible TB (Remox study). Clofazimine requires further study because it has been included in a successful short 9-month combined drug regimen for the treatment of multidrug-resistant TB. The diarylquinoline TMC207 is the most promising among the new TB drugs because of its clinical rate of culture conversion. Int J Tuberc Lung Dis. 2012 Aug;16(8):1005-14. Grosset JH 1, Singer TG, Bishai WR.Grosset JHSinger TGBishai WR

20. New drugs for the treatment of tuberculosis: hope and reality. 200 mg daily doses of the nitroimidazo-oxazine PA-824 and the nitro-dihydro-imidazooxazole OPC-67683 were safe and induced a bactericidal effect The new oxazolidinones PNU-100480 and AZD- 5847 might be at least as active as linezolid and much less toxic. SQ109 is an EMB analogue that does not have cross-resistance with EMB and might have synergistic activity in combined regimens. Benzothiazinones and dinitrobenzamides show exciting in vitro anti-microbial activity. Int J Tuberc Lung Dis.2012 Aug;16(8):1005-14. Grosset JH 1, Singer TG, Bishai WR.

21. Novel compounds and drugs and recent patents in treating multidrug-resistant and extensively drug- resistant tuberculosis. A number of recent studies revealed that successful treatment of the patients with MDR/XDR- TB was not achieved due to high resistant rates to many second-line drugs such as kanamycin and prothionamide including poor adherence of the lengthy treatment. Many new drugs and compounds such as benzothiazinones, meropenem, PA-824, isoflavonoids, rhein, PNU-100480, TMC207, SQ109, OPC-67683, AZD5847, and linezolid are currently in development pipeline. Recent Pat Antiinfect Drug Discov. 2012 Aug;7(2):141-56.Cheepsattayakorn A 1, Cheepsattayakorn R.

22. Tuberculosis: the drug development pipeline at a glance. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA- 824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. Eur J Med Chem. 2012 May;51:1-16. Villemagne B 1, Crauste C, Flipo M, Baulard AR, Déprez B, Willand N.

23. Improving the health of the tuberculosis drug pipeline. Moxifloxacin and levofloxacin have equally good efficacy and safety in the early phase of treatment of multidrug- resistant TB (MDR-TB), linezolid has the potential to cure refractory cases of MDR- TB. Bedaquiline and delamanid may be the best drug candidates for enhancing treatment options for MDR-TB. New chemicals, such as sutezolid, AZD5847, PA-824, SQ109, and BTZ043, show potent activity against Mycobacterium tuberculosis. Late-generation fluoroquinolones in combination with the first-line and second-line anti-TB drugs have been used to shorten the treatment duration in drug-susceptible and MDR-TB. Lancet Infect Dis.Lancet Infect Dis. 2014 Feb;14(2):102-3. Curr Opin Pulm Med.Curr Opin Pulm Med. 2014 May;20(3):280-6.

24. Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis. incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683 successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to as 9a). In vivo, 9a showed long half-lives and high volumes of distribution and a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents. 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis. PLoS One.2014 Feb 5;9(2):e87909. doi: 10.1371/journal.pone.0087909. eCollection 2014. Rakesh 1, Bruhn DF 1, Lee RB 1, Hurdle JG 1, McNeil MR 2, Lenaerts AJ 2, Meibohm B 3, Lee RE 4.

25. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4- trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro- 5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis. The addition of serum protein or albumin does not significantly alter this activity. Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. Upton AM 1, Cho S 2, Yang TJ 3, Kim Y 2, Wang Y 2, Lu Y 4, Wang B 4, Xu J 4, Mdluli K 3, Ma Z 3, Franzblau SG 2.Upton AMCho SYang TJKim YWang YLu YWang BXu JMdluli KMa Z Franzblau SG

26. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Spontaneous resistant mutants appear at a frequency of 3 × 10 -7. TBA-354 has high bioavailability and a long elimination half-life and a low risk of drug-drug interactions. It has time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. TBA-354 is suitable for once-daily oral dosing Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. Upton AM 1, Cho S 2, Yang TJ 3, Kim Y 2, Wang Y 2, Lu Y 4, Wang B 4, Xu J 4, Mdluli K 3, Ma Z 3, Franzblau SG 2.Upton AMCho SYang TJKim YWang YLu YWang BXu JMdluli KMa Z Franzblau SG

27. The anti-tuberculosis agents under development and the challenges ahead. Tuberculosis (TB) is a serious health problem causing 1.5 million deaths worldwide. Compounds such as gatifloxacin, moxifloxacin and linezolid, the already known antibiotics are currently being evaluated for their anti-TB activity. OPC-67683 and TMC207 have been approved for the treatment of MDR-TB patients recently, while – PA-824, SQ109, PNU-100480, AZD5847, LL3858, SQ609, SQ641, BTZ043, DC-159a, CPZEN-45, Q-203, DNB1, TBA-354 are in various phases of clinical and preclinical developments. Future Med Chem. 2015;7(15):1981-2003. Kumar D 1, Negi B 1, Rawat DS 1.

28. Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma. Delamanid (OPC-67683, Deltyba) was rapidly degraded by incubation in the plasma of all species tested at 37°C, with half-life values (hours) of 0.64 (human). A major metabolite, (R)-2-amino-4,5- dihydrooxazole derivative (M1), was formed in the plasma by cleavage of the 6-nitro-2,3- dihydroimidazo(2,1-b)oxazole moiety of delamanid by albumin. Drug Metab Dispos. 2015 Aug;43(8):1277-83. Shimokawa Y 1, Sasahara K 2, Koyama N 2, Kitano K 2, Shibata M 2, Yoda N 2, Umehara K 2.

29. Delamanid (OPC-67683) for treatment of multi-drug-resistant tuberculosis. The research and development of delamanid was carried out by Otsuka Pharmaceutical Development and Commercialization (Osaka, Tokyo, Japan). It belongs to the group of nitroimidazoles. It inhibits the synthesis of mycolic acids. Its market approval was obtained in April 2014 in Europe. Its bactericidal activity was demonstrated in individuals with drug-susceptible, MDR- and XDR-TB. The safety and tolerability profile was good; the notified increased QT interval was not clinically relevant. It was approved for adults but ongoing clinical trials in the pediatric population. Expert Rev Anti Infect Ther. 2015 Mar;13(3):305-15. Sotgiu G 1, Pontali E, Centis R, D'Ambrosio L, Migliori GB. Drug Des Devel Ther. 2015 Jan 29;9:677-82.Szumowski JD 1, Lynch JB 2. Ther Clin Risk Manag. 2015 May 13;11:779-91. doi: 10.2147/TCRM.S71076. eCollection 2015.Lewis JM 1, Sloan DJ 2. N Engl J Med 2015; 373:291-292July 16, 2015 DOI: 10.1056/NEJMc1415332 Article Citing Articles (3) Metrics

30. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Delamanid (Deltyba(®)), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. Drugs.2015 Jan;75(1):91-100. Blair HA 1, Scott LJ.

31. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6- month extension study, long-term (≤8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term (≤2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for ≥2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB. Drugs.2015 Jan;75(1):91-100. Blair HA 1, Scott LJ.

32. Delamanid does not inhibit or induce cytochrome p450 enzymes in vitro. delamanid is unlikely to cause clinically relevant drug-drug interactions when co-administered with products that are metabolized by the CYP enzyme system. Biol Pharm Bull. 2014;37(11):1727-35. Shimokawa Y 1, Sasahara K, Yoda N, Mizuno K, Umehara K.

33. Novel drugs against tuberculosis: a clinician's perspective. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. Eur Respir J. 2015 Apr;45(4):1119-31. Olaru ID 1, von Groote-Bidlingmaier F 2, Heyckendorf J 1, Yew WW 3, Lange C 4, Chang KC 5.

34. Tuberculosis treatment and drug regimens. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high (China, India, and former Soviet Union countries). Cold Spring Harb Perspect Med. 2015 Jan 8;5(5):a017822. Sotgiu G 1, Centis R 2, D'ambrosio L 2, Migliori GB 2.

35. Contribution of the nitroimidazoles PA-824 and TBA- 354 to the activity of novel regimens in murine models of tuberculosis. New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug- susceptible and drug-resistant forms of tuberculosis. PA-824 (nitroimidazo-oxazine) now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. Antimicrob Agents Chemother. 2015 Jan;59(1):129-35.Tasneen R 1, Williams K 1, Amoabeng O 1, Minkowski A 1, Mdluli KE 2, Upton AM 2, Nuermberger EL 3.

36. Contribution of the nitroimidazoles PA-824 and TBA- 354 to the activity of novel regimens in murine models of tuberculosis. TBA-354 monotherapy is 5 to 10 times more potent than PA- 824. (TBA-354 + bedaquiline) is 2 to 4 times more potent than (PA- 824 + bedaquiline), And at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen. Antimicrob Agents Chemother. 2015 Jan;59(1):129-35.Tasneen R 1, Williams K 1, Amoabeng O 1, Minkowski A 1, Mdluli KE 2, Upton AM 2, Nuermberger EL 3.

37. bedaquiline delamanide