1. Pr Ali Ben Kheder The First annuel conference of LATA 24 March 2016- Beyrouth

2. Group 1: TB drugs of 1 rst line - Isoniazide (H) - Rifampicine (R) - Ethambutol (E) - Pyrazinamide (Z) Group 2: TB drugs injected - Kanamycine (Km) - Amikacine (Am) - Capréomycine (Cm) - Streptomycine (S) Group 3: Fluoroquinolones - Ofloxacine (Ofx) - Moxifloxacine (Mfx) - Lévofloxacine (Lfx) Group 4: TB drugs bactériostatic de 2 nd line - Ethionamide (Eto)/ prothionamide (Pto) - Cyclosérine (Cs)/ Terizidone (Trd) - Acide p- aminosalicylique (PAS) Group 5: TB Drugs with unproven effectivness - Clofazimine (Cfz) - Linezolide (Lzd) - Amoxicilline/Acide clavulanique (Amx/Clv) - Thioacétazone ((Thz) - Imipénème/ Cilastatine (Ipm/Cln) - Isoniazide à dose élevée - Clarithromycine (Clr)

3. Why do we need new drugs/ regimens? Decrease toxicity Adverse effects are important Shorten therapy Multidrug-resistant TB, or intolerance to first-line drugs Improve efficacy+++

4. Anne F. Luetkemeyer AJRCCM 2011 Developing Drugs

6.  Moxifloxacin is generally regarded as later Of generation C-8-methoxy- fluoroquinolones.  This newer fluoroquinolones have potent anti- tuberculosis activity, much of which is due to fragment C-8-methoxy. MOXIFLOXACIN

7. Common Structure of quinolones Fluorine radical Fluorine radical: improve the antibacterial activity

9. Intracellulars Bacteria ++ L. pneumophila, Mycoplasmes, Chlamydia spp., Coxiella burnetii Mycobacterium M. tuberculosis (Moxiflo ++) Some atypical mycobacterium (Cipro ++) Francisella tularensis Fluoroquinolones : broad spectrum

10. Bioavailability Ciprofloxacine60-80 %3-5 2 x 200 mg ou2 x 500 mg ou 2 x 400 mg2 x 750 mg MoléculeBioavailt1/2 (h) IV doseOral dose Norfloxacine50%4-5-2 x 400 mg Pefloxacine>90%10 2 x 400 mg Ofloxacine85-95%5-7 2 x 200 mg Levofloxacine>90%6-81 x 500 mg Moxifloxacine90%101 x 400 mg

11. Drug Resistance : real problem Labreche MJ, Am J Health-Syst Pharm 2012

12. What justifies the role of moxifloxacin in treatment of tuberculosis ?

13. MOXIFLOXACIN Tested in : Clinical trial Phase II by the CDC TB trials Consortium (center of diseases control and prevention) Clinical multicentric trial Phase II I (WHO and European community)

14. MOXIFLOXACIN Clinical trial phase II  Objective : to compare bactercidal activity of Moxifloxacin, Isoniazid et Rifampcine  Protocol : Monotherapy of Moxifl (400mg/j), INH (300mg/j) or R (600mg/j) during 5 days Collection of Sputum D0, D2 and D5  Evaluation : ◦ Early bactericidal activity (D2) ◦ Time required to Kill 50% of bacteria Gosting RD. Am. J. Respir. Crit. Care Med 2003, 1; 168 (11) 1342-5

15. Conclusion Moxifloxacin has a bactericidal activity similar to that Rifampicin

16. MOXIFLOXACIN : Tolerance 38 patients (14 MDR) treated by Moxifloxacin +3 main TB drug duration of Treatment : 6 + 5 months Results 12 patients (31%) have at least an adverse effect ◦ 8 digestive AE ◦ 8 neurologic AE 4 patients (10.5%) have had Major AE  Stop of the Moxifloxacin thérapeutic success : 81.6% 51.7% in TBC MDR Codecasa LR. Respir. Med 2006. Feb 13

17. Conclusion Moxifloxacin has a good tolerance

18. Main Goal: Smear culture conversion after 8 WEEKS 26 Centers in USA and AFRICA 328 Patients with smear positive TB -No antecedent of treatment -No resistance known -65% in Africa -11% of HIV - 76% of cavitary lesions Randomized,double blind: -DOT Moxifloxacin 400mg versus INH 300mg 5/7 During 8 weeks + RIF –PZA-EMB

19. moxifloxacin could be an alternative to INH in case of resistance or major side effect Moxifloxacine vs INH

20. Moxifloxacin as an Alternative or Additive Therapy for Treatment of Pulmonary Tuberculosis Option/Bio 20(420):7-7 · June 2009 Option/Bio Although a final conclusion can be put forward, the available scientific data suggest that use of moxifloxacin seems to be as effective as ethambutol and possibly as effective as isoniazid for treatment of pulmonary tuberculosis. Given the limited availability of options in 2 nd pulmonary tuberculosis treatment line, moxifloxacin is an attractive option as an alternative for treating pulmonary tuberculosis.

21. Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study Authors: Manika, K. 1 ; Chatzika, K. 1 ; Papaioannou, M. 2 ; Kontou, P. 2 ; Boutou, A. 1 ; Zarogoulidis, K. 1 ; Kioumis, I. 1 The International Journal of Tuberculosis and Lung Disease, Volume 19, Number 11, 1 November 2015, pp. 1383-1387(5) 1 2 1 The International Journal of Tuberculosis and Lung Disease

22. Study Setting Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB).

23. Study Objective To study the MFX/RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen

24. Study Design Patients with pulmonary TB followed up by the Tuberculosis Out- patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2)

25. Conclusion Decrease in MFX level was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co- administration There is interaction between RMP and MFX leading to readjustement of MFX dose

26. Concerning Shortening of Treatment

27. Moxifloxacin could shorten duration of tuberculosis treatment The Pharmaceutical JournalThe Pharmaceutical Journal3 APR 2009

28. Study Design In a randomised trial conducted in Rio de Janeiro, Brazil, 80% of the 170 tuberculosis patients enrolled in the study who had received 400mg of MFX five days a week tested negative on the eighth week, compared with 63% in the group receiving just 15–20mg/kg ethambutol (P=0.03).

29. Results After one week, 13 % of 69 patients in the moxifloxacin group had sputum cultures that converted to negative compared with 3 % of those in the ethambutol group (P=0.03). At every week after enrolment, patients assigned to moxifloxacin had a significantly higher rate of culture conversion than those assigned to ethambutol

30. Conclusion Additional studies are required to confirm the safety of using moxifloxacin for longer periods, as well as to assess whether shorter courses of the antibiotic can cure tuberculosis as well as or better than the current six-month regimen. « the study authors say. »

31. Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis Stephen H. Gillespie, M.D., D.Sc., Angela M. Crook, Ph.D., Timothy D. McHugh, Ph.D., Carl M. Mendel, M.D., Sarah K. Meredith, M.B., B.S., Stephen R. Murray, M.D., Ph.D., Frances Pappas, M.A., Patrick P.J. Phillips, Ph.D., and Andrew J. Nunn, M.Sc., for the REMoxTB Consortium * N Engl J Med 2014; 371:1577-1587 October 23, 2014 * October 23, 2014

32. The REMoxTB study was a collaboration between : The TB Alliance, Bayer HealthCare AG, the University College London (UCL),Centre for Clinical Microbiology, the Medical Research Council Clinical Trials Unit at UCL and the University of St. Andrews. It enrolled 1,931 patients at 50 sites in nine countries (Kenya, Mexico, Tanzania, South Africa, China, India, Thailand, Malaysia and Zambia).

33. Methods a randomized, double-blind, placebo-controlled, phase 3 trial to test the non-inferiority of two moxifloxacin-containing regimens as compared with a control regimen (1931 patients enrolled)  One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group).  In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group),  and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group).

34. Objective a randomized, double-blind, placebo- controlled, phase 3 trial to test the non- inferiority of two moxifloxacin- containing regimens as compared with a control regimen (1931 patients enrolled )

35. End point  The primary end point was treatment failure or relapse within 18 months after randomization

36. RESULTS OF PHASE III REMOXTB CLINICAL TRIAL PUBLISHED Results of the Phase III REMoxTB clinical trial were published in the New England Journal of Medicine on September 7th, 2014. REMox or Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) was a trial designed to determine whether replacement of either ethambutol or isoniazid with moxifloxacin shortened the duration of therapy. In summary, while the regimens with moxifloxacin caused a more rapid decrease in mycobacterial load, moxifloxacin containing regimens did not shorten TB treatment to 4 months as predicted.

37. Conclusion The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, non-infe riority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383 NCT00864383

38. safety but not shortened tuberculosis treatment+++ Presented 7 September 2014 at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy The sponsor of the trial, the TB Alliance, stated in its press release that replacing one of the drugs (TB) patients to be shortened to four months”. “ While the experimental regimens initially killed more TB bacteria than the standard regimen, patients receiving those shortened regimens were more likely to relapse than those taking the standard treatment.” Prof. Charles Mgone, EDCTP Executive Director: “A shorter treatment regimen would have great significance for individual patients and TB care programmes alike. Unfortunately, this goal has not been achieved by the REMoxTB trial.

39. According to the researchers, REMoxTB was the most rigorous TB trial ever conducted, and although the experimental regimen wasn’t sufficient to reduce TB treatment time by 2 months, Mel Spigelman, MD, president and CEO of TB Alliance

40. High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis Amina Jindani, F.R.C.P., Thomas S. Harrison, F.R.C.P., Andrew J. Nunn, M.Sc., Patrick P.J. Phillips, Ph.D., Gavin J. Churchyard, Ph.D., Salome Charalambous, Ph.D., Mark Hatherill, M.D., Hennie Geldenhuys, M.B., Ch.B., Helen M. McIlleron, Ph.D., Simbarashe P. Zvada, M.Phil., Stanley Mungofa, M.P.H., Nasir A. Shah, M.B., B.S., Simukai Zizhou, M.B., Ch.B., Lloyd Magweta, M.B., Ch.B., James Shepherd, Ph.D., Sambayawo Nyirenda, M.D., Janneke H. van Dijk, Ph.D., Heather E. Clouting, M.Sc., David Coleman, M.Sc., Anna L.E. Bateson, Ph.D., Timothy D. McHugh, Ph.D., Philip D. Butcher, Ph.D., and Denny A. Mitchison, F.R.C.P., for the RIFAQUIN Trial Team* n engl j med 371;17 nejm.org October 23, 2014

41. We randomly assigned patients with newly diagnosed, smear- positive, drug-sensitive tuberculosis to one of three regimens:  a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin;  4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months  or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Methods

42. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with non- inferiority Methods

43. The 6-month regimen in which rifapentine and moxifloxacin are administered once weekly during the continuation phase is non inferior to the standard regimen, which requires daily administration of medication for 6 months. The new regimen could facilitate the strategy of directly observed treatment and could be used as first line treatment in certain settings, such as those with low rates of HIV coinfection or high ratesof isoniazid resistance.

44. JID JOURNAL SUPPLEMENT: TUBERCULOSIS DRUG DEVELOPMENT A supplement dedicated to TB drug development appears in the Journal of Infectious Diseases Volume 211, June 15, 2015. Topics include nonclinical models of TB drug development, PKPD and dose response, drug metabolism and interactions, and special populations. - See more at: http://www.newtbdrugs.org/blog/#sthash.AsmSs4iO.dpuf

45. Conclusion  MFX is an new interesting drug for fighting TB  Its role as a treament of second line is well accepted  However, further studies are needed to demonstrate its role in shortening of TB treatment

46. Conclusion First : We must better use FLD!!!