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Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux antituberculeux (CNR-MyRMA) Pi

Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux antituberculeux (CNR-MyRMA) Pitié-Salpêtrière, Paris. A « new » antituberculous agent : moxifloxacin. Fluoroquinolone activity In the mice ( Lalande AAC 1993, Ji AAC 1995, Ji AAC 1998).

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Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux antituberculeux (CNR-MyRMA) Pi

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  1. Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux antituberculeux (CNR-MyRMA) Pitié-Salpêtrière, Paris

  2. A « new » antituberculous agent : moxifloxacin

  3. Fluoroquinolone activity In the mice (Lalande AAC 1993, Ji AAC 1995, Ji AAC 1998) Man : early bactericidal activity: (EBA) equivalent to that of RMP but less than that of INH (Gosling AJRCCM 2003)

  4. Moxifloxacin in MDR TB treatment in mice amikacin + ethionamide + pyrazinamide (AEtZ) + fluoroquinolone Mean UFC in lungs Day 0 6 months Moxifloxacin 12 months Veziris AAC 2003 WHO standard

  5. Sterilizing activity in MDR TB (mice) : relapse 3 months after end of treatment % relapses Veziris ICAAC 2008 6 months : 58% 9-12 months required gold standard  40% 28% 16% 11% 11% 2RHZ +4RH 2JRZ +2JR 2AEtMZ +4EtM 2JAEtMZ +4JEtM 2JMZ +2JM 2JMZ +4JM

  6. Moxifloxacin in daily treatment of susceptible TB (with RMP or INH) (1) Negativation of organs Nuermberger AJRCCM 2004 2MHZ + 4MH Untreated 2RHM+ 4RH 2HRMZ + 4HRM 2RHZ + 4RH 2RMZ + 4RM

  7. Moxifloxacin in daily treatment of susceptible TB (with RMP or INH) in mice(2)Relapses 3 months after treatment completion *proportion of mice whose organs yielded positive cultures Nuermberger AJRCCM2004

  8. Moxifloxacin in man • HRZ + ethambutol or moxifloxacine (2 groups) • 336 patients, 277 (82%) evaluable • 206 (74%) with caverna • 60 (22%) HIV+ • 71% culture negativation at 2 months in both groups • More culture negativation at 1 month with moxifloxacin • more nausea (22 vs 9%) with moxifloxacin • Same rate of lost of follow up Burman AJRCCM 2006

  9. Moxifloxacin in man • HRZ + éthambutol or moxifloxacine • 170 patients, 146 evaluable Chaisson ICAAC 2007 % cultures neg p=0.021 weeks

  10. Moxifloxacin in man • HRE + isoniazid or moxifloxacin • 433 patients, 344 (79%) evaluable • 252 (73%) with caverna • 36 (11%) HIV+ • 60% (103/171) negativation after 2 months with moxifloxacin • 55% (93/173) negativation after 2 months with isoniazid P = 0,37  deceiving Dorman, ICAAC 2007

  11. Linezolid as antituberculous agent

  12. Linezolide • MIC M.tuberculosis = 0.5 mg/l (Alcala 2003) • Pharmacokinetics (Gee, 2001) • peak in serum = 18 mg/l • ½ life : 5 hours • EBA in man : week activity (AJRCCM 2008)

  13. Linezolide : activity in mice Bacterial load in spleen and lungs after 1 month of treatment in mice inoculated with 6.8 log UFC M.tuberculosis Cynamon AAC 1999 < 2 logs 3 logs 25 mg/kg oxazolidinone 100mg/kg

  14. Linezolide in man • 5 MDR TB treated by LZN + thiacetazone + clofazimine (+/- amox-clav) • Negativation of respiratory sample after 6 weeks • 5-24 months : 3  cured, 1 lost of follow up, 1 on tt after 11 months • 4 severe anemias leading to blood transfusions • 2 polynevritis • 1 pancreatitis Fortun JAC 2005

  15. Linezolide in man • 10 MDR TB treated by various regimens + LZN • Negativation of respiratory sample 9/10 • 5 anemias • 6 polynevritis Bent von der LippeJ Inf 2005

  16. DiarylquinolinesR207910 (TMC207)

  17. R207910 ATP synthase Janssen (Jonhson & Jonhson) Pharmaceutical Research and Development) Séquençage complet de 2 couples sauvage/mutant résistant (M.tuberculosis, M.smegmatis) : sous-unité c ATP synthase (gène atpE) Andries Science 2005

  18. Inhibition of ATP synthase Diarylquinoline : R207910 (TMC207) H+ H+ H+ F0 Subunit c (atpE) H+ F1 Andries Science 2005 ADP + Pi > ATP Ephraim Racker mitochondria 1961 Size : 9 nm Inhibited by oligomycin

  19. In vitro activity (MIC mg/l) of R207910 against clinical strains ofMycobacterium tuberculosis Andries Science 2005

  20. Rifampin 10 mg/kg J 25 mg/kg Control R = rifampin 10 mg/kg H = isoniazid 25 mg/kg Z = pyrazinamide 150 R207910 alone in established murine TB infection (2 months) Andries Science 2005 Log CFU in lungs R207910 is more active than rifampicine and as active as rifampicine + isoniazid + pyrazinamide

  21. H = isoniazid 25 mg/kg R = rifampin 10 mg/kg Z = pyrazinamide 150 mg/kg J = J 25 mg/kg 4 to 5 logs drop in 4 weeks R207910combined with 1st line drugsin mice (2 months) RHJ RJZ JHZ Untreated controls RHZ RHZJ 0 cfu lung ≤ 1 cfu spleen Z H R Andries Science 2005

  22. Relapses 3 months after stopping treatment in mice : impact of R207910 J: R207910 R: rifampicine H : isoniazide Z: pyrazinamide % Tt standard 2 JRZ + 2 JR Veziris AJRCCM2008

  23. R207910 combined with 2nd line drugs MDR TB in mice Log cfu AEtZ : 3 major drugs for MDR TB + moxiflox M = moxifloxacin A = amikacine Z = pyrazinamide Et = ethionamide + R207910 Lounis AAC 2006

  24. Sterilizing activity in MDR TB (mice) : relapse 3 months after end of treatment % relapses gold standard MDR TB  58% + J gold standard S TB  40% 28% 16% 11% 11% 2RHZ +4RH 2JRZ +2JR 2AEtMZ +4EtM 2JAEtMZ +4JEtM 2JMZ +2JM 2JMZ +4JM

  25. R207910 combined with other drugs, given 1/weekin mice (2 months) Log cfu J : R207910 M : moxifloxacine P : rifapentine Z : pyrazinamide DO J M PJP JPH JPM JPZ Veziris AJRCCM 2008

  26. R207910 (TMC207) in man (Diacon ICAAC 2008) MDR TB South Africa

  27. Nitro-imidazoles PA-824OPC-67683

  28. Nitro-imidazoles : PA-824(PathoGenesis Corp. >> global Alliance against TB) MIC on M.tuberculosis : 0.06 - 0.1 mg/L Stover Nature 2000

  29. PA-824 : initial phase in mice log CFU In initial phase PA-824 has a bactericidal activity slightly lower than that of INH Tyagi AAC 2005, Leanerts AAC 2005

  30. PA-824 : continuation phase in mice In continuation phase, PA-824 has apparently a bactericidal activity comparable to that of RIF + INH Tyagi AAC 2005

  31. PA-824 : relapse experiment in mice (PA en plus de RHZ) (PA remplace INH dans RHZ) Nuermberger AAC2006 Week Early Bactericidal Activity (EBA) in man

  32. Nitro-imidazoles : OPC-67683(Otsuka Pharmaceutical, Tokushima) MIC on M.tuberculosis : 0.01 mg/L Matsumoto PLos Medicine 2006

  33. OPC-67683 : activité en monothérapie chez la souris OPC INH RMP Matsumoto PLos Medicine 2006

  34. OPC-67683 : activité en association chez la souris ORZ RHEZ Matsumoto PLos Medicine 2006

  35. Conclusions (1) • Moxifloxacin • la bonne Fquinolone pour MDR TB , mais : • durée AEtMZ ? (6 mois non, 9 mois ?) • comment faire sans aminoside (injectable) ou sans éthionamide (40-50% R) ? • à ce jour plutôt décevant pour TB sensible • Linézolide : pour les cas désespérés (certains XDR) • Diarylquinoline (TMC207) : encourageant pour MDR TB et pour TB sensible 1/semaine (à suivre…) • Nitroimidazoles • PA824 décevant • OPC67683 : tout début

  36. Conclusions (2) • Le traitement standard 2 RHZE + 4 RH (OMS) a encore de beaux jours pour la tuberculose sensible • Le traitement supervisé « facile » (oral et 1 seule administration par semaine) n’est pas pour tout de suite • Le traitement des TB-MDR est amélioré (FQ) mais encore long et délicat • Le traitement des TB-XDR est très problématique • >> ne pas générer de TB-MDR à partir des TB sensibles • >> ne pas générer de TB-XDR à partir des TB MDR

  37. 2 majorantituberculous drugs : Rifampicine (R) Isoniazid (H) >> MDR : resistant to R and H Main antituberculous drugs for MDR : Aminoglycosides Fluoroquinolones (Ethionamide) (Pyrazinamide) MDR definition (WHO)

  38. MDR TB (WHO report 2004 ) • 424 000 cases/year • Primary : 243 000 (3% of new cases) • Secondary : 181 000 (19% of previously treated cases) • China, India, Russia : 261 000 (62% of total) • > 10% MDR : Estonia (17%), Georgia (16%), Azerbaïdjan (15%), Moldavia (15%), Kazakhstan (14%), Ouzbekistan (13%)

  39. M. tuberculosis with Extensive Resistance to Second-Line Drugs - Worldwide, 2000-2004MMWR March 24, 2006 XDR : resistance to isoniazid and rifampin and at least 3 of the 6 main classes of SLDs TB Extensive Resistance to 2nd line Drugs 17,690 TB isolates : 20% MDR and 2% XDR

  40. Revised Definition XDR-TBOctober 2006 • Resistant to INH and RIF (MDR-TB) and • Resistance to amikacin, kanamycin or capreomycin (injectable agents other than streptomycin) and • Resistance to fluroquinolones

  41. XDR-TB (in % of MDR cases) WHO 4th Report

  42. XDR-TB : key findings 4th report 2008 • Representative data available for 39 countries or regions (24 in Europe) • Total data for ~ 5.000 MDR TB cases 2002-07 % XDR TB among MDR TB : • 0 - 1% in 14/39 (e.g. Canada, UK, France, N.Zealand, Denmark, Poland) • 2 - 10% in 15/39 (e.g. Latvia, USA, Sweden, Netherlands, Israel, Australia, Argentina, Romania, Armenia, Georgia, Moldova, Korea) • > 10% in 10/39 (33% Ireland, 33% Slovenia, 31 % Japan, 24% Estonia, 20% Czech, 15% H.Kong, 15% Ukraine, 14% Lithuania, 13% Azerbaijan) • only 4 countries with 10-20 cases/year : Japan, Estonia, Latvia, Azerbaijan • South Africa : non representative data 1.000 cases 2004-07

  43. R207910 et antituberculeux de première ligne R = rifampicine H = isoniazide Z = pyrazinamide J = R207910 Andries, Science 2005 R207910 a une activité équivalente au traitement standard RHZ

  44. % rechutes R207910 : activité stérilisante Rifampicine Isoniazide Pyrazinamide + Diarylquinoline Rifampicine Pyrazinamide + Diarylquinoline Rifampicine Isoniazide Pyrazinamide Veziris AJRCCM 2008 la diarylquinoline réduit de 6 à 4 mois la durée du traitement

  45. R207910 in man : EBA R207910 25 mg/j 100 mg/j 400 mg/j isoniazide rifampicine Low activity in the 1st week

  46. Moxifloxacin-rifapentine in 2/week 4 months treatment in mice • Pas de rechute chez la souris traitée 4 mois : • 2 semaines RHZ ou RMZ • 6 semaines PHZ ou PMZ • 2 mois PH ou PM Rosenthal AJRCCM 2006

  47. In vitro activity (MIC mg/l) of R207910 against MOTT Andries Science 2005

  48. New agents active against Mycobacterium tuberculosis * Cynamon AAC 1999 ** Stover Nature 2000 *** Andries Science 2005

  49. Moxifloxacine in 1/week 6 months TB treatment in mice(P : rifapentine, H : isoniazide) *DO : 5.6 log10 Veziris AAC 2005

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