1 / 54

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).

aricin
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related