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

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Présentation au sujet: "Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux antituberculeux (CNR-MyRMA) Pitié-Salpêtrière, Paris."— Transcription de la présentation:

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) FQJ0 CFU reduction (log) at week 4 (spleen) Ofloxacin 200 mg/kg7,4- 0,9 Levofloxacin 200 mg/kg7,4- 2,4 Sparfloxacin 100 mg/kg6,8- 4,3 Moxifloxacin 100 mg/kg6,8- 4,8 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 Veziris AAC 2003 Moxifloxacin 6 months 12 months Day 0 Mean UFC in lungs WHO standard

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

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

7 Moxifloxacin in daily treatment of susceptible TB (with RMP or INH) in mice (2) Relapses 3 months after treatment completion Treatment length (months) Regimen3456 2RHZ/4RH11/12*5/121/160/12 1RMZ/RM 4/120/12 - 2RMZ/RM 2/120/120/13 - RMZ 4/120/12 - *proportion of mice whose organs yielded positive cultures Nuermberger AJRCCM 2004

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 % cultures neg weeks p=0.021 HRZ + éthambutol or moxifloxacine 170 patients, 146 evaluable Chaisson ICAAC 2007

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 Cynamon AAC 1999 Bacterial load in spleen and lungs after 1 month of treatment in mice inoculated with 6.8 log UFC M.tuberculosis < 2 logs 3 logs oxazolidinone 100mg/kg25 mg/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 Lippe J Inf 2005

16 Diarylquinolines R (TMC207)

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

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

19 NMIC susceptible R rifampicine10.03 R ethambutol10.01 R pyrazinamide10.03 R fluroquinolones R isoniazide R rifampicine + isoniazide (MDR)20.03 In vitro activity (MIC mg/l) of R against clinical strains of Mycobacterium tuberculosis Andries Science 2005

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

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

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

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

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

25 DO J M P JP JPH JPM JPZ R combined with other drugs, given 1/week in mice (2 months) Log cfu J : R M : moxifloxacine P : rifapentine Z : pyrazinamide Veziris AJRCCM 2008

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

27 Nitro-imidazoles PA-824 OPC-67683

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

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

30 PA-824 : continuation phase in mice lung culture + 4 months 6 months 2 RHZ / RH 0/6 2 RHZ / PA-824 0/6 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 Nuermberger AAC 2006 (PA remplace INH dans RHZ) Week Early Bactericidal Activity (EBA) in man (PA en plus de RHZ)

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

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

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

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

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

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

40 Revised Definition XDR-TB October 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 4 th Report

42 XDR-TB : key findings 4 th report 2008 Representative data available for 39 countries or regions (24 in Europe) Total data for ~ MDR TB cases % XDR TB among MDR TB : 0 - 1% in 14/39 (e.g. Canada, UK, France, N.Zealand, Denmark, Poland) % 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 cases/year : Japan, Estonia, Latvia, Azerbaijan South Africa : non representative data cases

43

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

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

46 R in man : EBA isoniazide rifampicine R mg/j 100 mg/j 400 mg/j Low activity in the 1st week

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

48 N MIC M. avium70.01 M. kansasii M. fortuitum50.01 M. abscessus10.25 M. ulcerans10.5 M. marinum M. xenopi In vitro activity (MIC mg/l) of R against MOTT Andries Science 2005

49 New agents active against Mycobacterium tuberculosis MIC mg/lAcivity in mice Linezolide (oxazolidinone) 0.5moderate* PA 824 (nitroimidazopyrane) 0.1good** R (diarylquinoline) 0.01high*** * Cynamon AAC 1999 ** Stover Nature 2000 *** Andries Science 2005

50 Moxifloxacine in 1/week 6 months TB treatment in mice (P : rifapentine, H : isoniazide) Initial phase 1/day continuation phase 1/week lung culture + 6 months 9 months 2 RHZ + 4 RH 5/7 00/ RHZM P 10 HM100 04/ RHZM P 15 HM100 02/ RHZM P 10 HM400 00/ RHZM P 15 HM400 00/13 6 HP 15 M400 (24 doses) 02/18 *DO : 5.6 log10 Veziris AAC 2005

51 In vitro activity of R against Mycobacterium tuberculosis Proportion of resistant mutants : 5 x to 5 x 10 – 8 (# rifampicine) Andries Science 2005

52 In vitro activity (MIC mg/l) of antituberculous agents against M.tuberculosis H37RV resistant to R selected in vitro Wild typeMutant BK12 R Isoniazide0.12 Rifampicine Ethambutol24 Streptomycine11 Amikacine12 Moxifloxacin0.25 Andries Science 2005

53 Early bactericidal activity (EBA) of moxifloxacin Change in CFU per ml of sputum Pletz AAC 2004 Nday 0day 2day 5EBA log/day INH6 mg/kg Moxiflox.400 mg

54 Nitro-imidazoles : PA-824 Activation par réduction requière FGD1, une glucose 6-phosphate déhyrogénase dépendante du cofacteur F- 420 (coenzyme de réduction) Mutants R = déficients en F-420 (60%) ou en FGD1 (20%) cible inconnue Manjunatha PNAS 2006


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