nouveaux antituberculeux vincent jarlier cnr des mycobactéries et de la résistance aux...
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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)
FQ J0 CFU reduction (log) at week 4 (spleen)
Ofloxacin 200 mg/kg 7,4 - 0,9
Levofloxacin 200 mg/kg 7,4 - 2,4
Sparfloxacin 100 mg/kg 6,8 - 4,3
Moxifloxacin 100 mg/kg 6,8 - 4,8
Man : early bactericidal activity : (EBA) equivalent to that of RMP but less than that of INH (Gosling AJRCCM 2003)
Moxifloxacin in MDR TB treatment in mice amikacin + ethionamide + pyrazinamide (AEtZ)
+ fluoroquinolone
J 0
6 mois
12 mois
RH
Z
SH
E
AE
tZO
AE
tZL
AE
tZM
0123
4
5
6
7
8 UFC moyennes dans les poumons
Veziris AAC 2003
Moxifloxacin
6 months
12 months
Day 0
MeanUFC
in lungs
WHO standard
0
10
20
30
40
50
60
2RHZ+4RH 2JRZ+2JR 2AEtMZ+4EtM 2JAEtMZ+4JEtM 2JMZ+2JM 2JMZ+ 4JM
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+2JM
2JMZ+4JM
gold standard
9-12 months required
Veziris ICAAC 2008
Moxifloxacin in daily treatment of susceptible TB (with RMP or INH)
(1) Negativation of organsNuermbergerAJRCCM 2004
2RMZ + 4RM
2HRMZ + 4HRM2RHZ + 4RH
Untreated2MHZ + 4MH
2RHM+ 4RH
Moxifloxacin in daily treatment of susceptible TB (with RMP or INH) in mice
(2) Relapses 3 months after treatment completion
Treatment length (months)
Regimen 3 4 5 62RHZ/4RH 11/12* 5/12 1/16 0/12
1RMZ/RM 4/12 0/12 0/12 -
2RMZ/RM 2/12 0/12 0/13 -
RMZ 4/12 0/12 0/12 -
*proportion of mice whose organs yielded positive culturesNuermberger AJRCCM 2004
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
Moxifloxacin in man
0
10
20
30
40
50
60
70
80
90
1 2 3 4 5 6 7 8
moxifloxacine
éthambutol
% cultures neg
weeks
p=0.021
• HRZ + éthambutol or moxifloxacine• 170 patients, 146 evaluable
Chaisson ICAAC 2007
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
deceivingDorman, ICAAC 2007
Linezolid as antituberculous agent
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)
0
1
2
3
4
5
6
7
8
9
Inoculum Isoniazide PNU-100480
Linezolid Eperezolid
UFC
(log
10)
rate
poumon
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 logs3 logs
oxazolidinone 100mg/kg25 mg/kg
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
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
Diarylquinolines
R207910 (TMC207)
R207910
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
Diarylquinoline : R207910 (TMC207)
Inhibition of ATP synthase
Andries Science 2005
Subunit c (atpE)
Ephraim Rackermitochondria 1961Size : 9 nm Inhibited by oligomycin
F1
F0
ADP + Pi > ATP
H+
H+ H+
H+
N MIC
susceptible 6 0.03-0.12
R rifampicine 1 0.03
R ethambutol 1 0.01
R pyrazinamide 1 0.03
R fluroquinolones 3 0.06-0.12
R isoniazide 7 0.03-0.06
R rifampicine + isoniazide (MDR) 2 0.03
In vitro activity (MIC mg/l) of R207910 against clinical strains of
Mycobacterium tuberculosis
Andries Science 2005
0
1
2
3
4
5
6
8 wks
4 wks
0
1
2
3
4
5
6
8 wks
4 wks
Log CFU Log CFU in lungs in lungs
R = rifampin 10 mg/kgH = isoniazid 25 mg/kgZ = pyrazinamide 150
Rifampin 10 mg/kg
ControlControl
J 25 mg/kg
R207910 alone in established murine TB infection (2 months)
R207910 is more active than rifampicine and as active as rifampicine + isoniazid + pyrazinamide
Andries Science 2005
0
1
2
3
4
5
6
8 wks
4 wks
0
1
2
3
4
5
6
8 wks
4 wks
Untreatedcontrols
Untreatedcontrols
RHZRHZ
4 to 5 logs drop in 4 weeks4 to 5 logs drop in 4 weeks
H = isoniazid 25 mg/kgR = rifampin 10 mg/kgZ = pyrazinamide 150 mg/kgJ = J 25 mg/kg
R207910 combined with 1st line drugs
in mice (2 months)
0 cfu lung≤ 1 cfu spleen
RHZJ RHJ RRJJZZ JHZ
Z HH RRAndries Science 2005
Relapses 3 months after stopping treatment in mice : impact of R207910
0
20
40
60
80
2 mois 3 mois 4 mois 6 mois
2RHZ - 4RH2JRZ - JR2JHZ - JH2JRHZ - JRH
J: R207910R: rifampicineH : isoniazideZ: pyrazinamide
Veziris AJRCCM 20082 JRZ + 2 JR Tt standard
%
0
1
2
3
4
5
6
D0 M J AEtZ AMZ AEtMZ JAEtZ JAMZ JAEtMZ
lung 1month
lung 2months
R207910 combined with 2nd line drugs MDR TB in mice
M = moxifloxacinA = amikacineZ = pyrazinamideEt = ethionamide
+ R207910
AEtZ : 3 major drugsfor MDR TB
+ moxiflox
Log
cfu
Lounis AAC 2006
0
10
20
30
40
50
60
2RHZ+4RH 2JRZ+2JR 2AEtMZ+4EtM 2JAEtMZ+4JEtM 2JMZ+2JM 2JMZ+ 4JM
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
0
1
2
3
4
5
6
7
8
1
D0JMPJPJPHJPMJPZ
DO J M P JP JPH JPM JPZ
R207910 combined with otherdrugs, given 1/week in mice (2 months)L
og c
fu
J : R207910
M : moxifloxacine
P : rifapentine
Z : pyrazinamide
Veziris AJRCCM 2008
R207910 (TMC207) in man (Diacon ICAAC 2008)MDR TB South Africa
Nitro-imidazoles
PA-824 OPC-67683
Nitro-imidazoles : PA-824(PathoGenesis Corp.
>> global Alliance against TB)
Stover Nature 2000
MIC on M.tuberculosis : 0.06 - 0.1 mg/L
PA-824 : initial phase in mice
0
1
2
3
4
5
6
D0 PA-824 H H+PA-824 RHZ
In initial phase PA-824 has a bactericidal activity slightly lower than that of INH
Tyagi AAC 2005, Leanerts AAC 2005
log
CF
U
PA-824 : continuation phase in mice
lung culture +4 months 6 months
2 RHZ / RH 0/6 0/6
2 RHZ / PA-824 0/6 0/6
In continuation phase, PA-824 has apparently a bactericidal activity comparable to that ofRIF + INH
Tyagi AAC 2005
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)
Nitro-imidazoles : OPC-67683(Otsuka Pharmaceutical, Tokushima)
Matsumoto PLos Medicine 2006
MIC on M.tuberculosis : 0.01 mg/L
OPC-67683 : activité en monothérapie chez la souris
Matsumoto PLos Medicine 2006
OPC
INH RMP
OPC-67683 : activité en association chez la souris
Matsumoto PLos Medicine 2006
ORZ
RHEZ
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
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
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)
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%)
TB Extensive Resistance to 2nd line Drugs
• 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
17,690 TB isolates :20% MDR and 2% XDR
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
XDR-TB (in % of MDR cases)
WHO 4th Report
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
0
1
2
3
4
5
6
D0 RHZ J
Poumons 1mo
Poumons 2mo
R207910 et antituberculeux de première ligne
R207910 a une activité équivalente au traitement standard RHZ
R = rifampicineH = isoniazideZ = pyrazinamideJ = R207910
Andries, Science2005
R207910 : activité stérilisante
0
5
10
15
20
25
30
35
3 mois 4 mois 6 mois
% rechutes
RifampicineIsoniazidePyrazinamide
la diarylquinoline réduit de 6 à 4 mois la durée du traitement
RifampicineIsoniazidePyrazinamide+ Diarylquinoline
RifampicinePyrazinamide+ Diarylquinoline
Veziris AJRCCM 2008
R207910 in man : EBA
isoniaziderifampicine
R207910
25 mg/j
100 mg/j
400 mg/j
Low activity in the 1st week
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
N MIC
M. avium 7 0.01
M. kansasii 1 0.003
M. fortuitum 5 0.01
M. abscessus 1 0.25
M. ulcerans 1 0.5
M. marinum
M. xenopi
1
5
0.03
4
In vitro activity (MIC mg/l) of R207910 against MOTT
Andries Science 2005
New agents active against Mycobacterium tuberculosis
MIC mg/l Acivity in mice
Linezolide (oxazolidinone) 0.5 moderate*
PA 824 (nitroimidazopyrane)
0.1 good**
R207910
(diarylquinoline)0.01 high***
* Cynamon AAC 1999** Stover Nature 2000*** Andries Science 2005
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 0 0/18
0.5 RHZM100 + 5.5 P10HM100 0 4/15
0.5 RHZM100 + 5.5 P15HM100 0 2/16
0.5 RHZM400 + 5.5 P10HM400 0 0/16
0.5 RHZM400 + 5.5 P15HM400 0 0/13
6 HP15M400 (24 doses) 0 2/18
*DO : 5.6 log10 Veziris AAC 2005
In vitro activity of R207910 against Mycobacterium tuberculosis
Proportion of resistant mutants :
5 x 10 - 7 to 5 x 10 – 8
(# rifampicine)
Andries Science 2005
In vitro activity (MIC mg/l) of antituberculous agents against M.tuberculosis H37RV resistant to R207910 selected in vitro
Wild type Mutant BK12
R20791 0.03 4
Isoniazide 0.12 0.12
Rifampicine 0.5 0.12
Ethambutol 2 4
Streptomycine 1 1
Amikacine 1 2
Moxifloxacin 0.25 0.25
Andries Science 2005
Early bactericidal activity (EBA) of moxifloxacin
Change in CFU per ml of sputum
Pletz AAC 2004
N day 0 day 2 day 5 EBA log/day
INH 6 mg/kg 9 12 3 1 0.21
Moxiflox. 400 mg 8 14 4 1 0.27
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