Nouveaux antituberculeux Vincent Jarlier CNR des mycobactéries et de la résistance aux...

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


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


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


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


OPC

INH RMP

OPC-67683 : activité en association chez la souris


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


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)


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


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

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