LA TERAPIA

della

TUBERCOLOSI

Angelo Cazzadori

Istituto Malattie Infettive

Università di Verona

21 – 23 ottobre 2010

PATSY’S CURE

Nov. 20, 1944

H. C. Hinshaw, W. H. Feldman,

and K. H. Pfuetze.

Streptomycin in treatment of

clinical tuberculosis.

Am Rev Tuberc 1946; 54: 191-

203.

STR vs BED REST

STR + PAS

STR + INI + PAS

HOME vs SANATORIUM

DOT

RIFAMPICIN

RIFAMPICIN +

PYRAZINAMIDE

SHORT-COURSE

CHEMOTHERAPY

INTERMITTENCY

THE UNITS WERE CLOSED IN 1986

194519461946

Streptomycin

P-aminosalicylic acid

Thioacetazone

1952 Isoniazid

1954 Pyrazinamide

195519581960

Cycloserine

Ethionamide

Capreomycin

1962 Ethambutol

1963………………1998

Rifampicin

…………….

…………….

Rifapentine

FARMACI ANTITUBERCOLARI

Initial Phase

(8weeks)

Continuation Phase

(18 weeks)

Drug Weeks /doses Drug Weeks /doses

INH

RIF

PZA

EMB

all days

5 days / wks

INH

RIF

all days

3 times in week

Standard Tuberculosis Treatment Regimen

The goals of modern anti-TB therapy

• An initial rapid elimination

of M.tuberculosis in

exponential phase of growth

• An elimination of slowly

replicanting and non

replicantig organism

Infettività

Resistenze

Fallimento

terapeutico

Ricadute a

distanza

e

AZIONE BATTERICIDA

AZIONE STERILIZZANTE

LUNGHEZZA DEL TRATTAMENTO

TOLLERABILITA’ DEI FARMACI ANTITUBERCOLARI

ADERENZA AL TRATTAMENTO

Isolamenti di Myc Tb. in relazione alla classe d'età e

alla provenienza geografica

0

20

40

60

80

100

120

140

160

I II III IV V VI VII VIII IX X

totali

italiani

stranieri

Analisi di 476 isolati a Verona dal 2000 al 2006

< 70 anni EPATITE > 70 anni

6%

9%

H

Z

25%

27%

1% RASH 9%

6% INTOLLERANZA 36%

84% Terapia Completata 62%

TUBERCOLOSI 2005: EFFETTI COLLATERALI

Istituto Malattie Infettive Università di Verona

Treatment success and death by age-group and sex,

pulmonary TB cases, EU & West, 2002

EuroTB

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0-4 5-9 10-1415-1920-2425-2930-3435-3940-4445-4950-5455-5960-6465-6970-7475-7980-84 85+

% of cases

Female success

Male success

Male death

Female death

WE NEED A SOLUTION FOR TUBERCULOSIS

RIGHT NOW

• NEW DRUGS ………………… at least 20 years

• CHANGING CURRENT DOSING OF EXISTING DRUGS

• NEW COMBINATIONS OF EXISTING QUINOLONES

TREATMENT DURATION COULD BE SHORTENED

WITH BETTER USE OF EXISTING DRUGS TO

3 MONTHS

Nuovi Farmaci antitubercolari

• RIFAPENTINE FDA approved for TB

• MOXIFLOXACIN FDA approved possible off-label role

• PA-824 nitroimidazole Chiron, TB Alliance

• OPC-67683 nitroimidazole Otsuka

• TMC-207 diarylquinolone Tibotec

• SQ-109 ethambutol derivative Sequella

• LL-3858 pyrrole Lupin

C

O

M

B

I

N

A

Z

I

O

N

I

?

Phase II

Phase I

RHZ

RHE

SHE

3 6 9 18

mesi

?

DURATA della TERAPIA anti-TB

1960196019601960

1980

2010

1970

Moxifloxacin-containing Regimen Greatly Reduces Time to

Culture Conversion in Murine Tuberculosis

AJRCCM 2004 and 2005

PLoS Med 2007

Weekly Moxifloxacin and Rifapentine is More Active than the

Denver Regimen in Murine Tuberculosis

Center for Tuberculosis Research,

Department of Medicine, Johns

Hopkins University, School of

Medicine, Baltimore, MD.

Daily Dosing of Rifapentine Cures Tuberculosis in Three

Months or Less in the Murine Model

1 2 3 4 days

1 2 3 4 days

Rifampicin

Rifapentine

3 mesi 6 mesi

RHZ

RMHZ

PMZ

X – SHORT TREATMENT for TB

R rifampicina H isoniazide

M moxifloxacina Z pirazinamide

P rifapentina

X – SHORT TREATMENT for TB

RIFAPENTINE 5 day x week x 3 months

MOXIFLOXACIN every day X 3 months

PIRAZINAMIDE every day x 2 months

X – SHORT TREATMENT for TB

?

?

? : quale dose ottimale

Aritmie

Colite C.difficile

Epatite

Tendinite

Artralgie

Strepomicina

Pirazinamide

Isoniazide

Rifampicina

Etambutolo

Moxifloxacina

10 20 30

?

40

Dose

Tossicità

TB DS

non RESISTENTE

a RIFAMPICINA e

ISONIAZIDE

TB MDR

RESISTENTE ad

almeno

RIFAMPICINA e

ISONIAZIDE

TB XDR

RESISTENTE a

RIFAMPICINA

ISONIAZIDE

CHINOLONICI ed

almeno un

FARMACO

INIETTABILE

Resistenze a Verona

Non Res.

Res.singola

MDR

Altre Res.

3% 3%11.7%

82.3%

Istituto di Malattie Infettive-Laboratorio di Microbiologia- -Verona

87%

9%3%1%

2004 - 2006

2000 -2003

324 isolati132 isolati

Farmaci di 1a linea

•INH

•RIF

•PZA

•EMB

Farmaci iniettabili

•SM

•KM

•AMK

•CM

Fluorochinoloni

•Cipro

•Oflox

•Levo

•Moxi

Farmaci orali di 2a linea

Farmaci di “3a linea”•ETA/PTA

•PASA

•CYS

Non raccomandati di routine,

efficacia non dimostrata,es:

linezolid, imipenem

amossi/clavulanato,

claritromicina,

clofazimina

Classificazione gerarchica dei farmaci

antitubercolari in 5 gruppi,

basata su efficacia e sicurezza

1. Usa almeno 5 farmaci

2. Usa tutti i farmaci di prima linea sensibili

3. Usa un fluorochinolone (se resistenza a cipro e

levo usa moxifloxacina)

4. Usa un aminoglicoside per almeno 6 mesi dopo

la conversione delle colture

5. Aggiungi i farmaci di seconda linea sensibili

6. Aggiungi linezolid

7. Se non raggiungi 5 farmaci aggiungi

amoxiclavulanato e clofazimine

I 7 steps della terapia della MDR / XDR TB

Individualized Treatment Regimen for MDR TB

Amikacin, Kanamycin

Ofloxacin, Moxifloxacin

Ethionamide,ProthionamideThioamides

PAS

Polypeptides

Serine analogues

Capreomycin

WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006.

Aminoglycosides

Fluoroquinolones

Cycloserine

First line

drugs

RZ(E)

+

Paser

Non in

commer

cio in

Italia

Treatment and Outcome Analysis of 205 Patients with

Multidrug-resistant Tuberculosis

AJRCCM 2004;169:1103-09

Time to sputum smear conversion

according to treatment received

Emerg Infect Dis 2008;14:1700-06

Grazie dell’attenzione

XXIII CORSO di ANTIBIOTICOTERAPIA 21-23 ottobre 2010