Post on 15-Feb-2019
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