tuberculoza curs 4
TRANSCRIPT
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Grigoriu Bogdan Ianuarie 2009
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Fate of Untreated Pulmonary Tuberculosis in SanatoriumPatients, Long-Term Follow-Up, Barmelweid, Switzerland
Years after first admission
0 2 4 6 8 10 12 14 16 18
Per
cen
t de
ad
0
20
40
60
80
100
"Open" tuberculosis
"Closed" tuberculosis
Krebs W. Beitr Klin Tbk 1930;74:345-79W. Krebs. 1930. Die Falle von Lungentuberkulose in der aargauischen Heilstatte
Barmelweid aus den Jahren 1912-1927 Beitrage zur Klinik der Tuberkulose 74: 345 - 79
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Tratamentul tuberculozei= Administrarea de antibiotice cu efect asupra
MTB (chimioterapie antituberculoasa)
Decizia administrarii tratamentului – argumente:epidemiologice cliniceradiologiceexamenul microscopic al sputei
Necesitatea de a asocia mai multe antibiotice pentru tratamentul tuberculozei deriva din caracteristicile de crestere a MTB si a evolutiei populatiilor bacteriene
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Populatiile micobacterieneLocalizare
intracelularExtracelular
Ritm de multiplicare rapidalentaIntermitenta
Rezistenta la tratamentMutatii somatice care survin aleator cu o
frecventa constanta in functie de zona chromozomica
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Efectul medicamentelor antiTBEfect bactericid - pe populatii cu X rapida
↓ rapid populatiilor micobacteriene (dispare contagiozitatea)
↓ durata tratamentului favorizeaza trecerea in faza de X lenta/intermitenta
Efect sterilizant - pe populatii cu X lenta/intermitentapreventia recidivelorcontribuie la ↓ duratei trat.trebuie administrate de la inceput
Postefectul = permite administrarea la intervale mai mari de 3-4x timpul de 1/2
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Efectul medicamentelor antiTBDinamica lenta a multiplicarii micobacteriene
+Postefectul antibiotic al medicamentelor
antiTB
Administrare medicamentelorin priza unica zilnicaintermitenta (de 2-3 ori pe saptamana)
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Chimiorezistentaapare prin mutatie genica spontana in populatiile
micobacteriene salbatice (1 la 105-108)
mutant rezistent la 2 antiTB – 1010 la -1013 (mutatii independente intre ele)
leziunile cavitare - 108-109 populatie micobacteriana insuficienta pentru aparitia spontana a mutantilor multirezistenti daca sunt utilizate cel putin 2 ATB
DAR durata tratamentului fiind de aprox 200 zile => riscul rezistenta = 108 x 100 = 1010 => 3 antituberculoase
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Chimiorezistenta
Chimiorezistenta dobandita – monoterapie cu un medicament antiTB
Chimiorezistenta initiala – infectare cu o tulpina deja rezistenta - creste riscul esecului pentru ca numarul de antituberculoase scade => dezvoltarea seriala de rezistente la tratament
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Cerinte tratament antituberculos
Asociere de minim trei antituberculoase eficiente
+Efect bactericid + Efect sterilizant
+Durata suficienta
Sterilizarea organismului prevenirea
recidivelor
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Istoricul tratamentuluiMarea majoritate a trialurilor moderne au fost
realizate de MRCTuberculoza a impus PRIMUL trial randomizat
din istorie : Streptomicina vs bed restDe-a lungul timpului au fost testate multiple
combinatii ale drogurilor disponibile1982: Primul tratament standard: 6 luni de
rifampicin + isoniazida + pirazinamida si etambutol in primele 2 luni
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Medicamente antiTBDe prima linie
eficienta toxicitate ↓utilizate in regimurile standard
De rezervaeficienta ↓toxicitate utilizate in regimuri individualizate in TB
multichimiorezistenta (MDR)
IzoniazidaRifampicinaPirazinamidaEtambutolStreptomicina
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Izoniazida (INH, I)Activitatea bactericida cea mai intensaActioneaza in special pe populatiile
cu multiplicare rapidaextracelulare
Intens bactericidaEfect sterilizant potentActiva pe toate populatiile micobacteriene
Rifampicina (RMP, R)
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INH + RMPAntituberculoase majore
Asocierea lor timp de 9 lunivindecarea TB cu germeni sensibiliprevine aparitia chimiorezistentei si recidivelor
INH
RMP
INH INH INH INH INH INH INH INH
RMP RMP RMP RMP RMP RMP RMP RMP
RMP
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Pirazinamida (PZM, Z)Modest bactericidaEfect sterilizant potentActioneaza pe populatii intracelulare, la pH
acid
Asocierea PZM in primele 2 luni de tratatament permite scaderea duratei la 6 luni
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INH
RMP
INH INH INH INH INH INH INH INH
RMP RMP RMP RMP RMP RMP RMP RMP
PZM PZM
INH
RMP
INH INH INH INH INH
RMP RMP RMP RMP RMP
INH
INH
INHRMP
RMP
RMP
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Streptomicina (SM, S)1943 by Albert SchatzEfect bactericid modestNu are efect sterilizant
Etambutol (EMB, E)
• Efect bacteriostatic modest• Nu are efect sterilizant
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INH INH INH INH INH INH
PZM PZM
RMP RMP RMP RMP RMP RMP
PZM PZM
INH
RMP
INH INH INH INH INH
RMP RMP RMP RMP RMP
EMB/SM EMB/SM
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Dozele medicamentelor antiTB la adult
Administrare
zilnica (6/7 sau 7/7) intermitenta (3/7)
Doza uzuala (mg/kC/priza)
Doza max. (mg) Doza uzuala (mg/kC/priza)
Doza max.
(mg)
H 5 300 10 600
R 10 600 10 600
Z 30 2000 40 2500
E 25 1500-1600 30 2000
S 20 1000 20 1000
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Principii de tratament antiTBAsociere de medicamente antiTB active2 faze
initiala (intensiva) – reducerea rapida a populatiei micobacteriene
de continuare – distrugerea micobacteriilor restante
Durata tratamentului – lunga (sterilizeaza organismul + previne recidivele)
Ritm de administrare:zilnic/intermitentpriza unica, a jeun
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Principii de tratament antiTBH + R (6 luni) + Z (in primele 2 luni)
vindeca > 95% din TB cu germeni sensibiliconstituie baza regimurilor de tratament
antiTB
Asocierea de S/E protejeaza fata de monorezistenta initiala
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Regimuri terapeuticeReg Tipuri de cazuri Regim terapeutic
1
Cat 1
TBP BAAR+ (caz nou)
TBEP severa
2
Cat 2
TBP BAAR+ (retratament)
3 TBP BAAR-
TPEP nonsevera
4
Individualizat
TBP BAAR+ cu esecul unui retratament
Individualizat
PZM PZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
PZM PZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
EMB/SM
PZMPZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
EMB EMB
INH INHRMP RMP
SM SM
PZMEMB EMB EMB EMB EMB EMB
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Adaptarea tratamentului
Daca la sfarsitul perioadei intensive pacientul este BK + durata acestei faze se prelungeste cu o luna
Rezistenta la PZM (M Bovis) = > 9 luniRar = laptele pasteurizat
Rezistenta la INHEvolutie favorabila => +7 luni de RMP + ETBNeafavorabil sau BK +++ de adaugat cel putin un
alt antituberculos (chinolone)
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Adaptarea tratamentului
MDR = aditia de monorezistenteCel putin 3 (preferabil 4-6 Antituberculoase active
40% opresc unul din medicamente din cauza efectelor secundare)
Antibiograma +++Tratament de atac 3-6 luni (frecvent mai mult)Cel putin un an de la negativareComplianta +++
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Lista de prioritatiAminozid
Streptomicina> amikacina/kanamicina>capreomicina (nu exista rezistenta incrucisata)
PirazinamidaEtambutol Izoniazida in caz de rezistenta de nivel jos ??Chinolona
(moxifloxacina>levofloxacina>ofloxacina>ciprofloxacina)Etionamida/protionamida (nu daca rezistenta low-level la INH
= mutatie inhA)CicloserinaPASTiacetazona (NU HIV)Linezolid (oxazolindinone)ALTE: Amixocilina/clavulanat, claritromicina, clofazimina
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Noi medicamenteDiarylquinolineNitroimidazopyraniGatifloxacina
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Locul chirurgieiIndicatii exceptionale Pentru cei cu rezistente ++ si prognostic
nefavorabilChirurgia de rezectie
Leziuni strict localizate si pacient operabil (functional)
Ideal la un pacient care s-a negativat la examenul direct
Urmat de un tratament post operator “normal”PNTX – solutie “de avarie”
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CorticoterapiaDaca pacientul este deja sub corticoizi (trat de
substitutie sau trat indispensabil pt o alta boala => doza trebuie crescuta cu aprox 50% (efect inductor al RMP)
Obligatorie in meningitele tuberculoase, utila in pericardite
Foarte rar cand starea generala este foarte alterataNu modifica succesul tratamentuluiDAR trebuie sa fim SIGURI ca MTB este sensibil
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Adaptarea tratamentuluiInsuficienta renala
Clearance > 30ml/Kg ATENTIE la ETB (efecte secundare +++) = 15 mg/Kg
Clearance <30 ml/Kg ETB 7-10 mg/kG, INH 3-4 mg/Kg, PZM 15 mg/Kg
Dializati: Tratament de 3 ori pe saptamana DUPA fiecare dializa ETB doar daca BK ++ (pt protectia RMP si INH) ETB= 10 mg/Kg, INH 3-4 mg/Kg
HIV+Conversie mai lentaPosibila utila prelungirea tratamentulu
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Anti TNF= oprit tratamentul cu anti-TNF reluat dupa controlul tuberculozei
Paciente insarcinateINH+ RMP = OKPZM = date putine : foarte probabil poate fi
administrata (recomandat in Romania)Localizari extrapulmonare
Putine dateTratament standardPrelungit eventual tratamentul in functie de
ranspunsul la tratament
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Evaluarea initiala a pacientuluiLocalizarea TB: pulmonara, extrapulmonaraTratamente antiTB anterioareAlti factori:
sarcina (H,R,Z,E se pot adm.)medicatie concomitenta (anticonceptionale,
anticoagulante orale)Boli asociate:
diabet zaharat insuficienta renala cronica hepatita cronica infectie HIV/SIDA
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Monitorizarea tratamentului1. Aderenta la tratament
2. Eficienta tratamentului
3. Monitorizarea efectelor adverse
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Aderenta la tratament
DOT (directly observed therapy) –
Comprimate cu combinatii fixe de medicamente (HR /HRZ) – impiedica monoterapia indusa de efectele secundare
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Eficienta tratamentuluiMonitorizare clinica
scaderea/disparitia febreireducerea/disparitia tuseirevenirea apetitului alimentarcresterea in greutate
Monitorizare bacteriologica - cea mai importanta !!!!!
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Tratament eficientNegativarea sputei in microscopie la sfarsitul
fazei intensive (absenta negativarii prelungirea fazei intensive la 3 luni)
Negativarea persistenta in culturi a sputei in cursul tratamentului, incepand de la sfarsitul a 4 luni de tratament
Completarea certa a intregului tratament, chiar in absenta examenelor bacteriologice
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Tratament ineficientExamen bacteriologic al sputei pozitiv
(microscopie / cultura) incepand de la sfarsitul a 4 luni de tratament
Oprirea prematura a tratamentului
Reluarea tratamentului (retratament) confirmare bacteriologica obligatorieantibiograma obligatorie (suspiciune mare de
chimiorezistenta)
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Monitorizarea efecte adverseHepatita medicamentoasaprincipalul efect adversdeterminata de H, R si/sau Zmai frecventa la cei cu alcoolism cronic, boli hepatice
cronicemonitorizarea enzimelor hepatice (TGO, TGP) la cei
cu factori de risc sau cu enzime crescute la debutul tratamentului
depistare: clinica (simptome) sau prin citoliza hepatica
atitudine: 5x oprirea H,R,Z (SE la cei gravi sau foarte contagiosi) urmata de reluarea secventiala pentru identificarea medicamentului incriminat care va fi oprit definitiv
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Monitorizarea efecte adverseEruptii cutanate (S, E)
Neuropatie periferica (H) – piridoxina
Surditate, vertij (S)
Nevrita optica retrobulbara (E)
Purpura trombocitopenica, anemie
hemolitica, insuficienta renala acuta (R)
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Tratamente adjuvanteCorticoterapia 0.5mg/kC/zi, 5-6 sapt.
meningita TB pericardita TB Nu are efecte in TB pulmonara, pleurala,
primara
Tratament chirurgical – complicatiile TB – TB cu germeni polichimiorezistenti
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Controlul tuberculozei in comunitate Elaborarea unor strategii in cadrul unui
Program National de Control Obiective:
1. Vindecarea a 85% din cazurile cu frotiu pozitiv.
2. Diagnosticul a minim 70% din cazurile de tuberculoza din comunitate
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Componentele programului de control
1. Rolul autoritatilor guvernamentale2. Rolul diagnosticului bacteriologic3. Organizarea tratamentului
antituberculos4. Asigurarea necesarului de medicamente5. Evaluarea periodica a eficientei acestui
program
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Organizarea tratamentuluiRegimuri standardizate de scurta durataSub directa observareFolosirea combinatiilor medicamentoase Programele DOTS
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Evaluarea individuala a tratamentuluiVindecat: tratament corect, 2 controale
bacteriologice negativeTratament incheiat: tratament corect, fara
control bacteriologicEsec terapeutic: BK pozitiv dupa luna 4 de
tratament Deces: deces prin orice cauza Abandon: intrerupere a tratamentului min. 2 luni Pierdut: nu poate fi evaluat
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Evaluare periodica a programului
Evaluare prin analiza de cohorta Proportia de cazuri confirmate bacteriologicProportia de cazuri vindecateProportia de cazuri negativate la 2 luni de
tratament (indicator precoce de eficienta)
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Organizarea depistariiDepistare pasiva: printre simptomatici
Ex. bacteriologic: minim 3 sputeExamen radiologic
Depistare activa: in grupurile populationale cu risc foarte ridicat
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Preventia tuberculozei si a infectiei tuberculoase
Administrarea gratuita a tratamentuluiAdministarea chimioprofilaxiei:
contacti cu varsta sub 5 ani selectiv pentru cei cu varsta 5-35 aniInfectati HIV
Vaccinare BCG
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Alte obiective ale programului de control a tuberculozei
Supravegherea rezistentei bacterieneSupravegherea prevalentei infectiei HIVControlul de calitate a laboratoarelor de
bacteriologie
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ConcluziiTuberculoza: problema de sanatate publicaNecesitatea unui program national de
controlImplicarea intregului personal in
indeplinirea obiectivelorNecesitatea evaluarii periodice