Panduan

Tatalaksana TB,
MDR TB dan Laten
TB
Bambang Sigit Riyanto
Divisi Respirologi dan Penyakit Kritis
Paru, Departemen Ilmu Penyakit Dalam
FK UGM/RSUP DR Sardjito
 PENDAHULUAN
Dari Global TB Report WHO 2015 : Indonesia
peringkat ke2 penyumbang kasus TB didunia setelah
India, dan negara dengan prevalensi ke3 terbanyak
setelah Afrika selatan dan Kambodia, sehingga
penting untuk mendapat perhatian yang serius
Program eliminasi TB global telah dicanangkan
dimana pada tahun 2035 ditargetkan tercapai :
1. penurunan kematian berturut-turut pada tahun
2020, 2025, 2030, 2035 sebesar 35%, 75%, 95%, 95%,
disbanding data tahun 2015.
2. penurunan insidensi berturut-turut pada tahun
2020, 2025, 2030, 2035 sebesar 20%(<85/100.000),
50%(<55/100.000), 80%(<20/100.000), 90%
(<10/100.000).
3. tidak ada kejadian catastrfik pada tahun 2020,
2025, 2030, 2035.
Bagaimana target eliminasi TB tersebut dapat
dicapai adalah melalui penemuan dan pengobatan
yang adekuat sesuai standar internasional.(9)
Transmission of tb

Speaking : 0 210 particles

Coughing : 0 3500 particles
Sneezing : 4500 106 particles
Comprises a microscopic agregation of epithelioid (activated ma
ussually surrounded by a collar lymphocyte

The cells
Antigen presenting cells
macrophages
dendritic cells

T-lymphocytes
 Transmission
4-6 weeks

Primary TB
6 month

Latent Progressive

Post primary TB

Cure 25% Died 50% Chronic case 25

Massive hemptysis
Colaps of lobus
Pneumothotaks
Bronchiectasis
Cardiopulmonary
insufficiency
Metastasis to the
 Clinical Presentation:
Extrapulmonary
Incidence/site may vary TB can involve any organ
More common in HIV/TB

Both, 9%

Extrapulmonary, 21%

Pleural, 17%
Lymphatic, 43%

Other, 13%
Pulmonary, 70%
Bone/joint, 11% Genitourinary, 5%
TB Cases by Form of
Disease, Peritoneal, 5% Meningeal, 6%
United States, CDC, 2006
Extrapulmonary
Tuberculosis
 Kebutuhan akan
ISTC..
Kebanyakan dokter praktek swasta (pribadi,
klinik maupun RS) bahkan sebagian RS
pemerintah belum tersentuh oleh DOTS
Solusi masalah ini adalah diperlukan suatu
jembatan yang dapat menyambung program
pemerintah dan sektor swasta
Jembatan itu adalah ISTC
 Mengapa?
Masalah Umum:
Diagnosis
Treatment
Public Health Responsibility
 Solusi: ISTC

Ketiga komponen tersebut tercakup dalam ISTC

ISTC berisi langkah langkah dan komponen,
syarat minimal yang harus dilakukan
Tidak menerangkan bagaimana mencapainya
Cara bagaimana melakukannya lihat dan ikuti
Pedoman atau guideline
Prinsip dasar pelayanan untuk
penderita atau diduga
menderita TB pada ISTC
Harus sama di seluruh dunia
Diagnosis cepat dan akurat
Paduan obat dgn efektifiti teruji dengan
pengawasan dan dukungan yang tepat
Memonitor respons pengobatan
Tanggung jawab kesehatan masyarakat
harus dilaksanakan
INTERNATIONAL STANDARD FOR
TUBERCULOSIS CARE (ISTC)
Didukung oleh :
World Health Organization (WHO)
Dutch Tuberculosis Foundation (KNCV)
American Thoracic Society (ATS)
International Union Against Tuberculosis
and Lung Disease
US Centers for disease control & prevention
Stop TB Partnership
Indian Medical Association
 ISTC di Indonesia
Sudah diterima dan didukung oleh IDI
dan berbagai organisasi profesi ( PDPI,
PAPDI, IDAI, POGI, PAMKI, PDS PATKLIN
)
Dalam fase sosialisasi berkoordinasi
dengan Depkes
Akan diimplementasikan sebagai pilot
project
Dalam sosialisasinya kepada anggota
PAPDI diselenggarakan secara Roadshow.
 Tujuan
Memberi gambaran
penanganan TB yang diterima luas di setiap
tingkat pelayanan.

untuk semua praktisi baik pemerintah

maupun swasta yang menangani pasienTB
digunakan dalam menangani pasien yang
diduga atau menderita TB
 Tujuan
Mefasilitasi hubungan kerjasama yang efektif antar
provider dalam memberikan pelayanan bermutu
tinggi kepada pasien TB :
Semua usia
BTA positif atau negatif
Ekstra paru
MDR
Ko-infeksi TB-HIV
 ISTC DAN
PEDOMAN( GUIDELINE)

Standard dan guideline saling

melengkapi.
Standard saling melengkapi dengan
program lokal atau nasional sesuai
rekomendasi WHO.
Standard tidak untuk menggantikan
guideline
Target Utama ISTC:

Penyelenggara pelayanan
kesehatan nonprogram
 ISTC (2014)
Standards for Diagnosis
Standard 1
To ensure early diagnosis, providers must be aware of individual
and group risk factors for tuberculosis and perform prompt clinical
evaluations and appropriate diagnostic testing for persons with
symptoms and findings consistent with tuberculosis.
Standard 2
All patients, including children, with unexplained cough lasting
two or more weeks or with unexplained findings suggestive of
tuberculosis on chest radiographs should be evaluated for
tuberculosis.
 ISTC (2014)
Standard 3
All patients, including children, who are suspected of having
pulmonary tuberculosis and are capable of producing sputum
should have at least two sputum specimens submitted for
smear microscopy or a single sputum specimen for Xpert
MTB/RIF* testing in a quality-assured laboratory. Patients at
risk for drug resistance, who have HIV risks, or who are
seriously ill, should have Xpert MTB/RIF performed as the
initial diagnostic test.
Blood-based serologic tests and interferon-gamma release
assays should not be used for diagnosis of active
tuberculosis.
 Evaluasi Foto Toraks
Abnormal
162 kasus TB dengan
Studi dari India: Biakan M. tb positif
20% tidak
menunjukkan
2229 Pasien rawat kelainan pada foto
jalan di evaluasi toraks
Foto toraks dan
Biakan M. tb Foto toraks saja tidak
cukup
227 kasus dianggap
TB berdasarkan foto
toraks saja
Foto toraks bermanfaat
36% mempunyai pada sputum BTA (-)
biakan M. tb negatif
Nagpaul DR, Proceedings of the 9th Eastern Region Tuberculosis Conference and 29th
National Conference on Tuberculosis and Chest Diseases. 1974 Delhi, as cited in
Tomans tuberculosis. Case detection, treatment and monitoring, 2 nd Edition: World
Health Organization, 2004
 Algoritma Diagnosis TB
Semua Pasien dengan kecurigaan TB paru

Mikroskopik sputum BTA

3x
Semua negatif
2-3 kali positif

Terapi antibiotika
Tdk
Tidak Perbaikan

Ulang BTA
Ya

1 kali positif Semua negatif

Foto toraks dan keputusan

TB dokter Bukan TB
 Alur Diagnosis TB: Sedian apus
Negatif
Semua Suspek TB

Pemeriksaan dahak mikroskopis

Sedian apus dahak 3 X negatif

Obat antibiotik spektrum luas (tidak termasuk fluoroquinolon)

Tidak Ada Perbaikan Ada Perbaikan

Ulang pemeriksaan
mikroskopis

>=1 hapusan positif Semua hapusan negatif

TB Foto toraks dan pertimbangan dokter Bukan TB

 ISTC (2014)
Standard 4
For all patients, including children, suspected of
having extrapulmonary tuberculosis, appropriate
specimens from the suspected sites of involvement
should be obtained for microbiological and
histological examination. An Xpert MTB/RIF test is
recommended as the preferred initial
microbiological test for suspected tuberculous
meningitis because of the need for a rapid
diagnosis.
 ISTC (2014)
Standard 5

In patients suspected of having pulmonary tuberculosis

whose sputum smears are negative, Xpert MTB/RIF
and/or sputum cultures should be performed. Among
smear- and Xpert MTB/RIF negative persons with
clinical evidence strongly suggestive of tuberculosis,
antituberculosis treatment should be initiated after
collection of specimens for culture examination.
 Standar 5 - LAMA

Diagnosis TB paru BTA negatif harus

berdasarkan kriteria sebagai berikut :
-
pemeriksaan mikroskopis sputum negatif paling
kurang 3x (termasuk minimal 1x sputum pagi)
foto toraks menunjukkan kelainan TB
Tidak respons terhadap terapi antibiotik spektrum
luas (Fluoroquinolon harus dihindari , krn aktif
thd M.tb perbaikan sesaat pada pasien TB)
Bila ada fasiliti, harus dilakukan pemeriksaan
biakan M. tb. Pasien HIV/ diduga HIV, evaluasi
diagnostik harus disegerakan
 ISTC (2014)
Standard 6

For all children suspected of having intrathoracic

(i.e., pulmonary, pleural, and mediastinal or hilar
lymph node) tuberculosis, bacteriological
confirmation should be sought through examination
of respiratory secretions (expectorated sputum,
induced sputum, gastric lavage) for smear
microscopy, an Xpert MTB/RIF test, and/or culture.
History of previous treatment
 Standards for
Treatment
Standard 7
To fulfill her/his public health responsibility, as
well as responsibility to the individual patient,
the provider must prescribe an appropriate
treatment regimen, monitor adherence to the
regimen, and, when necessary, address factors
leading to interruption or discontinuation of
treatment. Fulfilling these responsibilities will
likely require coordination with local public
health services and/or other agencies.
 Standard 8
All patients who have not been treated previously and
do not have other risk factors for drug resistance
should receive a WHO-approved first-line treatment
regimen using quality assured drugs. The initial phase
should consist of two months of isoniazid, rifampicin,
pyrazinamide, and ethambutol.*
The continuation phase should consist of isoniazid and
rifampicin given for 4 months. The doses of
antituberculosis drugs used should conform to WHO
recommendations. Fixed-dose combination drugs may
provide a more convenient form of drug administration.
Doses of first-line antituberculosis
drugs in adults and children
 Standard 9

A patient-centered approach to treatment

should be developed for all patients in order
to promote adherence, improve quality of life,
and relieve suffering. This approach should
be based on the patients needs and mutual
respect between the patient and the provider.
Standard 10

Response to treatment in patients with pulmonary tuberculosis

(including those with tuberculosis diagnosed by a rapid molecular
test) should be monitored by follow up sputum smear microscopy at
the time of completion of the initial phase of treatment (two months).
If the sputum smear is positive at completion of the initial phase,
sputum microscopy should be performed again at 3 months and, if
positive, rapid molecular drug sensitivity testing (line probe assays or
Xpert MTB/RIF) or culture with drug susceptibility testing should be
performed. In patients with extrapulmonary tuberculosis and in
children, the response to treatment is best assessed clinically.
 Category - 1
end end
1 2 3 4 5 6 7

+ Cure

+ + Cure
insertion

+ + + Cure
insertion

+ + Failure

+ + Failure

+ ? Complete
Continue the treatment
Ro (+) Complete

Ro (+) + + Failure
insertion +
 category - 2

1 2 3 end en
d
4 5 6 7 8 9
+ Cure

+ + Cure
Insertion

+ + + Cure
Insertion
+ + Failure

+ + + Failure
Insertion
+ ? Complete

+ + ? Complete
Insertion
+ Failure
 TERAPI TB
Kategori Pasien TB Regimen Terapi TB
Fase inisial Fase lanjut
I BTA positip, BTA negativ lesi 2 HRZE 4 HR
luas, HIV positif, ekstra paru 4 (HR)3
berat. optional optional
2HRZE 6 HE
Optional optional
2 (HRZE) 3 4 (HR)3
III BTA negative, ekstra paru tidak 2 HRZE 4 HR
berat 4 (HR)3
optional optional
2 HRZE 6 HE
Optional optional
2 (HRZE) 4 (HR)3
(WHO, 2004)

Kategori Pasien TB Regimen Terapi TB

Fase inisial Fase lanjut
II Relap, Terapi setelah Default 2 5 HRE
HRZES/IHRZE 5 (HR)3
optional
2(HRZES)3 /
1(HRZE)3
II Gagal Terapi Kategori I, setting: 2HRZE/1 HRZE 5 HRE
-TB MDR rendah Optional 5 (HRE)3
Tidak ada fasilitas kultur MDR 2
(HRZES)3/1(HR
ZE)
II Gagal Terapi Kategori I, setting: Obat diberikan secara individual
-TB MDR tinggi berdasarkan hasil sensitivitas test
tersedia obat second line dengan obat second line
IV Kronik, suspect MDR Obat diberikan secara individual
berdasarkan hasil sensitivitas test
dengan obat second line.
 TB TREATMENT REGIMENS
TB
DIAGNOSTIC TB PATIENTS INITIAL PHASE CONTINUATION PHASE
CATEGORY (Daily Or 3 Times (Daily Or 3 Times
Weekly) a Weekly) a

New smear-positive patients;

New smear-negative PTB with
I extensive parenchymal 4 HR
involvement; 2 HRZE b or
Severe concomitant HIV 6 HE daily
disease or severe forms of
extra-pulmonary TB (EPTB)

Previously treated sputum

smear-positive PTB :
- relapse; 2 HRZES/
II - treatment 1 HRZE
5 HRE
after interruption; -
treatment failure d
New smear-negative PTB
(other than in Category I);
4 HR
III Less severe forms of 2 HRZE e or
EPTB 6 HE daily c
Chronic and MDR-TB cases Specially designed standardized or
IV ( still sputum-positive after
supervised re-treatment)
individualized regimens are suggested for
his category
Recommended Treatment Regimens For Each Diagnostic Category (WHO2003)
 Standard 11
An assessment of the likelihood of drug resistance, based on
history of prior treatment, exposure to a possible source case
having drug-resistant organisms, and the community
prevalence of drug resistance (if known), should be
undertaken for all patients. Drug susceptibility testing should
be performed at the start of therapy for all patients at a risk
of drug resistance. Patients who remain sputum smear-
positive at completion of 3 months of treatment, patients in
whom treatment has failed, and patients who have been lost
to follow up or relapsed following one or more courses of
treatment should always be assessed for drug resistance. For
patients in whom drug resistance is considered to be likely an
Xpert MTB/RIF test should be the initial diagnostic test. If
rifampicin resistance is detected, culture and testing for
susceptibility to isoniazid, fluoroquinolones, and second-line
injectable drugs should be performed promptly. Patient
counseling and education, as well as treatment with an
empirical second-line regimen, should begin immediately to
minimize the potential for transmission. Infection control
measures appropriate to the setting should be applied.
 Standard 12
Patients with or highly likely to have tuberculosis caused by
drug-resistant (especially MDR/XDR) organisms should be
treated with specialized regimens containing quality-assured
second-line antituberculosis drugs. The doses of
antituberculosis drugs should conform to WHO
recommendations. The regimen chosen may be standardized
or based on presumed or confirmed drug susceptibility
patterns. At least five drugs, pyrazinamide and four drugs to
which the organisms are known or presumed to be
susceptible, including an injectable agent, should be used in
a 68 month intensive phase, and at least 3 drugs to which
the organisms are known or presumed to be susceptible,
should be used in the continuation phase. Treatment should
be given for at least 1824 months beyond culture
conversion. Patient-centered measures, including observation
of treatment, are required to ensure adherence. Consultation
with a specialist experienced in treatment of patients with
MDR/XDR tuberculosis should be obtained.
 Kategori OAT: WHO
Grup 1 - OAT lini pertama: isoniasid, rifampisin,
etambutol, pirasinamid
Grup 2 - Obat suntik: streptomisin, kanamisin,
amikasin, kapreomisin, (viomisin)
Grup 3 - Fluoroquinolon: ciprofloxasin, ofloxasin,
levofloxasin, moxifloxasin, (gatifloxasin)
Grup 4 - Obat bakteriostatis oral: etionamid,
cicloserin, para-aminosalicylic acid (prothionamid,
thioacetazon, terisadon)
Grup 5 - Obat belum terbukti: clofasamin,
amoxicillin/klavulanat, claritromisin, linezolid
 Regimen For MDR TB in
Indonesia
Km Eto Lfx Cs Z-(E) / Eto
Lfx Cs Z-(E)
 Standard 13

An accessible, systematically
maintained record of all medications
given, bacteriologic response,
outcomes, and adverse reactions
should be maintained for all patients.
 Standards for Addressing HIV
Infection and other Co-morbid
Conditions
Standard 14
HIV testing and counseling should be conducted for all
patients with, or suspected of having, tuberculosis unless
there is a confirmed negative test within the previous two
months. Because of the close relationship of tuberculosis
and HIV infection, integrated approaches to prevention,
diagnosis, and treatment of both tuberculosis and HIV
infection are recommended in areas with high HIV
prevalence. HIV testing is of special importance as part of
routine management of all patients in areas with a high
prevalence of HIV infection in the general population, in
patients with symptoms and/or signs of HIV-related
conditions, and in patients having a history suggestive of
high risk of HIV exposure.
 Standard 15
In persons with HIV infection and tuberculosis who
have profound immunosuppression (CD4 counts less
than 50 cells/mm3), ART should be initiated within
2 weeks of beginning treatment for tuberculosis
unless tuberculous meningitis is present. For all
other patients with HIV and tuberculosis,
regardless of CD4 counts, antiretroviral therapy
should be initiated within 8 weeks of beginning
treatment for tuberculosis. Patients with
tuberculosis and HIV infection should also receive
cotrimoxazole as prophylaxis for other infections.
 Standard 17

All providers should conduct a thorough assessment for co-morbid

conditions and other factors that could affect tuberculosis treatment
response or outcome and identify additional services that would
support an optimal outcome for each patient. These services should be
incorporated into an individualized plan of care that includes
assessment of and referrals for treatment of other illnesses. Particular
attention should be paid to diseases or conditions known to affect
treatment outcome, for example, diabetes mellitus, drug and alcohol
abuse, undernutrition, and tobacco smoking. Referrals to other
psychosocial support services or to such services asantenatal or well-
baby care should also be provided.
 Standard 16

Persons with HIV infection who, after

careful evaluation, do not have active
tuberculosis should be treated for
presumed latent tuberculosis infection
with isoniazid for at least 6 months.
 Standard 18

All providers should ensure that persons in close contact with patients who
have infectious tuberculosis are evaluated and managed in line with
international recommendations. The highest priority contacts for evaluation
are:

Persons with symptoms suggestive of tuberculosis

Children aged <5 years
Contacts with known or suspected immunocompromised states, particularly
HIV infection
Contacts of patients with MDR/XDR tuberculosis
 Standard 19

Children <5 years of age and persons

contacts of a person with infectious
tuberculosis, and who, after careful evaluation,
do not have active tuberculosis, should be
treated for presumed latent tuberculosis
infection with isoniazid for at least six months.
 Standard 20

Each health care facility caring for patients

who have, or are suspected of having,
infectious tuberculosis should develop and
implement an appropriate tuberculosis
infection control plan to minimize possible
transmission of M. tuberculosis to patients
and health care workers.
Bagan sistem tertutup
 Standard 21

All providers must report both new and

re-treatment tuberculosis cases and their
treatment outcomes to local public health
authorities, in conformance with
applicable legal requirements,
regulations, and policies.
TB EKSTRA
PARU
 Tata Diagnosis

Mikrobiologi : BTA, kultur, Xpert

histopatologi
Respon imunologi
- seluler : PPD
- humoral : IgG anti TB
- IGRA
- ADA
Adenosine Deaminase
( ADA test )
untuk Deteksi MTB
 Diagnosis pasti effusi pleura, effusi pericard atau
peritonitis yg disebabkan TB sulit karena
sensitifitas rendah & spesifitas alat diagnosa
terbatas

Pada sebagian besar pasien , uji BTA cairan effusi

hampir selalu negatif ( hanya < 25% positif )

Spesimen biopsi pleura 80 % pleuritis

granulomatosa.
 Diagnosa Tb extra paru memerlukan analisa
cairan effusi, sitologi & biopsi.

ELISA, PCR & IFN relatif mahal.

ADA dianggap memiliki sensitifitas & spesifitas

yang tinggi untuk diagnosa awal TB extra paru.
 Pleuritis TB reaksi hipersensitivitas type
lambat terhadap antigen M.Tb dalam kavum
pleura.

Reaksi imunologi stimulasi & diferensiasi

limfosit melepas Limfokin & aktivasi makrofag
meningkatkan kadar ADA.
 ADA enzim pada sebagian besar sel, terlibat dalam
proliferasi Limfosit T, dilepaskan karena adanya infeksi
mikroorganisme.

Meningkat pada efusi pleura, efusi perikardial, &

peritonitis TB.

ADA marker cell mediated immunity

( aktivasi Limfosit T )

Tes diagnosis tidak invasif, tidak mahal, mudah

diakses, cepat ( hanya 2 jam )
 Pada Effusi TB, radang pleura dominan oleh
Limfosit,.

ADA dilepas karena adanya M.Tb intraseluler

ADA yg tinggi juga terdapat pada keganasan

( adeno Ca,limfoma, leukimia ) & penyakit
kolagen vaskular ( SLE )

ADA meningkat tidak selalu dianggap adanya

M.Tb
 ADA pada cairan effusi pleura Pleuritis TB
Sensitivitas 90-100%
Spesifitas 89-100%

Cutt Off ADA : 47-60 U/L

Spesifitas meningkat jika rasio limfosit/neutrofil > 0.75

& kadar ADA > 50 U/L.
 Metode Pemeriksaan

Kolorimetri ( Guisti & Galanty ) paling banyak

dipakai

Kadar ADA menurun seiring waktu &

peningkatan suhu.

Stabiliser gliserol & etilen glikol/Na.sulfat.

( sampai 3 minggu pada 37c )
 Sampel diambil dengan pengumpulan cairan
tubuh :

Cairan Effusi Pleura Thoracocentesis

Cairan ascites Paracentesis

Cairan effusi Pericard Pericardiocentesis

 Nilai rujukan kadar ADA
Tipe Rentang Rerata
Cairan Pleura TB 45-160 100
Non TB 5-33 18
Cairan peritoneum TB 35-135 92
( ascites ) Non TB 1-28 12
Cairan Pericard TB 63-117 90
Non TB 1,5-29 15
 Supporting studies

Burgess, LJ : aktivitas ADA pada Effusi TB lebih

tinggi, pada 50 U/L sensitifitas 90% & spesifitas
89%

Shibagaki : ADA pada efusi TB lebih tinggi

dibandingkan effusi keganasan, ADA menurun
setelah tx OAT.

Gupta : pada ADA > 30 U/L untuk caira ascites,

sensitifitas 100% & spesifitas 94 %.
 OAT Lini Pertama
Kategori-1 : 2(HRZE) / 4(HR)
Alternatif 2(HRZE)/4(HR)3
Paduan OAT ini diberikan untuk pasien baru:
Pasien TB paru terkonfirmasi bakteriologis.
Pasien TB paru terdiagnosis klinis
Pasien TB ekstra paru
 OAT Lini Pertama
Kategori-1 : 2(HRZE) / 4(HR)
Alternatif 2(HRZE)/4(HR)3
Follow up : sputum BTA akhir bulan ke2, ke5,
akhir pengobatan
Tidak ada obat Sisipan pada gagal konversi pada
akhir fase intensif
Bila BTA masih positif pada bulan ke5, dinyatakan
gagal dan memulai kategori 2
 OAT Lini Pertama
Kategori -2: 2(HRZE)S / (HRZE) / 5(HR)3E3)
Paduan OAT ini diberikan untuk pasien BTA positif
yang pernah diobati sebelumnya (pengobatan
ulang):
Pasien kambuh
Pasien gagal pada pengobatan dengan paduan
OAT kategori 1 sebelumnya
Pasien yang diobati kembali setelah putus
berobat (lost to follow-up)
Efek Samping OAT
Tata Laksana Efek
Samping OAT
 Tata Laksana MDR TB
Terapi MDR TB direkomendasikan untuk
semua tuberkulosis resisten rifampicin
walaupun status resistensi isoniazid belum
dikonfirmasi

Clarithromycin dan golongan makrolide lain

tidak lagi termasuk dalam regimen MDR TB
MDR-TB Prevalence

www.who.int/tb/data
 Regimen TB MDR
Pengobatan TB MDR diberikan minimal 20 bulan
dimana minimal 6 bulan fase intensif dengan paduan
obat pirazinamid, etambutol, kanamisin,
levofloksasin, etionamid, sikloserin dan dilanjutkan
18 bulan fase lanjutan dengan paduan obat
pirazinamid, etambutol, levofloksasin, etionamid,
sikloserin (6Z-(E)-Kn-Lfx-Eto-Cs/18Z-(E)-Lfx-Eto-Cs).
Etambutol dan pirazinamid dapat diberikan namun
tidak termasuk obat paduan standar, bila telah
terbukti resisten maka etambutol tidak diberikan.
 Regimen Terapi Lebih
Pendek
Terapi MDR TB selama 9-12 bulan
Pasien dengan resisten rifampicin atau
multidrug-resistant TB yang sebelumnya
belum pernah diterapi dengan OAT lini
kedua dan pada pasien yang tidak resisten
terhadap fluorokuinolon serta OAT injeksi
lini kedua
 Regimen Terapi Lebih
Pendek
Fase Inisial (4 bulan)
6 bulan jika tidak konversi
Regimen: Gatifloxacin (atau Moxifloxacin),
Kanamycin, Prothionamide, Clofazimine,
Isoniazid dosis tinggi, Pyrazinamide, dan
Ethambutol
Fase Lanjutan (5 bulan)
Regimen: Gatifloxacin (atau Moxifloxacin),
Clofazimine, Etambutol, dan Pyrazinamide.
 Regimen Terapi Lebih
Pendek
4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E /
5 Mfx-Cfz-Z-E
Km=Kanamycin; Mfx=Moxifloxacin;
Pto=Prothionamide; Cfz=Clofazimine;
Z=Pyrazinamide; Hhigh-dose= high-dose
Isoniazid; E=Ethambutol
Exclusion criteria: 2nd line drug
resistance, extrapulmonary disease and
pregnancy
 Subgroup
Considerations

RR-TB tanpa MDR-TB

Seluruh pasien baik anak-anak maupun
dewasa dengan TB resisten terhadap
Rifampicin namun status resistensi Isoniazid
belum terkonfirmasi dapat diterapi dengan
regimen MDR-TB yang lebih pendek.
 Subgroup
Considerations

Resistensi tambahan terhadap MDR TB

Pada pasien yang terinfeksi dengan strain yang
diketahui atau diduga kuat menjadi resisten
terhadap satu atau lebih obat pada regimen MDR
TB yang diperpendek (misalnya Pirazinamid)
dianjurkan untuk tidak menggunakan regimen
pendek sampai lebih banyak bukti yang tersedia
tentang kinerjanya dalam situasi seperti ini.
 Subgroup
Considerations

Pasien dengan HIV

Pasien dengan HIV perlu diberikan
pertimbangan yang sama dengan pasien
dengan HIV seronegatif untuk terapi
dengan regimen MDR-TB yang lebih
pendek
 Subgroup
Considerations
Wanita hamil
Kehamilan merupakan kriteria eksklusi pada terapi
regimen MDR-TB yang lebih pendek. Dua komponen
regimen ini merupakan kontraindikasi pada kehamilan
(agen injeksi dan ethionamide (atau prothionamide)).
Sehingga pada wanita hamil direkomendasikan untuk
menggunakan regimen konvensional yang tidak bersifat
teratogenik

Penyakit ekstrapulmoner
Belum ada rekomendasi untuk kasus MDR-TB
ekstrapulmoner
 Pilihan Obat
1 obat dari group A ( quinolon )
1 obat dari group B ( injectable )
Paling tidak 2 obat dari group C ( core second
line )
1 obat dari group D1 ( first line yang masih
efektif )
. Total 5 obat efektif
Bila tidak memenuhi diambil obat dari D2 atau D3
 Tidak dapat memakai
Regimen Terapi Lebih
Pendek
terapi konvensional TB MDR
Intensive phase
Duration: Up to 8 months
Composition: 4 or more second-line drugs
Continuation phase
Duration: 12 months or more
Composition: 3 or more second-line drugs
 Fluorokuinolon

Fluorokuinolon (levofloxacin dosis tinggi,

moxifloxacin, dan gatifloxacin) secara
signifikan dapat meningkatkan hasil terapi
pada pasien dengan resisten Rifampicin
dan MDR-TB. Kelompok obat ini
merupakan regimen terpenting di dalam
terapi MDR TB
Agen Injeksi Lini Kedua
Amikacin, Capreomycin, atau
Kanamycin
Streptomycin tidak direkomendasikan
namun dapat digunakan jika ada
kontraindikasi terhadap ketiga agen
Efek samping: hearing loss dan
nefrotoksisitas
 Ethionamide dan
Prothionamide
Menyebabkan gangguan
gastrointestinal
Jika dikombinasikan dengan PAS
dapat menyebabkan hipotiroid
Agen Injeksi Lini Kedua
Cycloserine
Efek samping neuropsikiatrik
Linezolid
Trombositopenia, anemia, neuropati
perifer, asidosis laktat, dan neuropati optik
TatalaksanaTB
Pada
Kondisi Khusus
 TB pada HIV
Semua pasien TB dengan HIV ataupasien
TB yang tinggal di lingkungan dengan
prevalens HIV tinggi, pengobatan TB fase
awal dan fase lanjutan harus diberikan
setiap hari (Rekomendasi A)
Untuk pasien yang tidak mungkin
diberikan setiap hari, pemberian 3 kali
seminggu merupakan alternatif
(Rekomendasi B)
 TB pada Gagal
Ginjal
Stadium 1 : Klirens kreatinin dan fungsi normal namun
terdapat kelainan traktus urinarius seperti ginjal polikistik
dan struktur abnormal
Stadium 2 : Klirens kreatinin 60-90 ml/menit
Stadium 3 : Klirens kreatinin 30-60 ml/menit
Stadium 4 : Klirens kreatinin 15-30 ml/menit
Stadium 5 : Klirens kreatinin <15 ml/menit dengan atau
tanpa dialisis
 TB pada Gagal
Ginjal
yang Dosis direkomendasikan untuk pasien dewasa
dengan penurunan fungsi ginjal dan untuk pasien dewasa
dengan hemodialisis Obat
Perubahan pd Frekuensi?
Dosis & Frekuensi yang disarankan pada pasien dengan
klirenskreatinin< 30 ml/mnt atau pada pasien dialysis
Isoniazid Tidak ada perubahan
300 mg sekalisehari atau
900 mg 3x/minggu
 TB pada Gagal
Ginjal
Rifampin Tidak ada perubahan 600 mg
sekalisehari atau 600 mg 3x/minggu
Perubahan pd Frekuensi?
Dosis & Frekuensi yang disarankan pada pasien dengan
klirenskreatinin< 30 ml/mnt atau pada pasien dialysis
Pyrazinamide 25-35 mg/kg per dosis 3x/minggu (tidak
setiap hari)
Ethambutol 15-25 mg/kg per dosis 3x/minggu (tidak
setiap hari)

 TB pada Penyakit
Hati Kronis
Dua obat hepatotoksik - 9 bulan isoniazid + rifampisin +
etambutol
- 2 bulan isoniazid + rifampisin + etambutol + streptomisin diikuti 6
bulan isoniazid + rifampisin
- 6-9 bulan rifampisin + pirazinamid + etambutol
Satu obat hepatotoksik
- 2 bulan isoniazid, etambutol, streptomisin diikuti 10 bulan
isoniazid+etambutol
Tanpat obat hepatotoksik - 18-24 bulan streptomisin, etambutol,
fluorokuinolon
 TB pada Diabetes
Melitus
Paduan OAT pada prinsipnya sama dengan TB tanpa DM,
dengan syarat kadar gula darah terkontrol
Apabila kadar gula darah tidak terkontrol, maka lama
pengobatan dapat dilanjutkan sampai 9 bulan
Hati-hati dengan penggunaan etambutol, karena efek
samping etambutol pada mata; sedangkan pasien DM
sering mengalami komplikasi kelainan pada mata
Perlu diperhatikan penggunaan rifampisin karena akan
mengurangi efektivitas obat oral antidiabetes (sulfonil
urea) sehingga dosisnya perlu ditingkatkan
 TB pada Kehamilan

Isoniazid (Kategori Kehamilan A),suppl B6

50mg/hari
Rifampisin (Kategori Kehamilan C) , ibu diberi vit
K 10mg/hari, dan bayi setelah lahir
Etambutol (Kategori Kehamilan A)
Pirazinamid (Kategori Kehamilan belum tersedia)
bila tanpa PZA maka OAT 9 bulan RHE
Streptomisin (Kategori Kehamilan belum tersedia)
Fluorokuinolon (Kategori Kehamilan B3)
 MDR-TB Pada
Kondisi Khusus
Antituberculosis
Drugs
Algorithm MDR-TB treatment
Standardized Category 4
regimen
instructions (adult)
Antituberculosi
s Dose
MDR-TB treatment in Special
Conditions

MDR-TB in HIV patients

MDR-TB in Renal Failure
MDR-TB in Chronic Liver Disease
MDR-TB in Pregnancy
MDR-TB in DM Patients
 MDR TB in HIV
patients
Antiretroviral Therapy is not an excuse to
postpone MDR TB treatment
If patients havent started ART yet, start
MDR TB regimen fisrt, if tolerated, ART
can be initated.
Chosen ART regimen in MDR-TB is AZT-
3TC-EFZ.
Continue therapy if patients have started
How to start ART co-treatment in an
MDR-TB patient
 IRIS Management
IRIS, syndrome that occurs when TB symptoms
become worse in the first two to eight weeks of
ART.
Immune system is starting to work again, and it
does not mean that the ART is not working.
If IRIS occurs, use non-steroidal anti-
inflammatories such as ibuprofen.
Corticosteroids can be used to suppress IRIS in
severe cases.
Give prednisone 0.5 mg/kg for up to 21 days.
 MDR-TB in Liver Disease

Tuberculosis therapy in patients with liver disorder often

becomes a problem in treatment as TB drugs are able to
produce liver function disturbance
End stage liver disease patients and life-threatening
deterioration, do avoid all hepatotoxic drugs and it is
recommended to choose Levofloxacin, EMB,
Aminoglycocide, and Cycloserine if necessary.
It is needed to be underlined that INH and PZA are the
most common anti-tuberculosis drugs that cause
hepatotoxicity.
Second-line of anti-tuberculosis drugs have less
(Survival Guideline, 2011
hepatotoxicity effect
 MDR-TB in Liver Disease
Isoniazid, rifampicin and pyrazinamide associated
with hepatotoxicity.
Pyrazinamide is the most hepatotoxic of the three
first-line drugs.
Ethionamide, prothionamide and PAS can also be
hepatotoxic, although less so than any of the first-
line drugs.
Hepatitis occurs rarely with fluoroquinolones.
Hepatotoxic reactions to anti-TB drugs may be more
common in these patients and should be
 MDR-TB in Liver Disease

Patients with chronic liver disease should not receive

pyrazinamide.
Patient with TB may have concurrent acute hepatitis that is
unrelated to TB or anti-TB treatment; and here clinical
judgment becomes necessary.
In some cases, it is possible to defer anti-TB treatment until
the acute hepatitis has been resolved.
Viral hepatitis should be treated if medically indicated and
treatment can occur during drug-resistant TB treatment.
 MDR-TB in Liver
Drug
Isoniazid (INH)
Disease Effects on Liver
INH is the most common cause of hepatitis. In person with normal liver
function,the hepatotoxic effect is usually reversible when drug
administration is stopped when symptoms of liver disorder arises. Liver
toxicity increases when it is administered with Rifampicin.
Rifampin (RIF) RIF often causes cholestatic icterus and increases liver toxicity effect of
INH
Pyrazinamide PZA causes some hepatotoxicity episodes less often than INH but
(PZA) sometimes in more severe degree and longer period despite of anti-
tuberculosis drugs withdrawal.PZA causes the most severe liver
disorder.
Etionamid Etionamind and Paraaminosalicilate (PAS) also have hepatotoxicity
PAS effect
Fluoroquinolones Some fluoroquinolone like Ciprofloxaxin and Moxifloxacin are also
related to liver damage. Travafloxacin is related to severe liver damage.
Etambutol, Rarely cause liver damage
Aminoglycoside,
Cycloserine,
Levofloxacin
MDR TB in pregnancy
Pregnancy is not a contraindication to treatment MDR TB.
Starting therapy drug resistance in trimesters 2 or as soon
as possible if the patient's condition is very bad.
Most majority of teratogenic effects of TB drugs appeared in
the first trimester, therapy may be delayed until the second
trimester.
Avoid injection drug.
Aminoglycosides not used as a regimen in patients with
pregnancy fetal hearing development.
Capreomycin may also have the same risk associated
ototoxicity
Ethionamide increase the risk of nausea and vomiting and
has teratogenic effects
Management in pregnancy
 General principles
Consider Benefits and risks of
treatment
Treat with three or four second-line
anti-TB drugs plus pyrazinamide
Avoid injectable agents
Avoid ethionamide
Consider termination of pregnancy if
the mothers life is compromised
 TB Drugs in Pregnancy

Rohilla, et al, Case Report Multidrug-Resistant Tuberculosis during Pregnancy: Two Case Reports and Review of the
Literature, Case Reports in Obstetrics and Gynecology Volume 2016, Article ID 1536281,
 TB Drugs in Pregnancy

Safe drugs
Isoniazid, rifampicin, ethambutol, PZA
Unclear
Fluoroquinolones, cycloserine/terizidone, PAS
Avoid if possible
Injectables, ethionamide/prothionamide
 Management in pregnancy
Woman being treated for MDR-TB
Avoid pregnancy
Continue the same MDR-TB treatment
Stop MDR-TB treatment when pregnant
Adjust treatment for pregnancy
Terminate pregnancy
Woman is pregnant and diagnosed with MDR-
TB
Start normal MDR-TB treatment
Start a pregnancy adjusted MDR-TB treatment
Delay starting treatment
Terminate pregnancy
 MDR TB in Renal
Insufficiency
Renal insufficiency caused by long standing
TB infection itself or previous use of
aminoglycosides is not uncommon.
Great care should be taken in the
administration of second-line drugs in
patients with renal insufficiency
The dosing is based on the patients
creatinine clearance, which is an estimate of
the glomerular filtration rate or renal
function.
Influencing factor tuberculosis
treatment in renal failure
Drugs pharmacokinetics, especially drugs
proportion excreted by the kidneys and their
clearance by dialysis These factors may affect
the serum levels of drugs therefore their toxicity.
The severity of toxicity anticipated by an
escaladation of serum drug levels and the
possibility of alternative efficient drugs for the
healing of tuberculosis patients.
Coexistence of diverse pathologies with the
possibility
Mimi of anand
et al, Tuberculosis interaction
Chronic Renalbetween various
Failure; Therapy Patterns. Current
Health Sciences Journal Vol. 37, No. 2, 2011
drugs that may affect antituberculous therapy.
 MDR TB in Diabetes
Mellitus
Diabetic patients with MDR TB have poor prognosis.
Diabetes Mellitus will produce side effects of anti-
tuberculosis drugs, especially renal disorder and
peripheral neuropathy.
Diabetes must be well managed during MDR TB
therapy.
Oral Hypoglycemic Drug is not a contraindication for
during MDR TB treatment
Etionamide or Proteinamide might make it more
difficult to control insulin dose.
Creatinine and Potassium level must be observed
weekly within first month of therapy then at least once
a month afterward.
 Side effect of Therapy
Side effects Suspected Drugs Management
Nefrotoxicity Streptomycin, Kanamycin, Stop treatment
Amikacin, Capreomycyn Capreomycin can be used if
aminoglycoside becomes the
chosen injection therapy
Find other causes (NSAIDS,
Diabetic Nephropathy, CHF,
Obstructive Uropathy, etc)
Serum creatinine and
electrolyte evaluation every 1-
2 weeks
Drug dose adjustment based
on creatinine clearance
Peripheral Cyclosporine, Linezolid, Nutritional status and vitamin
Neuropathy INH, Streptomycin, deficiency correction,
Kanamycin, Capreomycin, pyridoxin addition to maximal
Floroquinolone dose (200 mg/day)
Drug dose adjustment to the
severity of side effect
NSAIDs, acetaminophen,or
trycyclic antidepressant
addition
Dysglycemia and Gatifloxacin, Ethionamide/ Stop Gatifloxacin and change
hyperglycemia prothionamide it to the new generation of
Fluoroquinolone, such as
Moxifloxacin
Treat Diabetes. Good glycemic
control is very important in
MDR TB management
Comment
Diabetes Mellitus and Renal
Failure are not
contraindications to anti-
tuberculosis drugs
administration but more
strict monitoring and
management are needed as
this patient have increased
risk for renal failure
Patient with Diabetes
Mellitus has got chronic
complication of neuropathy
and it will get more severe
with anti MDR TB
administration. But this is
not a contraindication and
drug withdrawal is barely
done.
-
 Monitoring in Diabetic
Patient with MDR TB
Creatinine To identify renal insufficiency or nephropathy
Serum due to chronic complication of diabetes or
other causes. Routine monitoring is done
monthly and can be more strict if renal toxicity
is suspected
Potassium Prior to treatment and routinely once a month
Serum
TB LATEN
 TB laten atau Latent TB
infection (LTBI)
Laten atau Tb tak aktif terjadi pada orang yang
terdapat kuman TB pada tubuhnya jumlahnya
sangat sedikit dan tetap terkontrol karena faktor
sistem imunnya dan tak menjadi penyakit
Pasien yang terinfeksi M tb persisten
subklinik replikasi minimal bakteri tak
menimbulkan gejala klinis Pasien dengan LTBI
tak terlihat sakit
LTBI dapat diketahui dari hasil tes Tuberkulin
dan Interferon Gamma Release Assays (IGRAs)
biasanya (+) , foto toraks normal
 Latent TB infection
(LTBI)
2 milyar orang dengan LTBI tetapi hanya < dari 10
juta yang menjadi TB aktif
Orang dgn LTBI banyak yang tidak pernah menjadi
sakit /TB aktif hanya 5-10% menjadi sakit
LTBI masalahnya secara klinik kondisi klinik
komplek
Perubahan status imun pada pasien replikasi
dan jumlah bakteri meningkat akan terdapat
gejala klinis
LTBI kondisi suspek M tb tak ada gejala klinik
M. tb bacilli tak dapat ditemukan dengan kultur
 Latent TB infection
(LTBI)
Pemeriksaan sputum mikroskopis dan kultur jika
dikerjakan hasilnya negatif
Tidak dapat menyebarkan bakteri tb pada orang lain
Harus diperhatikan bahwa pemberian terapi pada
LTBI untuk pencegahan TB
Pemeriksaan diagnosis untuk menegakkan diagnosis
LTBI kelemahannya tak gold standart
Sebelum memberi terapi pada LTBI harus
diperhatikan untuk menyingkirkan diagnosis TB
aktif karena jika ada TB aktif maka
pengobatannya tak adekuat akan berkembang jadi
TB resisten
RISIKO TINGGI TB LATEN
MENJADI TB AKTIF
Bayi dan anak berumur < 4 tahun
Orang yang dalam dua tahun
sebelumnya terinfeksi
Orang dengan HIV
Orang kondisi sistem immun yang
renadah : DM, gagal ginjal
Two-Step TST Testing
 Interferon Gamma Release
Assays (IGRAs)
Skrining untuk LTBI diantara orang yang
kontak dengan pasien TB
Skrining LTBI diantara orang dengan risiko
tinggi untuk menjadi TB aktif secara progresif
( immune suppression ) :
- Terapi pencegahan untuk menurunkan risiko
- Skrining untuk LTBIdan terapi pencegahan
direkomendasikan untuk
* HIV at diagnosis
* Penyakit difisiensi imun lainnya : yang
telah di
diagnosis sebelum pemberian pengobatan
KEY POINT OF IGRAs
 INDIKASI
KONTROVERSIAL IGRAs
Skrining ulangan pada petugas
kesehatan
Skrining untuk imigran
Untuk penambahan diagnosis pada
kasus TB yang sulit ( anak dan ekstra
paru )
Penilaian kesuksesan pengobatan
 Tes dianosis infeksi Mycobacterium tuberculosis
yang menggunakan spesimen darah

Mengukur reaktifitas imun terhadap M.tuberculosis

Sel darah putih dari orang yang terinfeksi

M.tuberculosis akan melepaskan interferon-gamma
(IFN-) saat dicampur dengan antigen dari
M.tuberculosis
 TB Laten
Orang dengan risiko tinggi terpapar pasien
TB
Orang yang berasal dari daerah endemic
TB
Orang yang bekerja di pelayanan
kesehatan yang mengobati pasien TB
 Terapi TB Laten
Isoniazid selama 6 bulan atau
Isoniazid selama 9 bulan atau
Isoniazid selama 3 bulan ditambah
rifapentine setiap minggu atau
Isoniazid selama 3-4 bulan ditambah
rifampicin
Rifampicin selama 3-4 bulan
 Program PPINH
Tidak terbukti TB
Sudah mendapatkan ART 2 bulan
Isoniazid selama 6 bulan.
Thank you