ICTROMI 2019

Multidrug-Resistant Tuberculosis
(MDR-TB)
Dr. Parluhutan Siagian,m.Ked(paru),sp.P(k),FISR

Department of Pulmonology and Respiratory Medicine

Medicine Faculty
University of North Sumatera
Introduction

 TB is one of the 10 most common causes of death in the world

 TB sufferers as much as 10.4 million (2015)-> 480,000 (MDR-

TB) -> 9.5% of MDR TB developed into XDR-T

 MDR-TB acquired without prior history of ATD is called primer

MDR-TB while patients who have received a history of ATD are
referred to as secondary MDR-TB

The key to the prevention of drug resistant by diagnose TB

early with appropriate treatment
 The global TB situation
Estimated number of Estimated number of
cases, 2016 deaths, 2016

All forms of TB 10.4 million 1.3 million

HIV-associated TB 1.03 million 374 000

Multidrug- 600 000 240 000

resistant TB

Source: WHO Global Tuberculosis Report 2017

Source: WHO Global Tuberculosis Report 2017
 MAIN CHANGES TO THE WHO POLICY RECOMMENDATIONS FOR THE
TREATMENT OF DRUG-RESISTANT TB

• A shorter MDR-TB treatment regimen is recommended

under specific conditions
• Medicines used in the design of longer MDR-TB
treatment regimens are now regrouped differently based
upon current evidence on their effectiveness and safety.
Clofazimine and linezolid are now recommended as core
second-line medicines in the MDR-TB regimen while p-
aminosalicylic acid is an add-on agent.
• MDR-TB treatment is recommended for all patients with
RR-TB, regardless of confirmation of isoniazid resistance.
• Specific recommendations are made on the treatment of
children with RR-TB or MDR-TB
• Clarithromycin and other macrolides are no longer
included among the medicines to be used for the
treatment of MDR/RR-TB.
• Evidence-informed recommendations on the role of
surgery are now included
 Discussion

FIVE DIFFERENT CATEGORIES of resistance to ATD :

1. Mono-resistance that is immune to one of the ATD.

2. Poly-resistance is resistance to more than one ATD, in addition to a

combination of Isoniazid and Rifampicin.

3. Multidrug-resistance (MDR) is resistance to at least Isoniazid and Rifampicin.

4. Extensive drug-resistant (XDR) TB is MDR plus resistance to any

fluoroquinolone drug class, and at least one of the second-line injectable ATD
(Capreomycin, Kanamycin, and Amikacin).

5. Total Drug Resistance (TDR) that is resistant to both first-line and second-
line. In this condition there is no medicine that can used.
MDR-TB

Multidrug-resistant (MDR) TB is is resistance

to at least Isoniazid and Rifampicin
 MDR-TB

The findings of such discoveries led to the conclusion that the primary mechanism of
multiple drug resistance in tuberculosis is due to alterations in individual drug target
genes

Genetic resistance to an anti-tuberculosis drug is due to spontaneous chromosomal

mutations at a frequency of 106 to 108 mycobacterial replications

In theory, the chance of drug resistance is thus virtually non-existent when three
effective drugs are used in combination for TB treatment

Amplification of the afore-mentioned genetic mutation through human error results in

clinically drugresistant TB. These include ‘monotherapy’ due to irregular drug supply,
inappropriate doctor prescription and, most importantly, poor patient adherence to
treatment
MDR-TB
MDR-TB

Symptoms of MDR-TB are not different from ordinary or drug

susceptible TB.
The diagnosis of pulmonary TB diagnosis based on clinical
symptoms, physical examination, bacteriological, radiological and
other investigations

Patients who meet the criteria for suspected TB should be referred to

a lab with external quality assurance checks designated for rapid
examination such a molecular testing/ PCR and Gene-xpert.

When MDR confirmed, examination continue by culture and drug sensitivity

testing. Diagnosis of MDR-TB or XDR TB confirmed by assay sensitivity. If the
test results are sensitive M. tuberculosis resistant not only to INH and RIF but
also to at least one of fluoroquinolones class and one of the second-line anti-
TB drugs injection then be enforced TB diagnosis XDR
9 CRITERIA OF SUSPECTED MDR TB
1. TB patients fail category 2 treatment.
2. Category 2 treatment TB patients who were not converted after 3
months of treatment.
3. TB patients who have history of non standart TB treatment and use
quinolones and 2nd line injection drugs for at least 1 month.
4. TB patients fail category 2 treatment.
5. Category 1 treatment TB patients who remained positives after 3 months
of treatment.
6. TB patients relapse or relapse in category 1 and category 2 treatment.
7. TB patients who return after loss to follow-up (default )
8. Suspected TB with closed contact history with Drug resistances TB
patients.
9. TB-HIV Co-infection patients who do not respond clinically and
bacteriologically to ATT.
 Terduga TB ALURPENGOBATAN
Tes Cepat Molekular TBRO–updated
(TCM)

MTB negatif TB rifampisin TB rifampisin resistan

sensitif (RR)
Kirim spesimen untuk DSTlini 1 & 2 (LPA lini kedua DAN
Penatalaksanaan Pengobatan TB kultur DST)
MULAI PENGOBATAN SETELAH MENGEVALUASI KRITERIABERIKUT
Yang sesuai dengan OAT lini KRITERIAPENGOBATAN TBRODENGAN PADUAN JANGKAPENDEK
pertama 1. Tidak ada bukti resistan terhadap fluorokuinolon / obat
injeksi lini kedua
2. Tidak ada kontak dengan pasien TBpre/XDR
3. Tidak pernah mendapat OAT lini kedua selama ≥ 1 bulan
4. Tidak terdapat intoleransi terhadap obat-obat pada paduan
standar jangkapendek
5. Tidak hamil
6. Bukan kasus TBekstra paru berat*

MEMENUHI
TIDAK MEMENUHI
KRITERIA
KRITERIA
Paduanstandar
Paduan pengobatan TB RO yang Paduan
jangka pendek
diberikan individual

Sensitif / toleran Resistan/ intoleran Resistan/ intoleran

Perubahan paduan Sensitif / toleran terhadap FQ dan
terhadap FQdan terhadap FQ dan terhadap FQ dan atauSLI
berdasarkan: atau SLI
atau SLI atau SLI
Hasil DST LANJUTKAN paduan individual sambil
lini kedua
LANJUTKAN paduan KONSULTASI TAK untuk kemungkinan
Toleransi
obat
LANJUTKAN paduan GANTI ke Paduan Individual perubahan paduan berdasarkan hasil
jangka pendek individual DST dan kondisi klinis
 THE SEVERE AND LESS SEVERE FORMS OF
EXTRAPULMONARY TB

SEVERE LESS SEVERE

• Meningitis • Lymphnode
• Miliary • Pleural
• Pericarditis effusion(unilateral)
• Bilateral or extensive • Bone (excluding spine)
pleural effusion • Periperal joint
• Spinal • Adrenal gland
• Intestinal
• Genito-urinary
TREATMENT OF DRUG-RESISTANT TB

Setelah hasil TCM keluar

 MDR-TB

WHO guidelines for the treatment of MDR-TB divided into A,B,C and D groups based on
potency and efficacy can seen in table
In patients with MDR/RR-TB, a regimen with at least five effective TB medicines during
the INTENSIVE PHASE : one from Group A, one from B and at least two from Group C. If
the minimum number of effective TB medicines cannot be composed as given above, an
agent from Group D2 and other agents from Group D3 may be added
MDR-TB

SHORT TERM REGIMEN

4-6 Km – Mfx – Eto (PTO) – Hdt – Cfz – E – Z / 5 Mfx – Cfz – E - Z

 STR DOSES
WEIGHT GROUP
DRUG
<33 kg 33 – 50 kg >50 – 70 kg >70 kg

Kanamisin* 0,5 g 0,75 g 0,75 g 1g

Moxifloxacin 400 mg 600 mg 800 mg 800 mg
Clofazimin 50 mg# 100 mg 100 mg 100 mg
Etambutol 600 mg 800 mg 1000 mg 1200 mg
Pirazinamid 750 mg 1500 mg 2000 mg 2000 mg
IsoniazidDT 300 mg **450 mg **600 mg 600 mg 600 mg
Etionamid 500 mg 500 mg 750 mg 1000 mg
Protionamid 500 mg 500 mg 750 mg 1000 mg
MDR-TB

ETIONAMID can be administered in divided doses to reduce the occurrence of

side effects.
In addition, divided doses are recommended when administered in conjunction
with ART.

CLOFAZIMINE is given at a dose of 200-300 mg per day single

dose for 2 months, followed by a dose of 100 mg per day.
SHORT TERM REGIMEN
 OUTCOMES
Sembuh  Pasien menyelesaikan pengobatan sesuai durasi pengobatan yang
ditetapkan
 Pemeriksaan BTA pada akhir pengobatan (bulan ke – 9 atau 11) hasilnya
NEGATIF
 Pemeriksaan biakan 3 kali berturut-turut dengan jarak minimal 30 hari
hasilnya NEGATIF pada tahap lanjutan
Pengobatan Lengkap  Pasien menyelesaikan pengobatan sesuai durasi pengobatan yang
ditetapkan
 Tidak ada bukti untuk dinyatakan sembuh atau gagal
Gagal  Pemeriksaan BTA pada akhir bulan ke – 6 hasilnya POSITIF,
 Pemeriksaan BTA pada akhir pengobatan hasilnya POSITIF,
 Terjadi Reversi BTA (BTA atau biakan kembali jadi positif) pada tahap
lanjutan. Jika terjadi reversi, maka pemeriksaan BTA dan biakan diulang
pada bulan selanjutnya
 Terjadi efek samping berat yang mengakibatkan pengobatan jangka
pendek harus dihentikan
 Terjadi resistensi tambahan terhadap OAT lini kedua golongan kuinolon
dan atau injeksi lini kedua
Pasien meninggal dalam masa pengobatan oleh sebab apapun
Meninggal
Loss to follow up Pasien berhenti berobat selama 2 bulan berturut – turut atau lebih

Tidak dievaluasi  Pasien pindah berobat tapi hasil akhir pengobatan tidak diketahui atau
tidak dilaporkan kembali
 Pasien tidak ada hasil pengobatan sampai periode pelaporan
MDR-TB
DISSCUSSION

BEDAQUILINE and DELAMANID have been recently approved for the

treatment of MDR-TB. Bedaquiline, a diarylquinoline, and delamanid,
a nitromidoxazole, have received conditional stringent regulatory
approval and have World Health Organization interim policy guidance
for their use. These two new drugs offer a real opportunity to improve
the outcomes of these patients

BEDAQUILINE is a agent that specifically affects the proton pump of

the M tuberculosis ATP synthase
DELAMANID is a novel nitro-dihydro-imidazo-oxazole derivative that
specifically inhibits mycolic acid biosynthesis

WHO recommends the use of bedaquiline for a maximum duration of

24 weeks
Nausea and hepatitis are the most common side-effects associated
with bedaquiline. However, the main safety concern is cardiotoxicity