Management

Multidrug Resistance Tuberculosis (MDR TB)

PRAYUDI SANTOSO
Respirology and Critical Respiratory Division Internal Medicine Department Hasan Sadikin Hospital Universitas Padjadjaran Medical School Bandung Indonesia

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

Current TB Classification based on Drug Resistance

Monoresistance : resistance to one first line anti TB drug only Polydrug resistance : resistance to more than one first line anti TB drug (other than both isoniazid and rifampicin) Multidrug resistance : resistance to at least both isoniazid and rifampicin Extensive drug resistance : resistance to any fluoroquinolone and to at least one of three second line injectable drugs (capreomycin, kanamycin and amikacin), in addition to MDR Rifampicin resistance: resistance to rifampicin detected using phenotypic or genotypic methods with or without resistance to other anti TB drugs. It includes any resistance to rifampicin, whether monoresistance, multidrug resistance, polydrug resistance or extensive drug resistance

Definition and Reporting Framework for TB WHO 2013 Revision

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

MDR/XDR TB Epidemiology
630.000 MDR TB cases among 12 million TB patients Almost 60% of world TB cases are in India, China, Russia and South Africa Highest proportion of MDR TB is in eastern Europe and central Asia (9-32% of new cases and >50% of previously treated) Globally 3.7% (2.1 5.2%) of new cases and 20% (13 -26%) of previously treated cases are estimated to have MDR TB
WHO global Tuberculosis report 2012 Stop TB Partnership, WHO The Global Plan to Stop TB 2011-2015

MDR/XDR TB Epidemiology
Two-thirds of MDR TB cases are not enrolled on treatment according to guideline Treatment success low 50 70% Only 30 0f 107 countries reach target success rate > 75% Globally XDR TB has been identified in 84 countries Proportion of XDR-TB in MDR-TB cases is 9%
WHO global Tuberculosis report 2012 Stop TB Partnership, WHO The Global Plan to Stop TB 2011-2015

Causes of DR

Causes of MDR

Patient mismanagement

MDR TB In INDONESIA
DST Data Before PMDT Implementation
Year 2004
2006 2007 2009
MDR TB

Location Kab. Timika Papua

Prov. Central Java Kota Makassar Prov East Java

New Cases 2% 1.9% 4.1% 2%

Prev Treated 17.1% 19.2% 9.7%

Second Line anti TB (FQ and Kanamycin) in the Market this is likely to create XDR TB

Source : Subdit TB MoH

Result Indonesia PMDT 2009 and 2010 cohorts

Source : Register TB MDR Subdit TB MoH

11

PMDT In Indonesia
Up to February 2013 : - 4770 MDR TB suspect screened - 1177 MDR TB patients - 976 enrolled in treatment Treatment success 71% Up to November 2012 : 27 XDR TB diagnosed

Source : Register TB MDR Subdit TB MoH

DRUG RESISTANCE MECHANISM

The development and spread of drug- and multidrug-resistant tuberculosis.( WHO [2000]. Anti-tuberculosis drug resistance in the world )

WILD MTB STRAIN

( contains a small number [ 106 ] of naturally drug-resistant organisms arising through spontaneous mutations )
SELECTION by monotherapy ( inadequate drug regimen or poor compliance )

ACQUIRED DRUG RESISTANCE

( mono, then MDR-TB )
TRANSMISSION due to diagnostic delay , over crowding and inadequate infection control

PRIMARY DRUG RESISTANCE

( mono drug or MDR-TB )

Frekuensi mutasi spontan resisten

Isoniazid ( H ) Rifampicin ( R ) Streptomycin ( S ) Ethambutol ( E ) Pyrazinamide ( Z ) Quinolones Others 1 x 10 5-10 6 bacilli 1 x 10 7-10 8 bacilli 1 x 10 5-10 6 bacilli 1 x 10 5-10 6 bacilli 1 x 10 2-10 4 bacilli 1 x 10 5-10 6 bacilli 1 x 10 3-10 6 bacilli

Pada TB paru kasus BARU

terdapat >10 8 kuman TB dalam kavitas
1 resistant ( R ) 100 resistant ( H ) 100 resistant ( S) 100 resistant ( E ) 0 resistant ( R + H ) 0 resistant ( R + H + E )

mekanisme terjadinya resistensi : seleksi

H Z

S
S E S

cavitas = 10 8 kuman

mekanisme terjadinya resistensi : seleksi

H S Z S S S S E S S S S S S S S

S
S

cavitas = 10 8 kuman

mekanisme terjadinya resistensi : seleksi

H S Z S S SRS S S S

S
S E

S S S SH S S SE S S SZ S S S S S S

cavitas = 10 8 kuman

cavitas = 10 8 kuman

Fall and Rise phenomenon

Populasi campuran (sensitif dan resisten) Basil resisten thd INH terjadinya strain resisten thd INH karena pengobatan tidak efektif (INH monoterapi)

pengobatan multidrug yang efektif

10

12 14 Minggu

16

18

20

22

24

cegah mekanisme seleksi : terapi kombinasi

H Z

S E

R H Z E

Terbunuh semua

cavitas = 10 8 kuman

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

22

Kriteria Suspek TB MDR (KLINIS)

1. 2. 3. 4. 5. 6. 7. 8. 9. Kasus kronik Pasien TB tidak konversi pengobatan ulang (kategori 2) Pasien TB yang pernah diobati, termasuk pemakaian OAT lini kedua (pengobatan Non DOTS) Pasien TB gagal pengobatan dengan kategori 1 Pasien TB dengan hasil pemeriksaan dahak tetap positif setelah pemberian OAT sisipan (OAT kategori 1) Pasien TB kambuh Pasien TB yang kembali setelah lalai/default (setelah pengobatan kategori 1 dan atau kategori 2) Suspek TB yang kontak erat dengan pasien TB-MDR, termasuk petugas kesehatan yang merawat pasien TB-MDR Ko-infeksi TB-HIV yang tidak respons secara klinis terhadap pengobatan TB

GeneXpert

With GeneXpert
Any person at high risk of MDR-TB could undergo rapid testing start an appropriate treatment immediately while waiting for conventional culture and DST

25

Sensitivity 94.4% and Specificity 98.3%

Validity GeneXpert MTB/RIF in Detecting MDR-TB at Hasan Sadikin Hospital Bandung

Proportion Method Media L-J MDR TB (+) PCRGeneXpert MTB/RIF Total RIF Resistant RIF Sensitive 36 3 39 MDR TB (-) 3 9 12 Total 39 12 51

Sensitivity: 92,3%; Specificity: 75,0%

Sirait N, Parwati I,Dewi SN, Suraya N 2013

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

29

2000

30

PENGELOMPOKAN OAT WHO

Grup 1 - OAT oral 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, terizidon) Grup 5 - Obat belum terbukti: clofasamin, amoxicillin/klavulanat, claritromisin, linezolid
Obat dalam kurung = kesediaannya terbatas
Indonesia ISTC 2008

Adults and adolescent

Drug
Average Daily dosage Isonazid ( H) (100, 300 mg) Rifampicin (R) (150, 300 mg) 4 6 mg/kg daily 10 -20 mg / kg daily 33 50 KG 200 300 mg 450 600 mg

Weight class
51 70 KG 300 mg 600 mg >70 KG (max dose) 300 mg 600 mg

Ethambutol (E) (400 mg)

Pyrazinamide (Z) (500 mg) Streptomycin (S) (1 g vial) Kanamycin (Km) (1 g vial) Capreomycin (cm) (1 g vial) Ofloxacyn (Ofx) Levofloxacin (Lfx) (250 mg, 500 mg) Moxifloxacin (Mfx) (400 mg) Ethionamide (Eto) (250 mg)

25 mg / kg daily
30 40 mg/kg daily 15 20 mg/kg 15 20 mg/kg daily 15 20 mg/kg daily Usual adult dose is 800 mg Usual adult dose is 1000 mg Usual adult dose is 400 mg 15 -20 mg/kg daily

800 1200 mg
1000 1750 mg 500 750 mg 500 750 mg 500 750 mg 800 mg 750 mg 400 mg 500 mg

1200 1600 mg
1750 mg 1000 mg 1000 mg 1000 mg 800 mg 750 1000 mg 400 mg 750 mg

1600 2000 mg
2000 2500 mg 1000 mg 1000 mg 1000 mg 800 1000 mg 750 1000 mg 400 mg 750 1000 mg

Cycloserine (Cs) (250 mg)

Terzidone 9Trd) 250 mg PASER (4G sachets)

15 20 mg/kg
15 20 mg/kg daily 150MG/KG DAILY

500 mg
500 mg 8g

750 mg
750 mg 8g

750 1000 mg
750 1000 mg 8 -12 g

Recommendation for MDR-TB Drug Regimen

34

WHO 2011 update

Step 1
Use any available
Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities

PLUS

One of these

PLUS

One of these

First-line drugs
Pyrazinamide Ethambutol

Fluoroquinolones
Levofloxacin Moxifloxacin

Injectable agents
Amikacin Capreomycin Streptomycin Kanamycin

Step 2
Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously)

Pick one or more of these Oral second line drugs

Cycloserine Ethionamide PAS

Step 3
If there are not 4-6 drugs available consider 3rd line in consult with MDRTB experts

Consider use of these Third line drugs

Imipenem Linezolid Amoxicillin/Clavulanate Macrolides

37

BS

Standardized PMDT Treatment Regimens

Z-Eto-Lfx-K-Cs/ Z-Eto-Lfx-Cs
Kanamycin Resistance: Change to Capreomycin Fluoroquinolone Resistance: Add PAS High dose Levofloxacine Resistance to both Kanamycin and Fluoroquinolone: Change to Capreomycin add PAS High dose Levofloxacine

Source : Indonesia MoH

Outline
New definitions of DR TB and MDR Treatment Outcome Data on MDR and XDR - TB Current MDR-TB diagnosis MDR-TB treatment Guideline Recommendation PMDT implementation at Hasan Sadikin General Hospital Bandung Indonesia

39

Struktur Organisasi Tim TB RSHS

DIREKTUR UTAMA dr. H. Bayu Wahyudi, MPHM, Sp.OG DIREKTUR MEDIK dr. Rudi Kurniadi Kadarsyah, Sp.An, MM, M.Kes KETUA Arto Yuwono Soeroto, dr., SpPD-KP, FCCP DEWAN KONSULTAN Prof. Dr. Zulkarnain Dahlan, dr., SpPD-KP Prof. Cissy B Kartasasmita, dr., SpA(K), PhD Prof. Ida Parwati, dr., SpPK Rista D. Soetikno, dr., SpRad(K) Edi Sampurno, dr., SpP, MM

SEKRETARIS Iceu Dimas Kulsum, dr., SpPD

UNIT DOTS Koordinator Dedy Suyanto, dr.

UNIT TB-HIV Koordinator Rudi Wicaksana, dr., SpPD, KPTI

UNIT TB-MDR Koordinator Prayudi S, dr., SpPD-KP, M.Kes, FCCP

KNCV Lab. Kes. Propinsi

Medis Iceu Dimas Kulsum, dr., SpPD Sasmayani Eko Winanti, dr., SpP Diah Asri W, dr., SpA Basti Andriyoko, dr., SpPK Leny Santani, dr., SpRad PPDS

RR Rini Rahmawati, AMK H. Darsito, AMK Lies Ratnasari, SST

Farmasi Dina Ilham

KIE Rina

Medis Yovita, dr., SpPD Iceu D. Kulsum, dr., SpPD Sasmayani E. Winanti, dr., SpP Novita, dr. Intan Meilana, dr. Mery Lestari, dr. PPDS

RR Sigit, AMK Dian HU, Skep, Ners. Lies Ratnasari, SST Nunung Nuraeni

Farmasi Lia Ega

KIE Nirmala, dr.

TAK (Tim Ahli Klinik) Arto Y. Soeroto, dr.,SpPD-KP, FCCP Dr. Emmy HP, dr., SpPD-KP, KIC Edi Sampurno, dr., SpP, MM Yana Ahmad S, dr., SpPD-KP Prayudi S, dr., SpPD-KP, M.Kes, FCCP Iceu D. Kulsum, dr., SpPD Sasmayani E. Winanti, dr., SpP Dedy Suyanto, dr.

Tim Multidisipliner Tri Wahyu, dr., SpBTKV Dolvy Girawan, dr., SpPD-KGEH Rudi Supriyadi, dr., SpPD-KGH Nani Nathalia, dr., SpPD-KEMD Indra Wijaya, dr., SpPD Leny Santari, dr., SpRad Dominica, dr., SpM Lucky, dr., SpKJ Lina Lasminingrum, dr., SpTHT Eppy Darmadi Ahmad, dr., SpOG(K) Ahmad Rizal, dr., SpS Basti Andriyoko, dr., SpPK Yunita Damopolii, dr., SpKK, M.Kes

Medis TAK PPDS

Paramedis Ii Sariningsih, AMK Iis Nurhayati, AMK Dedi Rahmadi, AMK Lies Ratnasari SST

RR Dedi Rahmadi, AMK

Social Workers

Farmasi Yulia Setiawati, dra., Apt. Ilham

MDR TB Unit Hasan Sadikin Hospital

HASAN SADIKIN GENERAL HOSPITAL

Isolation Ward/ICU
25 beds for pulmonary TB 6 beds for MDR TB 4 beds for critical TB Patients (ICU)

Clinics
1 TB DOTS clinic 1 TB-HIV clinic 2 MDR clinics - 1 Pre conversion MDR TB patients - 1 Post conversion MDR TB patients

RAPAT TIM AHLI

RAPAT TIM AHLI

RUANG RAWAT TB-MDR

POLI TB-MD

POLI TB-MD

POLI TB-MDR

(WHO 2011)

Mostly MDR TB patients are treated ambulatory from the beginning, unless Psychiatric problems Pneumonia, pneumothorax, lung abscess, pleural effusion Severe liver disorder Thyroid diseases Renal insufficiency Electrolyte imbalance Severe malnourished DM uncontrolled Malabsorbstion Severe/ multiple comorbidities No family support

Hasan Sadikin Hospital Interim Result (April 2012 March 2013)

n Percentage 100 32.4 6.8 74.4 33.4

Screened (GeneXpert) MDR TB XDR TB Treated Conversion

361 117 8 87 26

Reversion
Died Cure Treatment Completed

0
12 Data is not available yet Data is not available yet

0
15.7

DST Result Jan 2012 March 2013

Expensive and toxic drugs are necessary

53

Side Effect
Nausea + vomiting Dizziness Arthralgia Anorexia Electrolyte imbalance Anxietas + sleep disturbances Tinnitus and hearing disturbances Peripheral neuropaty Psychosis Allergic reaction Depression Diarrhea Visual disturbance Erectile disfunction hypothyroidism Concentration disturbance

n
67 32 21 12 11 8 6 5 5 4 3 3 2 2 2 1

Percentage
77 36.8 24.1 13.8 12.6 9.2 6.9 5.7 5.7 4.6 3.4 3.4 2.3 2.3 2.3 1.2

Global Policy: MDR-TB and XDR-TB

1. 2.
3. 4.

Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

5. 6.
7. 8.

55

Studies (ongoing and future)

at Hasan Sadikin Hospital MDR TB Patients Validity of GeneXpert Risk Factors analysis for MDR TB development Vitamin D in MDR TB patients Cytokines in MDR TB patients Gene Polymorphisms in MDR TB Patients

Nobody wants me around..

57

THANK YOU