1. MULTIDRUG- RESISTANT TUBERCULOSIS (MDR-TB) by Dr Mat Zuki Mat Jaeb 1

2. LEARNING OBJECTIVES  To identify those at risk of MDR-TB  To learn on what to do when MDR-TB is suspected  To learn the basic principles of treatment 2

3. MULTIDRUG- RESISTANT TUBERCULOSIS (MDR-TB) Outline  Introduction  Definition  Risk Factors  Diagnosis  Principle of Management 3

4. INTRODUCTION  MDR & Extensively drug-resistant TB (XDR-TB) incidence & prevalence are increasing worldwide including Malaysia  Rate of MDR-TB cultures had increased from 0.3% in 2005 to 1.3% in 2011 of all MTB cultures positive in Malaysia 1  High mortality & morbidity  In a study in Vietnam, mortality during MDR-TB treatment was 8.7% 2 1 Sistem Maklumat Tibi KKM, 2011 2 Quy HT et al., Int J Tuberc Lung Dis, 2006 4

5. INTRODUCTION  Complex treatment, costly & long treatment duration  Drugs adverse effects - compliance issues  Importance of strict infection control measures 5

6. MDR-TB WORLDWIDE IN 2011 - ABSOLUTE NUMBER OF CASES 6 http://www.who.int/topics/tuberculosis/en/

7. 7 MDR-TB TREATMENT OUTCOME IN WESTERN PACIFIC REGION http://www.who.int/topics/tuberculosis/en/

8. DEFINITION  Monodrug resistant  MTB resistant to any one of antiTB drugs  Polydrug resistant  MTB resistant to 2 or more antiTB drugs  Multidrug resistant  MTB resistant to both isoniazid & rifampicin with or without resistance to other antiTB drugs 8

9. DEFINITION  Extensively drug-resistance (XDR)  MDR TB with resistance to at least one injectable second-line antiTB drugs & any fluoroquinolone  Extremely/Total drug-resistant TB  not well-defined  MTB resistant to all tested first-line & second-line antiTB drugs 9

10. TYPE OF MDR-TB  Primary drug resistance  Patient has never received antiTB drug  Secondary/acquired drug resistance  Patient has received antiTB drug Inadequate treatment or improper use of the antiTB medications remains an important cause of drug-resistant TB 10

11. RISK FACTORS  Previously treated TB patient ● Relapse ● Treatment failure ● Treatment after interruption (TAI) are at higher risk of having secondary MDR-TB with OR of 9.1 & 10.2. 1,2 1 Conaty SJ et al., Epidemiol Infect, 2004 2 Faustini A et al., Thorax, 2006 11

12. RISK FACTORS  Independent risk factors for MDR-TB among previously treated patients: 1 i.Smear-positive disease (OR=5.8) ii.New immigrants from a country with high MDR- TB prevalence (OR=6.9) iii.Frequent traveller to a country with high MDR-TB prevalence (OR=2.5) iv.Younger age group (OR=0.95) 1 Law WS et al., Int J Tuberc Lung Dis, 2008 12

13. RISK FACTORS  HIV-positive patients have more than twice risk of primary MDR-TB. 1 1 Suchindran S et al., PLoS ONE, 2009 13 Clinical specimen from all TB cases must have Mycobacterium tuberculosis culture & sensitivity test done at diagnosis & repeated whenever drug resistance is suspected.

14. DIAGNOSIS MDR- & XDR-TB is a laboratory diagnosis  Culture & DST for Mycobacterium tuberculosis  LJ Media  Automated/liquid media  Nucleic Acid Testing (NAAT)  Line Probe Assay - detects resistance to isoniazid & rifampicin  Gene expert system (Xpert MTB/RIF) - detects MTB resistance to rifampicin (surrogate marker for MDR) 14

15. PRINCIPLES OF TREATMENT  Rapid diagnosis & prompt treatment  MDR-TB patients should be referred to physician with experience in management of MDR TB  Empirical MDR-TB regimen may be commenced for patients who are highly likely to have MDR-TB while waiting for laboratory confirmation  Infection control measures - strict isolation of smear positive MDR-TB patients 15

16. MDR-TB TREATMENT REGIMEN 1. Standard MDR-TB regimen (standardised approach) or 2. Individually-tailored regimen - regimen will be based on DST for second-line drugs 1. 16

17. SECOND-LINE ANTITB DRUGS 17

18. STANDARD MDR-TB REGIMEN  Consist of 4 second-line antiTB drugs that are most likely to be effective in the intensive phase  Regimens should include: ● Fluoroquinolone ● Parenteral agent (aminoglycosides) ● Ethionamide & ●Either cycloserine or PAS (if cycloserine cannot be used) & ● Pyrazinamide later-generation fluoroquinolone (e.g. levofloxacin & moxifloxacin) should be used 18 Second- line antiTB drugs

19. STANDARD MDR-TB REGIMEN  Ethambutol & Group 5 drugs may be used but is not included among the drugs making up the standard regimen.  Each drug in an MDR-TB regimen is given as DOT throughout the treatment. 19

20. MONITORING  Monthly sputum smears & cultures until smear & culture conversion occur  “Conversion”- 2 consecutive negative smears & cultures taken 30 days apart  After conversion, smears are monitored monthly & cultures 3-monthly  Monthly monitoring by clinician until sputum conversion, then every 2 - 3 monthly  At each visit, patient’s weight & side effects to antiTB drugs should be monitored 20

21. DURATION OF TREATMENT  Intensive phase  Defined by the duration of treatment with the injectable agent WHO recommends 8 months for most patients  Duration of treatment  Newly MDR-TB (i.e. not previously treated for MDR-TB), a total treatment duration is 20 months for most patients May be modified according to the response to treatment based on patient’s cultures, smears, CXR & clinical status 21

22. CASE YCL, 50 y.o., F Newly diagnosed DM on OHA PTB sp AFB +ve on 5/11/2009 & treated at KK Initially she responded to SHRZ & HR biweekly but with minimal weight gain (49 - 51kg) July 2010 noted smear positive again, continue H3R3 Restarted EHRZ in November 2010 (smear 50/L), weight 45 kg- awaiting MTB C&S, referred to RC Treatment failure MTB C&S revealed resistance to R & H 22

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24. CASE (cont.) Started on KECOZ, on 25/1/2011 April 2011 - complained of tinnitus, headache, reduced hearing - mild ototoxicity Kanamycin stopped after referred to ENT surgeon Could not tolerate PZA due to arthritis - under rheumatology Continue CEOC May 2011 - weight increased to 47 kg from 44 kg, smear negative 24

25. CASE (cont.) September 2011 - nausea, vomiting, numbness & poor appetite, weight reduced to 42 kg, hypoglycaemia - admitted to ward for dehydration CEOC was withheld few days then continued…. Oct 2011, Dec 2011, Jan 2012, Feb 2012 - tolerating CEOC but not much improvement of appetite & weight with on/off cough March 2012 - weight 39 kg, symptomatic, smear positive Persistent smear positive….. Story continues….. 25

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27. TAKE HOME MESSAGES  MDR-TB must be suspected & investigated promptly in previously treated TB patient & high risk groups  Rapid test to diagnose MDR-TB should be carried out on MDR-TB suspect  MDR-TB should be treated by physician with experience in managing MDR  Strict infection control measures should be practiced to prevent MDR-TB transmission 27

28. 28 THANK YOU  mzek4708@yahoo.com mzek4708@yahoo.com