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Soedarsono Departemen Pulmonologi & Kedokteran Respirasi FK Unair-RSUD Dr.

Soetomo Surabaya

Infection Exposed to DR-TB
Infection with drug –resistant strain
Risk factors Risk factors


Drug-resistant tuberculosis Drug-susceptible Tuberculosis

Risk factors

Exposed to DS-TB

Infection with drug-susceptible strain

Definition of drug-resistant (DR) TB

Drug resistant TB is confirmed through laboratory tests that show that the infecting isolates of M. tuberculosis grow in vitro in the presence of one or more anti tuberculosis drugs.

e.g. amikacin. capreomycin • Complete (Totally) Drug Resistance .Categories of DR-TB: Definitions • Mono Drug Resistance  against only one drug • Poly Drug Resistance  against two or more drugs. using first-line TB drugs) • Multi Drug Resistance (MDR)  against at least H and R • Extensive Drug Resistance (XDR-TB)    MDR AND against a fluoroquinolone AND against one or more of the injectable drugs: kanamycin. against S & H (These are less serious because they can be effectively treated with the cat I and II regimen. but not against both H and R.

Based on history of TB treatment : Definitions Primary resistance  drug resistance among new cases   never received TB drugs or received them for < 1 month new terminology adopted by WHO : Resistance among new cases Secondary (Acquired) resistance   drug resistance in a patient who previous received at least 1 month of TB therapy new terminology adopted by WHO : Resistance among previously treated cases WHO/IUATLD Global Project Drug-Resistance Surveillance Report No. 3 .

tuberculosis colony Mutation Nature Resistant mutants Selection due to inadequate treatment Man Acquired (M)DR-TB Transmission Inadequate infection control Diagnostic delay HIV More primary (M)DR-TB Primary (M)DR-TB .How does drug-resistant TB emerge? PATHWAY OF MDR-TB M.

How to detect MDR-TB .

Failure Cat I I am a suspect MDR-TB • Exposure to known MDR-TB case (80%) .M(X)DR-TB Suspects (1) High probability of resistance • Failures Cat II and Chronics (>80%).

poor .M(X)DR-TB Suspects (2) Middle probability of resistance • Failures from private sector • Cat I remaining AFB+ at months 2-3 • Relapses I am a suspect MDR-TB • Return after default • Exposure in institutions with high MDR-TB • Residence in high MDR-TB prevalence area • History!! of poor (or unknown) quality TB drugs.

M(X)DR-TB Suspects (3) Low probability of resistance • Diarrhoea: malabsorption of drugs • HIV in some areas associated with MDR-TB .

After category 1 and/or category 2 treatment 7) 8) Return after default 9) Symptomatic TB suspects reporting close contact with confirmed MDR-TB patients Patients positive HIV and TB (Updated since 2011) .1) 2) 3) 4) 5) 6) Chronic cases Non Converters Category 2 Previous SLD Treatment in Private Sector Failure Category 1 Non Converters Category 1 Relapse cases .After category 1 and/or category 2 treatment .

Hasil uji sensitivitas suspek MDR-TB (n=435) th 2012 (RSDS dan RSSA) .

R H S H Z S How to prevent development of MDR-TB Z E E Z .

Causes of Drug Resistant TB • Microbial – Natural resistance – Sequential drug administration”amplifier effect” • Clinical and programmatic – Inadequate or poorly administered treatment regimen • Health-care providers • Patients • Drugs – Sequential drug administration “amplifier effect” – Ongoing transmission of DR-TB .

M.TB Resistance: A Natural Phenomenon Isoniazid Rifampicin Streptomycin Ethambutol Isoniazid Rifampicin 1 x 105-106 bacilli 1 x 107-108 bacilli 1 x 105-106 bacilli 1 x 105-106 bacilli 1 x 102-104 bacilli 1 x 105-106 bacilli Streptomycin 1 x 103-106 bacilli .

TERJADINYA RESISTENSI OBAT Populasi campuran (sensitif dan resisten) Basil resisten thd INH Terjadinya strain resisten thd INH karena pengobatan tidak efektif (INH monoterapi) Pengobatan multi-drug yang efektif 0 2 4 6 8 10 12 1 4 Minggu 16 18 20 22 24 .

.Treatment that is effectively monotherapy in a patient whose isolate was initially resistant to isoniazid (H) and susceptible to rifampicin (R) Inappropriate treatment with only two drugs (H and R) led to the development of resistance to rifampicin. Inappropriate addition of a single drug (pyrazinamide. Z) to a failing regimen led to the emergence of resistance to pyrazinamide. followed by clinical deterioration.

and Multidrug Resistant Tubercle Bacilli H H HR HR Never add a single drug to a failing regimen .Selection of Mono.

M. Partners in Health. Harvard Category I treatment Category II treatment H RH Z R H EZ R SE E Amplification Effect H R Z H E R Amplification of Resistance H H H R R R E Z E Resistance S pattern . Rich.

M. Rich. Partners in Health. Harvard Cat I failure Category II failure Amplification Effect S H R E Z Z H H R R E E H R E Z S Cfx Amplification of Resistance H R Z E H R Z E S H R E Z S Cfx .

TB Rx: Correct Combination. Pts Relapse (%) 102 90 98 100 14 11 28 30 80 74 10 5 84 80 0 1 • Treatment must be extended – To kill persisters – To prevent mutation . Pts 2SHRZ/ HRZ 2SHRZ/ HR 2SHRZ/ HZ 2SHRZ/ H Relapse (%) Singapore No. Pts Relapse (%) 6-Month Regimen Singapore No. Dose & Duration 4-Month Regimen East Africa Regimen No.

“You Cannot Cure MDR-TB As Fast As You Can Create It” Lalloo UG et al Recent Advances in the Medical & Surgical Treatment of MDR-TB Curr Opin Pulm Med (2004) .

intensive phase. HRE for 5 mos. I 2HRZE / 4HR CAT 2: 2HRZES/ 1HREZ / 5HRE CAT 3: 2HRZ / 4HR Type of TB Patient • New pulmonary smear (+) cases • New seriously ill pulmonary smear (-) cases w/ extensive lung lesions • New severely ill extra-pulmo TB • Failure cases • Relapse cases • Return after default RAD (smear +) • Other (smear +) • New smear(-) but with minimal pulmonary TB on radiography as confirmed by a medical officer • New extra-pulmo TB (not serious) Drug / Duration of Treatment HRZE for 2 mos. of intensive phase. as maintenance phase Same as Regimen I . during maintenance phase HRZES for 2 mos. then HRZE for 1 mo. HR for 4 mos.Regimen CAT.

. . except for few small studies (West Java MDR: ± 5% !!!).Problem Analysis MDR-TB in Indonesia     Only ± 20% of hospitals & < 5% of private providers are currently involved in DOTS No data on TB drug resistance. Some second line drugs are free available on the market and currently used in first line regimens! Neglect to take treatment history causes ‘’missclassification and ’’under-treatment’’.

no monitoring no registration. inadequate drug supplies and distribution . no reporting high costs to the patients (fees) Un-controlled use of second-line drugs in hospitals and private sector (quinolones. kanamycin etc) Poor treatment performance in most hospitals: low conversion rate & low cure rate because many patients drop-out from treatment. not following DOTS unsupervised treatment.Risk Factors for Increase of MDR-TB in Indonesia (1) Therapeutic ‘’chaos’’ : prescription of inadequate doses / combinations of drugs • Many TB patients are treated by private providers.

Risk Factors for Increased MDR-TB in Indonesia (2)  Currently the chronic TB cases cannot be treated (no DOTS plus available) These chronic cases continue to transmit drug resistant TB TB.HIV is looming…  .

(DOTS strategy) X Second line drugs : effetiveness adverse reaction .TB Drug supllies Staff & resources involvement Skill & experience Reliable susceptibility testing .cost MDR .

Strategies in the Management of Multidrug-resistant Tuberculosis NTP Θ Θ Patients with MDR-TB DOTS FDC Θ Rapid DST Conventional DST Diagnosis Phenotypic & Genotypic Tests DOT ATD Specific Alternative Chemotherapy New Drugs Fluoroquinolone s Rifamycins Lung Resection Other Novel Classes Surgery Adjunctive Therapy Immunotherapy Cytokines Vaccines Others Outcomes Others Davies PDO. Expert Opin Investig Drugs (2003). . Recent Developments in the Treatment of TB. Yew WW.

Grouping Anti TB Drugs Grouping Group 1 First-line oral agents Group 2 Injectable agents Group 3 Fluoroquinolones Drugs Isoniazid (H) Rifampin (R) Kanamycin (Km) Streptomycin (Sm) Moxifloxacin (Mfx) Ofloxacin (Ofx) Ethambutol (E) Pyrazinamide (Z) Amikacin (Am) Capreomycin (Cm) Levofloxacin (Lfx) Protionamide (Pto) Terizodone (Trd) Ethionamide (Eto) Group 4 Cycloserine (Cs) Oral bacteriostatic agents P-aminosalicylic (PAS) Group 5 Agents with unclear efficacy Clofazimine (Cfz) Linezolid (Lzd) Thioacetazone (Thz) Clarithromycin (Clr) Amoxacillin/Clavulanate (Amx/Clv) Imipenem/cilastin (Ipm/Cln) High-dose INH (high-dose H) .

Cm. Weak anti-TB action . Less efficacious and poorly tolerated Other 2nd line drugs: Eto/Pto. Thioacetazone. S Bactericidal Highly bactericidal Fluoroquinolone: Mfx. PAS.Heirarchy of drugs for the Programmatic MDR TB Management 1st line drugs: (HR)ZE Most efficacious and best tolerated Injectable: Km. Linezolid. high does H. Lfx. Imipenem. Trd Unclear efficacy: Cfx. Ofx. Am. Cs. Amx/Clv.

Standardized Regimen example First-line Isoniazid X Second-line Injectable Streptomycin Kanamycin Amikacin Capreomycin Third-line Rifampin X Ethambutol Pyrazinamide Quinolone Ofloxacin Gatifloxacin Levofloxacin Moxifloxacin Other 2nd-line Ethionamide Cycloserine PAS Other agents AMX/CLV Clofazimine Clarithromycin 6 (E)-Z-Km-Lfx-Eto-Cs/ 18 (E)-Lfx-Eto-Cs 31 .

pain. voice fears) .Nutritional support .Psychological support (depression.Social support (involve family and community) .Involving patient in treatment decision (willing to stop TB treatment?) .Management of symptoms (breathlessness.Spiritual counselling whenever is requested/demanded . affirming life in face of death.Problems and patients need . etc) .

000 .10.400 $1.000 80 60 40 20 0 All TB Re-treatment MDR TB .MDR is More Costly to Cure (Peru) 100 Treatment success (%) $20-40 $50 .

Korea Peru Hong Kong Espinal MA et al. JAMA 2000.MDR-TB is harder to cure 100 all TB 80 60 40 20 0 MDR-TB Treatment success (%) Russia Dominican Rep. 283:2537-2545 .

give rise to even more resistant organisms   MDR-TB patients in Dr. when improperly monitored. Soetomo Hospital . drawing resources away from the treatment of pan-susceptible disease Treatment of drug-resistant strains. Technically difficult and yields low cure rates Expensive.

3.How do we respond to the MDR-TB/XDR-TB problem? We need to address the known factors contributing to drug-resistance 1. 6. 4. No supervised treatment Bad adherence / supervision No standard treatments Frequent drug stock-outs Anti-TB drugs of poor quality Non-programmatic management No hospital infection contro To implement a good DOTS Programme. 5. 7. with quality Prior to starting an MDR-TB project. 2. it is mandatory to address adequately all these factors J P Caminero .

 DOTS is our best hope of preventing the emergence of resistance to anti-TB drugs . TB is being defeated by model DOTS program.