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Anti-TB Medication

Anti-TB Medication. 95 年度北區醫師結核病診治課程 2006 年 5 月 7 日 衛生署桃園醫院內科加護病房主任 莊子儀醫師. Outline. TB Microbiology Basic Concept Treatment of TB Drug-Resistant TB. TB Microbiology.

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Anti-TB Medication

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  1. Anti-TB Medication 95年度北區醫師結核病診治課程 2006年5月7日 衛生署桃園醫院內科加護病房主任 莊子儀醫師

  2. Outline • TB Microbiology • Basic Concept • Treatment of TB • Drug-Resistant TB

  3. TB Microbiology • M. tuberculosis is an aerobic, non-spore forming, non-motile bacillus with a high cell wall content of high-molecular weight lipids (up to 60% dry weight content). • Cell division occurs from 15-20 hours • Share the staining characteristic known a acid-fastness: red stain seen upon application of acid-alcohol stain

  4. TB Microbiology • The rigid core of the cell wall is composed of three STRUCTURAL COMPONENTS • Peptidoglycan, Arabinogalactan, Mycolic acids • External to the peptidoglycan and the arabinogalactan are the mycolic acids, which together with free lipids act as a hydrophobic permeability barrier

  5. TB Microbiology • Actively multiplying/growing organisms (susceptible to chemotherapy) • Slowly growing and metabolically inactive (relatively poor response to antibiotics) • Intracellular bacilli slowly growing in macrophages (difficult to treat due to poor accessibility for antibiotics ) • Dormant population (resistant to chemotherapy)

  6. Basic Concept • All drugs as a single dose on empty stomach • The use of a single drug should be avoided (except for prophylaxis) • In multiple drug regimens at least one drug should be bactericidal

  7. Basic Concept • Use multiple drugs to which the organisms susceptible • Mutation rate about 10-7 • Patient with TB may have 1010 organisms • Never add single drug to failing regimen • Ensure adherence to therapy • Duration of therapy: 6-9 months

  8. Return after default • Relapse • Failure • Chronic case 過去治療史 Y TB Case N 新案 照會專業醫師 標準初次治療 Basic Concept

  9. Basic Concept • 新案 (new case)：不曾接受過抗結核藥治療或曾接受少於 4 週抗結核藥治療之病人。 • 復發 (relapse)：曾接受一個完整療程之抗結核藥治療並經醫師宣告治癒而再次痰塗片陽性之病人。 • 失敗復治 (treatment after failure)：治療五個月後依然痰塗片陽性的病人，或者治療前痰塗片陰性、治療二個月後變成痰塗片陽性的病人。 • 失落復治 (Treatment after default)：中斷治療兩個月以上而再次痰塗片陽性之病人。 • 慢性病人(chronic case)：在監督下接受完整之復治處方治療後依然痰塗片陽性之病人。

  10. Treatment of TB • First-line agents: • Isoniazid (INH) • Rifampin (RIF) • Ethambutol (EMB) • Pyrazinamide (PZA) • Streptomycin (SM) • Second-line agents: • Rifabutin, p-Aminosalicylic acid (PAS), Amikacin, Ciprofloxacin/Levofloxacin, Prothionamide (TBN)

  11. Treatment of TB • Cell Wall Biosynthesis: • Isoniazid (INH) • Ethambutol (EMB) • Protein Synthesis: • Streptomycin (SM), Amikacin • Transcription/DNA Replication: • Rifampin (RIF) • Ciprofloxacin/Levofloxacin

  12. Treatment of TB • Four drugs should be given initially -- Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol -- for at least two months. • Where sensitivity tests are awaited, they should be continued until the results are available. • 4 months of Isoniazid and Rifampicin are required to prevent relapse in the fully drug-sensitive patient. • If resources are scarce -- 6 months of Isoniazid and Ethambutol can replace 4 months of Isoniazid and Rifampicin. • Streptomycin may be substituted for Ethambutol

  13. Isoniazid • Resembles B-vitamin and nicotinic acid • Need supplementation with the vitamin during Rx • Soluble in water - penetrates readily into all body fluids, cells (MF), and tissues including the CSF (similar to concentrations as in plasma). • Bactericidal at most concentrations (rapidly kills the actively dividing bacilli and reduces the active bacterial count in the sputum initially by at least an order of magnitude for every day of treatment)

  14. Isoniazid • INH is a prodrug activated by bacterial catalase-peroxidase (katG gene) • The main mechanism of INH resistance is deletion or point mutation in katG gene (catalase). • Strains with deletion of katG are highly Isoniazid-resistant. • Resistance to INH (9% of all clinical isolates!)

  15. Isoniazid • Daily Dose • Adults 5 mg/kg; maximum dose: 300 mg/d • Children 10-20 mg/kg; maximum: 300 mg/d

  16. Isoniazid • Common adverse effect: • Hepatitis is the most common adverse effect: 12-15% patients on INH may have elevated transaminase levels in the blood. This does not preclude the use of INH • Less common adverse effect: • Cutaneous Hypersensitivity (2%) • Peripheral neuropathy (1%) – Caused by elimination or inhibition of pyridoxine (a cofactor in the synthesis of synaptic neurotransmitters). Concomitant administration of pyridoxine is recommended (10-50 mg daily).

  17. Isoniazid • Alcohol (especially daily use) increases hepatic hazards of INH • Inhibits metabolism of the following drugs: • Phenytoin • Carbamazepine • Primidone • Warfarin • These medicines may increase the chance of liver damage if taken with Isoniazid Should be closely monitored and adjusted

  18. Rifampin • Bactericidal drug, penetrates various tissues and cells for intracellular killing (kills slowly dividing persistent organisms and is important in “sterilizing” TB infection). • Well absorbed after oral administration • Excreted mainly by the liver • Always used in a combination with other drugs to prevent resistance

  19. Rifampin • Daily Dose • 600 mg/d (10 mg/kg/d) for TB treatment gives 5-7 mg/mL serum concentration

  20. Rifampin • Common adverse effect: • Orange-red color stains tissues, secretions, urine etc. • Less common adverse effect: • Hepatitis, cutaneous hypersensitivity, gastrointestinal reactions, thrombocytopenic purpura, febrile reactions, “flu syndrome”.

  21. Rifampin • Rifampin may decrease the effects of: • Methadone; Clofibrate, Digitoxin; Cyclosporine, Propranolol, Metoprolol, oral contraceptives and anticoagulants, Quinidine, and Ketoconazole. • Rifampin increases the chance of liver damage if taken with: • Estrogens (female hormones) or oral contraceptives containing estrogen • Phenytoin

  22. Ethambutol • Synthetic water-soluble drug • No effect on bacteria other than mycobacteria -- inhibits synthesis of component of mycobacterial cell wall -- arabinogalactan • EMB is bacteriostatic but useful in preventing the emergence of resistance

  23. Ethambutol • Daily Dose • 15-25 mg/kg peaking serum level of 2-5 mg/ml in 2-4 hrs • Widely distributed in the body including CSF • Primarily excreted in urine – accumulates if renal failure – must monitor and adjust the dose

  24. Ethambutol • Common adverse effect: • Optic neuritis (reversible) - Dose related: Occurs in 15% of patients receiving 50 mg/kg/d and 5% with 25 mg/kg/d. • Decreases visual acuity and promote red/green color blindness. • Less common adverse effect: • Chills; difficult breathing; dizziness; fever; headache; itching; muscle and bone pain; shivering; skin rash and redness

  25. Pyrazinamide • Activated in acidic pH environment (pH < 5.5) in intracellular compartments • Exhibits activity against intracellular M.tuberculosis residing in macrophages (kills semi-dormant bacilli) • PZA kills more slowly dividing persistent organisms. Used as “sterilizing” agent in a combination with INH and RIF in short-course protocols.

  26. Pyrazinamide • Daily Dose • Oral dose of 25 mg/kg/d gives serum concentration range of 30-50 mg/ml in 1-2 hrs

  27. Pyrazinamide • Common adverse effect: • Anorexia, nausea, flushing, hyperuricemia • Less common adverse effect: • Hepatitis, vomiting, arthralgia, cutaneous hypersensitivity

  28. Fixed Dose Combination • Rifater (RFT, 衛肺特) = INH 80 mg + RMP 120 mg + PZA 250 mg • 成人依體重每增加十公斤，則加服一錠，最多每日五錠。 • Rifinah 300 (RFN 300, 樂肺寧 300) = INH 150 mg + RMP 300 mg • Rifinah 150 (RFN 150, 樂肺寧 150) = INH 100 mg + RMP 150 mg • 體重五十公斤以上者，每日服用RFN 300兩錠；而體重未滿五十公斤者，每日服用RFN 150三錠。

  29. Fixed Dose Combination

  30. Streptomycin • Streptomycin is bactericidal antibiotic • Penetrates the blood-brain barrier • Active against extracellular bacilli only since poorly penetrates into macrophage • Use in a combination with other drugs due to resistance

  31. Streptomycin • Daily Dose • IV dose of 10 - 15 mg/kg/d

  32. Streptomycin • Common adverse effect: • Cutaneous hypersensitivity, dizziness, numbness, tinnitus ("ringing in the ears“) • Uncommon adverse effect: • Vertigo, ataxia, deafness • Rare adverse effect: • Renal damage, aplastic anemia, agranulocytosis • Renal toxicity (needs to adjust the dose) • Toxicity is age- and dose-dependent. Limit Streptomycin therapy for no more than 6 months

  33. Treatment of TB • HRZ (2M) + HR (4M) • HERZ (2M) + HER (4M) • HR 9M • HE 18M, if R cannot be used • RE 18M, if H cannot be used • HRZS 2M + HR 4M

  34. Treatment of TB Liver disease (AST, ALT 3-5x in recent one year; liver cirrhosis Child C) YesNo F/U AST/ALT q1-2w q4w x 3m, then q2m ↑AST/ALT YesNo HERZ(2M) + HER(4M) E ± SME + FQN ± SM (SM for smear(+) or advance disease RechallengeRechallenge No recurrent- HER x 6-9m HER x 6m Causing agent (+) ohters x 9m Causing agent (+) others + FQN

  35. Treatment of TB INH 50 mg/d PZA 250 mg/d INH 300 mg/d PZA 1000 mg/d RMP 75 mg/d < 50kg: PZA 1500 mg/d ≧ 50kg: PZA 2000 mg/d RMP 300mg/d < 50kg: RMP 450 mg/d ≧ 50kg: RMP 600 mg/d BTS guideline, 1998

  36. Treatment of TB • 65-y/o男性，liver cirrhosis Child B – C, pneumoconiosis • 因UGI bleeding住院後發現open TB • 2004/11: RFT(HRZ) + EMB • 2004/11: EMB + Cravit + SM (Petechiae, jaundice, prolonged PT, normal GOT/GPT) • 2004/12: EMB + Cravit + SM + Rifabutin (Acceptable jaundice and PT, normal GOT/GPT) • 2005/2: EMB + Cravit + Rifabutin

  37. Drug-Resistant TB • Causes of drug-resistant TB: • Prescription of anti-TB medication • Management of drug supply • Case management • Process of drug delivery • Definition of multi-drug resistant TB (MDR-TB): Resistance to both INH and RIF

  38. Drug-Resistant TB • The prescription of inadequate chemotherapy to the multibacillary pulmonary tuberculosis • The addition of one extra drug in the case of failure, and repeating the addition of a further drug when the patient relapses after what amounts to monotherapy

  39. Drug-Resistant TB • Drug resistant rate: • RIF: 10-8 • INH, PZA, EMB, SM: 10-6 • PAS: 10-3

  40. Treatment of MDR-TB • 21-y/o越南新娘 • 在北部某醫學中心治療 • 2003/7: RFT(HRZ) + EMB • 2003/9: RFT(HRZ) + EMB + Cipro (Resistance to HR) • 2003/12: HER + Cipro (2003/11 CXR improved) • 2004/8: HERZ + Cipro (2004/6, 2004/8 CXR worsen) • 2004/10: RFT(HRZ) + Cipro (2004/10 CXR worsen) • No sputum F/U during treatment • MDR-TB should never be treated without expert consultation.

  41. Thank You for Your Attention • In memory of NTUH Dr.廖永祥for providing excellent slides. • Reference: • ATS guideline 2003. • Murray and Nadel’s Textbook of Respiratory Medicine, 4th ed.

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