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Treatment of Tuberculosis
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Treatment of Tuberculosis


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  • 1. ID Workshop March 14, 2009 Ada Kong
  • 2. Incidence of TB Worldwide: • 1/3 of world’s population have TB. • 9 million TB illnesses worldwide/year. • 2 million TB-related deaths/year. US incidence: • 4.4 TB cases per 100,000 persons in 2007 (13,293 cases reported). • 644 TB deaths in 2006. • Overall TB rate has been declining in the US.
  • 3. Overview of TB • Caused by Mycobacterium tuberculosis • Airborne transmission via inhalation of droplet nuclei containing tubercle bacilli • 5% of infected patients develop disease within 2 years, another 5% develop disease in lifetime. • Primarily pulmonary disease: coughing • Extrapulmonary TB: lymph nodes, meninges, bones, pleura, kidneys • Miliary TB: generalized infection, rare but serious, “millet seed” appearance on CXR
  • 4. RISK FACTORS High Risk for contracting High Risk for developing TB Infection TB disease • Exposure to known or • Medical conditions (e.g. suspect TB HIV, diabetes, silicosis, • emmigration from high cancer, organ transplant, incidence country (e.g. immunosuppressives/ Asia, Africa) anti-TNF therapy) • Injectable illegal drug • Infants & children < 4 use years old. • High-risk settings (e.g. • Recent TB infection in LTCF, correctional last 2 years. facilities, homeless)
  • 5. DIAGNOSIS OF TB Suspect TB if: • Unexplained wt loss, ↓appetite, night sweats, fever, fatigue. • Coughing > 3wks, hemoptysis, chest pain TESTS: • TST/PPD skin test. • Chest X-ray (cavities, infiltrates) • AFB sputum smear and culture. • Drug susceptibility testing • Nucleic acid amplification • Interferon-gamma ray release assay
  • 6. Consider Treatment Initiation if: • Positive AFB smear, epidemiological, clinical symptoms, pathological findings. Do not delay treatment because of negative AFB smears if high suspicion: • History of cough & weight loss • Characteristic findings on CXR • Emmigration from high-incidence country
  • 7. Antituberculosis Drugs First-Line Drugs Second-Line Drugs • Isoniazid (INH) • Streptomycin (SM) • Rifampin (RIF) • Cycloserine • Pyrazinamide (PZA) • p-Aminosalicylic acid • Ethambutol (EMB) • Ethionamide • Rifabutin (RPT)* • Amikacin/kanamycin* • Rifapentine • Capreomycin • Levofloxacin* • Moxifloxacin* • Gatifloxacin* *Not FDA approved for treatment of TB
  • 8. Treatment Algorithm for TB QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. From: MMWR June 2003/52(RR11);1-77
  • 9. From: MMWR 2003;52(31): 735-739
  • 10. Treatment of Culture Positive TB Initial Phase 2 months: INH, RIF, PZA, EMB daily (56 doses, 8 weeks) or 5 days/week (40 doses, 8 weeks, DOT required) Continuation Phase 1) 4 months: INH + RIF daily (126 doses, 18 weeks) 2) 4 months: INH + RIF twice/week (36 doses, 18 weeks) 3) 7 months*: INH + RIF daily (217 doses, 31 weeks) 4) 7 months*: INH + RIF twice/week (62 doses, 31 weeks) *Continuation phase - to 7 months if initial CXR shows cavitation & culture positive at end of initial phase (2 months)
  • 11. When can I consider Rifapentine (RPT) in Continuation Phase? • Patient is HIV negative • Has non-cavitary pulmonary TB • Negative sputum smears at 2 month initial phase May use:  INH + RPT once weekly for 4 months (by DOT) If culture positive at end of initial phase:  INH + RPT once weekly for 7 months (by DOT)
  • 12. Treatment of Culture-Positive TB TWICE-WEEKLY OPTIONS (Rated BII for HIV positive w/CD4 count>100µ/L. Not recommended for CD4<100µ/L) Initial Phase 0.5 month: INH, RIF, PZA, EMB daily (14 doses, 2 wks) THEN 1.5 months: INH, RIF, PZA, EMB twice/week (12 doses, 6wks) Continuation Phase 1) 4 months: INH + RIF twice/week (36 doses, 18 weeks) 2) 7 months: INH + RIF twice/week (62 doses, 31 weeks)
  • 13. Treatment of Culture Positive TB THRICE-WEEKLY OPTIONS (Rated BI for HIV negative, BII for HIV positive) Initial Phase 2 months: INH, RIF, PZA, EMB 3x/week (24 doses, 8 weeks) Continuation Phase 1) 4 months: INH + RIF 3x/week (54 doses, 18 weeks) 2) 7 months: INH + RIF 3x/week (93 doses, 31 weeks)
  • 14. Regimens without Pyrazinamide (Rated CI for HIV negative, CII for HIV positive) Initial Phase 2 months: INH, RIF, EMB daily (56 doses, 8 weeks) Continuation Phase 1) 7 months: INH + RIF daily (217 doses, 31 weeks) 2) 7 months: INH + RIF twice/week (62 doses, 31 weeks) * *Twice weekly not recommended for patients with CD4+ count <100/µL
  • 15. When to extend continuation phase to 7 months? • Cavitary pulmonary disease and positive sputum cultures at end of 2 month initiation phase • Initial phase did not contain PZA • Patients taking once weekly INH+rifapentine and positive 2 month sputum culture
  • 16. Adult Dosing of TB Drugs DAILY 2 days/week 3 days/week (DOT only) (DOT only) Isoniazid 5mg/kg 15mg/kd 15mg/kg (max 300mg) (max 900mg) (max 900mg) Rifampin 10mg/kg 10mg/kg 10mg/kg (max 600mg) (max 600mg) (max 600mg) Pyrazinamide ~ 25mg/kg ~ 50mg/kg ~ 35-40mg/kg *based on est. (max 2g) (max 4g) (max 3g) lean body wt. Ethambutol ~15-20mg/kg ~ 50mg/kg ~ 25-30mg/kg *based on est lean (max 1600mg) (max 2400mg) (max 4000mg) body wt. Rifabutin 5mg/kg 5mg/kg 5mg/kg (max 300mg) (max 300mg) (max 300mg)
  • 17. LATENT TUBERCULOSIS • Inactive tubercle bacilli. Noninfectious. • At high risk for progression to active TB Diagnosis: Positive PPD. Asymptomatic. Normal CXR, negative sputum smears & cultures. Preferred INH daily or twice/week (DOT) for 9 regimen months. Alternative RIF daily for 4 months (adults), 6 months (children)
  • 18. MONITORING • Sputum for AFB smear & culture every month (until 2 consecutive negative cultures) • Drug susceptibility testing on initial positive culture. • HIV & Hep B/C (if high risk) when tx initiated • CXR: at 2 month initiation phase if initial negative cultures OR at end of treatment for culture negative TB • Baseline serum creatinine, AST/ALT, bilirubin, alk phosphatase, platelets • Visual acuity & color vision monthly if EMB treatment longer than 2 months or receiving greater than recommended mg/kg doses
  • 19. ADVERSE EFFECTS OF TB DRUGS DRUG ADVERSE EFFECTS MONITORING PARAMETERS Isoniazid • Hepatotoxicity, lupus-like syndrome, • LFTs, flushing, peripheral neuropathy tingling in hands & • Monoamine toxicity feet. Rifampin • GI upset, hepatotoxicity, flu-like • Baseline LFTs, syndrome, hemolytic anemia, CBC, SCr, clinical thrombocytopenia, renal failure, symptoms. LFTs orange-discoloration of body fluids. monthly if abnorm • Drug interactions: potent enzyme baseline or ↑ risk for inducer hepatotoxicity. Pyrazinamide • Hepatoxocity, hyperuricemia, • Basline LFTs, SCr arthralgias, GI upset, rash • Uric acid if symptomatic Ethambutol • Optic neuritis (blurred vision, • Baseline & monthly scotomata “blind spot”, red-green visual acuity & color color blindness), hyperuricemia vision, SCr.
  • 20. TB DRUG RESISTANCE Multi-drug resistant TB (MDR-TB): resistant to INH & RIF. Extensively drug-resistant TB (XDR-TB): resistant to INH, RIF, fluoroquinolone & injectables (aminoglycosides, polypeptides) Guidelines: • Never add single new agent to failing regimen. • Always attempt to add at least 3 unused drugs (1 should be injectable) with in vitro susceptibility. • Request expert consultation. • DOT strongly recommended. • Cross-resistance between RIF, rifabutin and rifapentine. • No cross-resistance between SM & other injectables. • Cross-resistance between amikacin & kanamycin. • Monoresistance to PZA is uncommon (consider M. bovis)
  • 22. REFERENCES • Blumberg HM, Burman WJ, Chaisson RE et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of Tuberculosis. Am J Respir Crit Care Med 2003;167(4):603-662. • Blumberg HM, Leonard MK, Jasmer RM. Update on the Treatment of Tuberculosis and Latent Tuberculosis Infection. JAMA 2005;293(22):2776-2784. • Centers for Disease Control and Prevention. Trends in tuberculosis incidence-United States, 2007. MMWR Morb Mortal Wkly Rep. 2008;57(11):281-285. • Inge L, Wilson JW. Update on the Treatment of Tuberculosis. Am Fam Physician 2008;78(4):457-465.