1. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 89 Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection

2. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.2 Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection  Caused by these three species of mycobacteria  Mycobacterium tuberculosis  Mycobacterium leprae  Mycobacterium avium

3. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.3 Treatment for Mycobacterial Infections  Slow-growing microbes  Requires prolonged treatment  Drug toxicity and poor patient adherence  Promotes drug-resistant mycobacteria emergence

4. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4 Tuberculosis  Global epidemic  Approximately 2 billion infected worldwide  Kills approximately 2 million/year  New cases in U.S. are declining  Cases increasing outside U.S. 95% occur in developing countries 95% occur in developing countries Increase due to AIDS and emerging multidrug-resistant mycobacteria Increase due to AIDS and emerging multidrug-resistant mycobacteria

5. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.5 Tuberculosis  Pathogenesis  Mycobacterium tuberculosis  May be limited to lungs or may disseminate  Bacteria quiescent  No obvious symptoms  U.S. – approximately 10 million people harbor tubercle bacilli but show no symptoms

6. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.6 Tuberculosis  Primary infection  Transmitted from person to person  Inhalation of infected, aerosolized sputum  Coughing, sneezing  Initial infection in lung  Immunity usually develops within a few weeks  90% with normal immune systems never develop clinical or radiologic evidence of TB

7. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.7 Tuberculosis  Immune system failure to control primary infection – TB develops  Necrosis and cavitation of lung tissue  Severe destruction without treatment  Reactivation  Renewal of dormant tubercle bacilli  60% of new infections may be caused by reactivation

8. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.8 Tuberculosis  Treatment overview  More effective drugs make hospitalization generally unnecessary.  Always treat with two or more drugs.  Direct observation of drug administration is considered standard care.  Treatment is considered effective when no mycobacteria are observed in sputum and no colonies are present in culture.

9. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9 Tuberculosis  Diagnosis  Indications for testing  Definitive diagnosis Chest x-ray Chest x-ray Sputum culture Sputum culture  Evaluation of drug susceptibility

10. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.10 Causes of Drug Resistance  Some infecting bacilli inherently resistant  Some develop resistance over course of treatment  Resistance to one drug versus many drugs  Infection with resistant TB acquired through:  Contact with someone who harbors resistant bacteria  Repeated ineffectual courses of therapy

11. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.11 Multi-Drug Resistance With Tuberculosis  Multidrug-resistant TB (MDR TB)  Resistant to both isoniazid and rifampin  Extensively drug-resistant TB (XDR TB)  Resistant to: Isoniazid (INH) and rifampin Isoniazid (INH) and rifampin All fluoroquinolones All fluoroquinolones At least one of the injectable second-line drugs At least one of the injectable second-line drugs

12. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.12 Treatment Regimens for Tuberculosis  The prime directive of treatment: ALWAYS treat tuberculosis with two or more drugs!

13. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13

14. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.14 Treatment Regimens for Tuberculosis  Determine drug sensitivity  Treatment regimens – two phases  Induction phase Eliminate actively dividing tubercle bacilli Eliminate actively dividing tubercle bacilli  Continuation phase Eliminate intracellular “persisters” Eliminate intracellular “persisters”

15. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.15 Treatment Regimens for Tuberculosis  Drug-sensitive tuberculosis  Isoniazid or rifampin-resistant tuberculosis  MDR TB and XDR TB  Patients with TB and HIV infection  Duration of treatment  Minimum 6 months for drug-sensitive TB  Up to 24 months for MDR or HIV/AIDS

16. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.16 Promoting Treatment Adherence  Direct observation therapy (DOT)  Patient nonadherence  Allows for ongoing assessment of clinical signs  Intermittent dosing  2-3 times a week

17. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.17 Evaluation of Treatment  Three modes to evaluate therapy  Bacteriologic evaluation of sputum  Clinical evaluation  Chest radiographs

18. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.18 Diagnosis and Treatment of Latent Tuberculosis  9-14 million people in U.S. have LTB  5%-10% will develop active TB without treatment  Targeted TB testing  Who should be tested?  Testing for latent TB  TB skin test (TST)  QuantiFERON-TB Gold (QFT-G) blood test

19. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.19 Diagnosis and Treatment of Latent Tuberculosis  INH  Treatment of choice  Drawbacks of INH  Short-course therapy: rifampin alone  Short-course therapy: rifampin plus pyrazinamide  Vaccination against tuberculosis

20. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20

21. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.21 Antituberculosis Drugs  First-line drugs  Isoniazid, rifampin  Rifapentine, rifabutin, pyrazinamide, and ethambutol  Second-line drugs  Levofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid, ethionamide, and cycloserine

22. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.22 Isoniazid  Primary agent  Bactericidal  Adverse effects  Peripheral neuropathy (pyridoxine, vitamin B 6 )  Hepatotoxicity  Optic neuritis  Anemia

23. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.23 Rifampin (Rifadin)  Broad-spectrum antibiotic  Uses  Tuberculosis  Leprosy  Haemophilus influenzae  Legionella

24. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.24 Rifampin (Rifadin)  Adverse effects  Hepatotoxic/hepatitis  Discoloration of body fluids  GI disturbances  Drug interactions  Induces P450 – can hasten drug metabolism  Oral contraceptives  Warfarin  Drugs for HIV infection

25. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.25 Pyrazinamide  Bactericidal to M. tuberculosis  Use  Tuberculosis  Adverse effects  Hepatotoxicity  Hyperuricemia  GI disturbances

26. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.26 Ethambutol (Myambutol)  Bacteriostatic  Use  Tuberculosis  Adverse effects  Optic neuritis  Allergy  Hyperuricemia

27. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.27 Second-Line Anti-TB Drugs  Fluoroquinolones  Injectable drugs  Capreomycin  Kanamycin and amikacin  Other second-line drugs  Para-aminosalicylic acid  Ethionamide  Cycloserine  R207910

28. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.28 Leprosy (Hansen’s Disease)  Chronic infection  Caused by M. leprae  Causes gross disfiguration if untreated  Most can be cured with drug treatment  Affects skin, peripheral nerves, and mucous membranes of upper respiratory tract

29. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.29 Leprosy (Hansen’s Disease)  Overview of treatment  Multidrug therapy  Monotherapy will cause resistance  World Health Organization (WHO) recommends 12 months treatment with three drugs: Rifampin, dapsone, clofazimine Rifampin, dapsone, clofazimine  The ROM regimen

30. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.30 Mycobacterium avium Complex Infection  Mycobacterium avium complex  M. avium  M. intracellulare  Colonization begins in the lungs or GI tract  May spread to the blood, bone marrow, liver, spleen, lymph nodes, brain, kidney, and skin

31. Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.31 Mycobacterium avium Complex Infection  Prophylaxis  Azithromycin  Clarithromycin  Acute infection  Same as prophylaxis  Plus ethambutol  Plus rifampin or rifabutin  Additional drugs may also be added