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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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!
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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.13
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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”
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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
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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
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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
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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
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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
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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.20
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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