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Chapter 89. Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection. Tuberculosis, Leprosy, and Mycobacterium avium Complex Infection. Caused by these three species of mycobacteria Mycobacterium tuberculosis Mycobacterium leprae - PowerPoint PPT Presentation
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Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.
Chapter 89Chapter 89
Antimycobacterial Agents: Drugs for Antimycobacterial Agents: Drugs for Tuberculosis, Leprosy, and Tuberculosis, Leprosy, and
Mycobacterium aviumMycobacterium avium Complex Infection Complex Infection
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Tuberculosis, Leprosy, and Tuberculosis, Leprosy, and Mycobacterium aviumMycobacterium avium Complex Infection Complex Infection
Caused by these three species of Caused by these three species of mycobacteriamycobacteria Mycobacterium tuberculosisMycobacterium tuberculosis Mycobacterium lepraeMycobacterium leprae Mycobacterium aviumMycobacterium avium
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Treatment for Mycobacterial Treatment for Mycobacterial InfectionsInfections
Slow-growing microbesSlow-growing microbes Requires prolonged treatmentRequires prolonged treatment Drug toxicity and poor patient adherenceDrug toxicity and poor patient adherence Promotes drug-resistant mycobacteria Promotes drug-resistant mycobacteria
emergenceemergence
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TuberculosisTuberculosis
Global epidemicGlobal epidemic Approximately 2 billion infected worldwideApproximately 2 billion infected worldwide Kills approximately 2 million/yearKills approximately 2 million/year New cases in U.S. are decliningNew cases in U.S. are declining Cases increasing outside U.S.Cases increasing outside U.S.
• 95% occur in developing countries95% occur in developing countries• Increase due to AIDS and emerging multidrug-resistant Increase due to AIDS and emerging multidrug-resistant
mycobacteriamycobacteria
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TuberculosisTuberculosis
PathogenesisPathogenesis Mycobacterium tuberculosisMycobacterium tuberculosis May be limited to lungs or may disseminateMay be limited to lungs or may disseminate Bacteria quiescentBacteria quiescent No obvious symptomsNo obvious symptoms U.S. – approximately 10 million people harbor U.S. – approximately 10 million people harbor
tubercle bacilli but show no symptomstubercle bacilli but show no symptoms
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TuberculosisTuberculosis
Primary infectionPrimary infection Transmitted from person to personTransmitted from person to person Inhalation of infected, aerosolized sputumInhalation of infected, aerosolized sputum Coughing, sneezingCoughing, sneezing Initial infection in lungInitial infection in lung Immunity usually develops within a few weeks Immunity usually develops within a few weeks 90% with normal immune systems never develop 90% with normal immune systems never develop
clinical or radiologic evidence of TBclinical or radiologic evidence of TB
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TuberculosisTuberculosis
Immune system failure to control primary Immune system failure to control primary infection – TB developsinfection – TB develops Necrosis and cavitation of lung tissueNecrosis and cavitation of lung tissue Severe destruction without treatmentSevere destruction without treatment
ReactivationReactivation Renewal of dormant tubercle bacilliRenewal of dormant tubercle bacilli 60% of new infections may be caused by 60% of new infections may be caused by
reactivationreactivation
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TuberculosisTuberculosis
Treatment overviewTreatment overview More effective drugs make hospitalization More effective drugs make hospitalization
generally unnecessary.generally unnecessary. Always treat with two or more drugs.Always treat with two or more drugs. Direct observation of drug administration is Direct observation of drug administration is
considered standard care.considered standard care. Treatment is considered effective when no Treatment is considered effective when no
mycobacteria are observed in sputum and no mycobacteria are observed in sputum and no colonies are present in culture.colonies are present in culture.
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TuberculosisTuberculosis
DiagnosisDiagnosis Indications for testingIndications for testing Definitive diagnosisDefinitive diagnosis
• Chest x-rayChest x-ray• Sputum cultureSputum culture
Evaluation of drug susceptibilityEvaluation of drug susceptibility
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Causes of Drug ResistanceCauses of Drug Resistance
Some infecting bacilli inherently resistantSome infecting bacilli inherently resistant Some develop resistance over course of Some develop resistance over course of
treatmenttreatment Resistance to one drug versus many drugsResistance to one drug versus many drugs Infection with resistant TB acquired through:Infection with resistant TB acquired through:
Contact with someone who harbors resistant Contact with someone who harbors resistant bacteriabacteria
Repeated ineffectual courses of therapyRepeated ineffectual courses of therapy
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Multi-Drug Resistance With Multi-Drug Resistance With TuberculosisTuberculosis
Multidrug-resistant TB (MDR TB)Multidrug-resistant TB (MDR TB) Resistant to both isoniazid and rifampinResistant to both isoniazid and rifampin
Extensively drug-resistant TB (XDR TB)Extensively drug-resistant TB (XDR TB) Resistant to:Resistant to:
• Isoniazid (INH) and rifampinIsoniazid (INH) and rifampin• All fluoroquinolonesAll fluoroquinolones• At least one of the injectable second-line drugsAt least one of the injectable second-line drugs
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Treatment Regimens for Treatment Regimens for TuberculosisTuberculosis
The prime directive of treatment:The prime directive of treatment:
ALWAYS ALWAYS treat tuberculosis with treat tuberculosis with two or moretwo or more drugs! drugs!
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Treatment Regimens for Treatment Regimens for TuberculosisTuberculosis
Determine drug sensitivityDetermine drug sensitivity Treatment regimens Treatment regimens – t– two phaseswo phases
Induction phaseInduction phase• Eliminate actively dividing tubercle bacilliEliminate actively dividing tubercle bacilli
Continuation phaseContinuation phase• Eliminate intracellular “persisters”Eliminate intracellular “persisters”
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Treatment Regimens for Treatment Regimens for TuberculosisTuberculosis
Drug-sensitive tuberculosisDrug-sensitive tuberculosis Isoniazid or rifampin-resistant tuberculosisIsoniazid or rifampin-resistant tuberculosis MDR TB and XDR TBMDR TB and XDR TB Patients with TB and HIV infectionPatients with TB and HIV infection Duration of treatmentDuration of treatment
Minimum 6 months for drug-sensitive TBMinimum 6 months for drug-sensitive TB Up to 24 months for MDR or HIV/AIDSUp to 24 months for MDR or HIV/AIDS
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Promoting Treatment AdherencePromoting Treatment Adherence
Direct observation therapy (DOT)Direct observation therapy (DOT) Patient nonadherencePatient nonadherence Allows for ongoing assessment of clinical signsAllows for ongoing assessment of clinical signs
Intermittent dosingIntermittent dosing 2-3 times a week2-3 times a week
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Evaluation of TreatmentEvaluation of Treatment
Three modes to evaluate therapyThree modes to evaluate therapy Bacteriologic evaluation of sputumBacteriologic evaluation of sputum Clinical evaluationClinical evaluation Chest radiographsChest radiographs
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Diagnosis and Treatment of Diagnosis and Treatment of Latent TuberculosisLatent Tuberculosis
9-14 million people in U.S. have LTB9-14 million people in U.S. have LTB 5%-10% will develop active TB without 5%-10% will develop active TB without
treatmenttreatment Targeted TB testingTargeted TB testing Who should be tested?Who should be tested? Testing for latent TBTesting for latent TB
TB skin test (TST)TB skin test (TST) QuantiFERON-TB Gold (QFT-G) blood testQuantiFERON-TB Gold (QFT-G) blood test
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Diagnosis and Treatment of Diagnosis and Treatment of Latent TuberculosisLatent Tuberculosis
INH INH Treatment of choiceTreatment of choice Drawbacks of INHDrawbacks of INH
Short-course therapy: rifampin aloneShort-course therapy: rifampin alone Short-course therapy: rifampin plus Short-course therapy: rifampin plus
pyrazinamidepyrazinamide Vaccination against tuberculosisVaccination against tuberculosis
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Antituberculosis Drugs Antituberculosis Drugs
First-line drugsFirst-line drugs Isoniazid, rifampinIsoniazid, rifampin Rifapentine, rifabutin, pyrazinamide, and Rifapentine, rifabutin, pyrazinamide, and
ethambutolethambutol Second-line drugsSecond-line drugs
Levofloxacin, moxifloxacin, kanamycin, amikacin, Levofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid, capreomycin, para-aminosalicylic acid, ethionamide, and cycloserineethionamide, and cycloserine
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IsoniazidIsoniazid
Primary agentPrimary agent BactericidalBactericidal Adverse effectsAdverse effects
Peripheral neuropathy (pyridoxine, vitamin BPeripheral neuropathy (pyridoxine, vitamin B66)) HepatotoxicityHepatotoxicity Optic neuritisOptic neuritis Anemia Anemia
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Rifampin (Rifadin)Rifampin (Rifadin)
Broad-spectrum antibioticBroad-spectrum antibiotic UsesUses
TuberculosisTuberculosis LeprosyLeprosy Haemophilus influenzaeHaemophilus influenzae LegionellaLegionella
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Rifampin (Rifadin)Rifampin (Rifadin)
Adverse effectsAdverse effects Hepatotoxic/hepatitisHepatotoxic/hepatitis Discoloration of body fluidsDiscoloration of body fluids GI disturbancesGI disturbances
Drug interactionsDrug interactions Induces P450 – can hasten drug metabolism Induces P450 – can hasten drug metabolism Oral contraceptivesOral contraceptives WarfarinWarfarin Drugs for HIV infectionDrugs for HIV infection
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PyrazinamidePyrazinamide
Bactericidal to Bactericidal to M. tuberculosisM. tuberculosis UseUse
TuberculosisTuberculosis Adverse effectsAdverse effects
HepatotoxicityHepatotoxicity HyperuricemiaHyperuricemia GI disturbancesGI disturbances
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Ethambutol (Myambutol)Ethambutol (Myambutol)
BacteriostaticBacteriostatic UseUse
TuberculosisTuberculosis Adverse effectsAdverse effects
Optic neuritisOptic neuritis AllergyAllergy HyperuricemiaHyperuricemia
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Second-Line Anti-TB DrugsSecond-Line Anti-TB Drugs
FluoroquinolonesFluoroquinolones Injectable drugsInjectable drugs
CapreomycinCapreomycin Kanamycin and amikacinKanamycin and amikacin
Other second-line drugsOther second-line drugs Para-aminosalicylic acidPara-aminosalicylic acid EthionamideEthionamide CycloserineCycloserine R207910R207910
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Leprosy (Hansen’s Disease)Leprosy (Hansen’s Disease)
Chronic infectionChronic infection Caused by Caused by M. lepraeM. leprae Causes gross disfiguration if untreatedCauses gross disfiguration if untreated Most can be cured with drug treatmentMost can be cured with drug treatment Affects skin, peripheral nerves, and mucous Affects skin, peripheral nerves, and mucous
membranes of upper respiratory tractmembranes of upper respiratory tract
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Leprosy (Hansen’s Disease)Leprosy (Hansen’s Disease)
Overview of treatmentOverview of treatment Multidrug therapyMultidrug therapy Monotherapy will cause resistanceMonotherapy will cause resistance World Health Organization (WHO) recommends World Health Organization (WHO) recommends
12 months treatment with three drugs:12 months treatment with three drugs:• Rifampin, dapsone, clofazimineRifampin, dapsone, clofazimine
The ROM regimenThe ROM regimen
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Mycobacterium aviumMycobacterium avium Complex Complex InfectionInfection
Mycobacterium aviumMycobacterium avium complex complex M. aviumM. avium M. intracellulareM. intracellulare
Colonization begins in the lungs or GI tractColonization begins in the lungs or GI tract May spread to the blood, bone marrow, liver, May spread to the blood, bone marrow, liver,
spleen, lymph nodes, brain, kidney, and skinspleen, lymph nodes, brain, kidney, and skin
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Mycobacterium avium Mycobacterium avium Complex Complex InfectionInfection
ProphylaxisProphylaxis AzithromycinAzithromycin ClarithromycinClarithromycin
Acute infectionAcute infection Same as prophylaxis Same as prophylaxis Plus ethambutolPlus ethambutol Plus rifampin or rifabutinPlus rifampin or rifabutin Additional drugs may also be addedAdditional drugs may also be added
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