chapter 89

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

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. 2

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


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


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



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



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



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



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.



DiagnosisDiagnosis Indications for testingIndications for testing Definitive diagnosisDefinitive diagnosis

• Chest x-rayChest x-ray• Sputum cultureSputum culture

Evaluation of drug susceptibilityEvaluation of drug susceptibility


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


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


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!



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”



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


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


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


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


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


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


IsoniazidIsoniazid

Primary agentPrimary agent BactericidalBactericidal Adverse effectsAdverse effects

Peripheral neuropathy (pyridoxine, vitamin BPeripheral neuropathy (pyridoxine, vitamin B66)) HepatotoxicityHepatotoxicity Optic neuritisOptic neuritis Anemia Anemia


Rifampin (Rifadin)Rifampin (Rifadin)

Broad-spectrum antibioticBroad-spectrum antibiotic UsesUses

TuberculosisTuberculosis LeprosyLeprosy Haemophilus influenzaeHaemophilus influenzae LegionellaLegionella


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


PyrazinamidePyrazinamide

Bactericidal to Bactericidal to M. tuberculosisM. tuberculosis UseUse

TuberculosisTuberculosis Adverse effectsAdverse effects

HepatotoxicityHepatotoxicity HyperuricemiaHyperuricemia GI disturbancesGI disturbances


Ethambutol (Myambutol)Ethambutol (Myambutol)

BacteriostaticBacteriostatic UseUse

TuberculosisTuberculosis Adverse effectsAdverse effects

Optic neuritisOptic neuritis AllergyAllergy HyperuricemiaHyperuricemia


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


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


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


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


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

chapter 89

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