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““55 year old female with acute 55 year old female with acute respiratory illness” respiratory illness”

Barb Stowe-Carpenter, M.D.Barb Stowe-Carpenter, M.D.Professor of MedicineProfessor of Medicine

Department of Medicine / General Internal MedicineDepartment of Medicine / General Internal Medicine

Primary Care Conference PresentationPrimary Care Conference PresentationWednesday, June 14, 2006Wednesday, June 14, 2006

University of Wisconsin School of Medicine and Public Health

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Disclaimer Disclaimer

• I have not received research support from I have not received research support from pharmaceutical companies.pharmaceutical companies.

• I am not a consultant or paid speaker for any I am not a consultant or paid speaker for any pharmaceutical companies.pharmaceutical companies.

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Learning Objective Learning Objective

• Review Nontuberculous mycobacterial diseasesReview Nontuberculous mycobacterial diseases

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March 2006March 2006

55 yo female presents in March 2006 with acute 55 yo female presents in March 2006 with acute respiratory illnessrespiratory illness

Patient was in Bahamas had 5d T>101, pleuritic chest Patient was in Bahamas had 5d T>101, pleuritic chest pain, productive cough with some blood, marked pain, productive cough with some blood, marked dyspneadyspnea

In ER found to be hypoxic OIn ER found to be hypoxic O2 2 Sat 85%, WBC 16,000Sat 85%, WBC 16,000Chest x-ray showed mixed interstitial and parenchymal Chest x-ray showed mixed interstitial and parenchymal

disease In right lung and left lung basedisease In right lung and left lung base

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20022002• s/p partial colectomy for ruptured appendix or diverticula and s/p partial colectomy for ruptured appendix or diverticula and

left ovariectomyleft ovariectomy

• Abnormal CT of lung noted at preopAbnormal CT of lung noted at preop

• Over the course of the next two years, fluctuating pulmonary Over the course of the next two years, fluctuating pulmonary nodules and interstitial lung disease, emphysema changes nodules and interstitial lung disease, emphysema changes with apical blebwith apical bleb

• Only symptom was DOE on two flightsOnly symptom was DOE on two flights (-) PPD(-) PPD (-) sputum x3(-) sputum x3

Past Medical History Past Medical History

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20022002

• 25 py smoking history, no smoking in 10 years25 py smoking history, no smoking in 10 years

• FEVFEV11 2.59 FVC 3.85 FEF 25-75% 38% 2.59 FVC 3.85 FEF 25-75% 38%

• DLCO 57%DLCO 57%

• pH 742, pCOpH 742, pCO22 36, pO 36, pO22 62 62

• Bronchoscopy and washing for AFB and culture MACBronchoscopy and washing for AFB and culture MAC

• Treatment was begun Azithromycin, rifabutin, ethambutolTreatment was begun Azithromycin, rifabutin, ethambutol

• Stayed on three months and discontinued because of losing Stayed on three months and discontinued because of losing jobjob

Past Medical History Past Medical History

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NG

802/23/2006

902/24/2006

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04/25/2006

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RS

1203/27/2006

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05/11/2006 10/07/2003

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Table 1Table 1

MAIMAI

©2006 UpToDate®

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EpidemiologyEpidemiology

• SourcesSources

Most NTM organisms have been isolated Most NTM organisms have been isolated from water and soilfrom water and soil

Animal to human transmission is not an Animal to human transmission is not an issueissue

Human to human transmission is rareHuman to human transmission is rare

• PrevalencePrevalence

MAC 1.1/100,000MAC 1.1/100,000

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Clinical Presentation Clinical Presentation and Diagnostic Criteriaand Diagnostic Criteria

1.1. Chronic Pulmonary DiseaseChronic Pulmonary Disease

2.2. LymphadenitisLymphadenitis

3.3. Skin and soft tissue infectionSkin and soft tissue infection

4.4. Disseminated DiseaseDisseminated Disease

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Chronic Pulmonary DiseaseChronic Pulmonary Disease• Generally olderGenerally older

– Common Symptoms:Common Symptoms: Chronic coughChronic cough Sputum productionSputum production FatigueFatigue

– Other Symptoms:Other Symptoms: MalaiseMalaise DyspneaDyspnea FeverFever HemoptysisHemoptysis Weight lossWeight loss Chest painChest pain

• NTM often occurs in the context of pre-existing lung NTM often occurs in the context of pre-existing lung disease especially COPD, bronchiectasis, disease especially COPD, bronchiectasis, pneumonoconiosis, cystic fibrosis, previous TBpneumonoconiosis, cystic fibrosis, previous TB

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Chronic Pulmonary Disease (cont’d)Chronic Pulmonary Disease (cont’d)• MAC—3 major clinical presentationsMAC—3 major clinical presentations

1.1. Disease in middle age or elderly maleDisease in middle age or elderly male

• +/- Etohic and/or smoker with underlying lung +/- Etohic and/or smoker with underlying lung diseasedisease

• Looks like TB with upper lobe infiltrates and cavities, Looks like TB with upper lobe infiltrates and cavities, cough, weight losscough, weight loss

2.2. Disease in Areas of BronchiectasisDisease in Areas of Bronchiectasis

3.3. Disease associated with nodular reticular pattern or Disease associated with nodular reticular pattern or interstitial lung disease in nonsmoking women >50interstitial lung disease in nonsmoking women >50

*Solitary nodules and dense consolidation have been *Solitary nodules and dense consolidation have been describeddescribed

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Chronic Pulmonary Disease (cont’d)Chronic Pulmonary Disease (cont’d)

• Colonization is quite rareColonization is quite rare

• Contamination and transient infection does occurContamination and transient infection does occur

• HRCT has been instrumental in defining disease and HRCT has been instrumental in defining disease and showing that there is slow progressionshowing that there is slow progression

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Table 2Table 2

©2006 UpToDate®

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LymphadenitisLymphadenitis

• Usually in children 1-5 years oldUsually in children 1-5 years old

• 80% is MAC80% is MAC

• Unilateral 95%Unilateral 95%

• Rare systemic symptomsRare systemic symptoms

• Nodes enlarge rapidlyNodes enlarge rapidly

• Sinus tracts and fistulas develop with prolonged Sinus tracts and fistulas develop with prolonged drainagedrainage

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Skin and Soft Tissue InfectionSkin and Soft Tissue Infection

• Usually M. fortuitum, M absessus, M. marinum, M. Usually M. fortuitum, M absessus, M. marinum, M. ulceransulcerans

• ““swimming pool granulara” fish tank granulomaswimming pool granulara” fish tank granuloma

• Bursa joints tendon sheaths and bones can also be Bursa joints tendon sheaths and bones can also be infected. These can be nosocomial or from infected. These can be nosocomial or from contamination in the environmentcontamination in the environment

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Disseminated DiseaseDisseminated Disease

• Immunosuppressed—cardiac transplant, chronic Immunosuppressed—cardiac transplant, chronic steroids, leukemiasteroids, leukemia

• AIDS rare unless CDAIDS rare unless CD44<50<50

• 90% have prolonged fevers90% have prolonged fevers

• Symptoms: night sweats, weight loss, abdominal pain, Symptoms: night sweats, weight loss, abdominal pain, diarrhea, decreased WBC, anemia, increase Alk phos diarrhea, decreased WBC, anemia, increase Alk phos HSM, retroperitoneal lymphadenopathy, cough and HSM, retroperitoneal lymphadenopathy, cough and other pulmonary symptomsother pulmonary symptoms

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Treatment: Pulmonary DiseaseTreatment: Pulmonary Disease

MAC Usually multi drugMAC Usually multi drug

1.1. Clarithromycin 500 mg bid or Azithromycin 250 mg q day Clarithromycin 500 mg bid or Azithromycin 250 mg q day or 500 mg tiwor 500 mg tiw

2.2. Ethambutol 25 mg/Kg/d x 2 mo then 15 mg/Kg/dEthambutol 25 mg/Kg/d x 2 mo then 15 mg/Kg/d

3.3. Rifampin or rifabutinRifampin or rifabutin+/- intermittent streptomycin 2-3 mo for extensive +/- intermittent streptomycin 2-3 mo for extensive diseasedisease

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Treatment: Pulmonary Disease (cont’d)Treatment: Pulmonary Disease (cont’d)

• Treatment recommended 12 mo post negative sputumTreatment recommended 12 mo post negative sputum

• Cheek sputums q monthCheek sputums q month

• Should show clinical improvement 3-6 moShould show clinical improvement 3-6 mo

• Cultures should be negative within 12 moCultures should be negative within 12 mo

• Surgery in MAC if poor response to therapy or macrolide Surgery in MAC if poor response to therapy or macrolide resistance in patient with disease in 1 loberesistance in patient with disease in 1 lobe

• Susceptibility testing recommended to macrolide if Susceptibility testing recommended to macrolide if previously treated on a macrolidepreviously treated on a macrolide

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M. kansasiiM. kansasii

• Since rifampin success rate has improved (nearly Since rifampin success rate has improved (nearly 100%), surgery has no role in routine cases100%), surgery has no role in routine cases

• Usual regimen: INH 300 mg/day, rifampin 600 mg/day, Usual regimen: INH 300 mg/day, rifampin 600 mg/day, ethambutol 25 mg/Kg/day x 2 mo, then 15 mg/Kg/day x ethambutol 25 mg/Kg/day x 2 mo, then 15 mg/Kg/day x 18 mo (at least 12 mo of negative cultures)18 mo (at least 12 mo of negative cultures)

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Treatment: LymphadenitisTreatment: Lymphadenitis

• Usually caused by MAC or M. scrofulaceumUsually caused by MAC or M. scrofulaceum

• Treat by excision 95% successful without chemotherapyTreat by excision 95% successful without chemotherapy

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Treatment: Skin Tissue Skeletal DiseaseTreatment: Skin Tissue Skeletal Disease

• Usually a combination of excisional surgery and Usually a combination of excisional surgery and chemotherapy (drug therapy 6-12 mo)chemotherapy (drug therapy 6-12 mo)

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Treatment: Disseminated MACTreatment: Disseminated MAC

• In AIDS—median survival 134 days, 13% alive at 1 yearIn AIDS—median survival 134 days, 13% alive at 1 year

• Multi-drug with clarithromycin or azithromycin, Multi-drug with clarithromycin or azithromycin, ethambutol, rifabutin ( preferred because can still use ethambutol, rifabutin ( preferred because can still use indinavir), rifampin (cannot be used with protease indinavir), rifampin (cannot be used with protease inhibitors)inhibitors)

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Prophylaxis of Disseminated Prophylaxis of Disseminated Disease in AIDSDisease in AIDS

• Has been shown to be effectiveHas been shown to be effective

• Development of resistance is a concernDevelopment of resistance is a concern

• Clarithromycin decreased incidence of disseminated Clarithromycin decreased incidence of disseminated disease from 16% to 6%disease from 16% to 6%

• Rifabutin decreased incidence from 17% to 8%Rifabutin decreased incidence from 17% to 8%

• Azithromycin was shown to be effective at 1200 mg/wk Azithromycin was shown to be effective at 1200 mg/wk +/- rifabutin+/- rifabutin

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Treatment in Rapidly Growing Treatment in Rapidly Growing Mycobacterial DiseaseMycobacterial Disease

• Isolates of M. fortuitum are susceptible to Amikacin 100%, Isolates of M. fortuitum are susceptible to Amikacin 100%, Cipro 100%, Sulfonamides 100%, Cefoxitin 80%, imipenem Cipro 100%, Sulfonamides 100%, Cefoxitin 80%, imipenem 100%, Clarithromycin 80%, doxycycline 50%100%, Clarithromycin 80%, doxycycline 50%

• Isolates of M. abscessus are susceptible to Clarithromycin Isolates of M. abscessus are susceptible to Clarithromycin 100%, 100%, Clofazimine, Clofazimine, amikacin 90%, Cefoxitin 70%, imipenem amikacin 90%, Cefoxitin 70%, imipenem 50%50%

• Isolates of M. chelonae are susceptible to Amikacin 80%, Isolates of M. chelonae are susceptible to Amikacin 80%, tobramycin 100%, clarithromycin 100%, imipenem 60%, tobramycin 100%, clarithromycin 100%, imipenem 60%, clofazimine , doxycycline 25%, Cipro 25%clofazimine , doxycycline 25%, Cipro 25%

• Usually causes cutaneous diseaseUsually causes cutaneous disease

• Some minor infections resolved spontaneously or after Some minor infections resolved spontaneously or after surgical debridementsurgical debridement

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Treatment in Rapidly Growing Treatment in Rapidly Growing Mycobacterial Disease (cont’d)Mycobacterial Disease (cont’d)

• Pulmonary disease is increasingly being recognizedPulmonary disease is increasingly being recognized

• >60 year old female nonsmoker with underlying disease >60 year old female nonsmoker with underlying disease like lung damage from previous TB, GI disorders like lung damage from previous TB, GI disorders especially chronic vomiting, cystic fibrosis, especially chronic vomiting, cystic fibrosis, bronchiectasisbronchiectasis

• Tends to be indolentTends to be indolent

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Drug ToxicityDrug Toxicity• GI Intolerance: clarithromycin, azithromycin, rifabutin, GI Intolerance: clarithromycin, azithromycin, rifabutin,

rifampinrifampin

• Abnormal LFTs: clarithromycin azithromycin, rifabutin, Abnormal LFTs: clarithromycin azithromycin, rifabutin, rifampin, INH, ethionamiderifampin, INH, ethionamide

• Decreased WBC: rifabutinDecreased WBC: rifabutin

• Impaired visual acuity and color vision: ethambutolImpaired visual acuity and color vision: ethambutol

• Auditory and Vestibular Function: streptomycin, amikacin, Auditory and Vestibular Function: streptomycin, amikacin, clarithromycin, azithromycinclarithromycin, azithromycin

• Renal Function: Streptomycin, AmakacinRenal Function: Streptomycin, Amakacin

• Peripheral Neuropathy: EthanbutolPeripheral Neuropathy: Ethanbutol

• Clarithromycin enhances rifabutin toxicity especially uveitis Clarithromycin enhances rifabutin toxicity especially uveitis

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BibliographyBibliography

1.1. UpToDate including ATS Guidelines: Diagnosis and UpToDate including ATS Guidelines: Diagnosis and Treatment of Disease caused by non-TB mycobacteria. Treatment of Disease caused by non-TB mycobacteria. 20062006

2.2. Diagnosis and Treatment of Disease caused by Diagnosis and Treatment of Disease caused by Nontuberculosis mycobacteria, Am Rev Respir Dis Nontuberculosis mycobacteria, Am Rev Respir Dis 1990;142(4):940-53.1990;142(4):940-53.

3.3. Reich, J and Johnson RE. Mycobacterium avium Reich, J and Johnson RE. Mycobacterium avium complex pulmonary disease. Am Rev Respir Dis complex pulmonary disease. Am Rev Respir Dis 1991;143(6):1381-5. 1991;143(6):1381-5.