Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases

American Thoracic Society DocumentsAm J Respir Crit Care Med 2007; 175:367-

416www.atsjournals.org

Diagnostic Criteria

CXR, or chest HRCT on non-cavitary disease3 or > sputum for AFBExclusion of other pulmonary dis, eg TBMycobacterium avium complex (MAC), M kansasii,

M abscessusPulmonary symptoms, nodular or cavity in CXR, HRCT shows multifocal bronchiectasis with nodulesPositive culture: 2 sputums or 1 bronchial lavageLung biopsy with granuloma or AFB, culture+NTM

Susceptibility testing for

MAC: clarithromycin only

M kansasii: rifampin only

M fortuitum, M abscessus, M chelonae: amikacin, imipenem, doxycycline, the fluoroquinolones, a sulfonamide, cefoxitin, clarithromycin, linezolid, tobramycin

Prophylaxis and Treatment of NTM DiseaseMAC Pulmonary Disease

Nodular/bronchiectatic MAC lung disease;initial

3 times weekly regimenClarithromycin 1000 mg or azithromycin 500 mgRifampin 600 mgEthambutol 25 mg/Kg

Follow with sputum culture monthlyTreatment to be continued until culture negative for

1 year

Prophylaxis and Treatment of NTM DiseaseMAC Pulmonary Disease

Fibrocavitary or severe nodular/bronchiectasis,init

Daily treatmentClarithromycin 500-1000 or azithro 250/dayRifampin 600 mg,or rifabutin 150-300 mgEthambutol 15 mg/Kg, +/- 3 times weekly amikacin or streptomycin for 3

months.Treatment continued until culture negative for 1

year.

Treatment of Macrolide-resistant MAC Lung Disease

Analogous to treatment for drug resistant TBRisk factor for resis: macrolide monotheray,

inadequate companion drug use. Parenteral aminoglycoside: parenteral

streptomycin or amikacin Surgical resection (debulking)4 drug regimen: INH, Rifampin, ethambutol,

streptomycin for 3-6 mo moxifloxacin?INF gamma?

MAC disseminated

Clarithromycin 500 mg bid or azithro 500/dEthambutol 15 mg/K/d+/- Rifabutin 300 mg/d (interferes with metabolism

of protease inhibitors and mononucleoside reverse transcriptase inh.

Therapy discontinued with resolution of symptoms and reconstitution of cell mediated immune function (CD4 count >100/mcL for 12 mo). Otherwise, treatment should be life long.

Prophylaxis of Disseminated MAC disease

When CD4 T-lymphocyte count is <50cells/mcL

Azithromycin 1200 mg/week or clarithromycin 1000 mg/d or rifabutin 300 mg/d

Treatment of M kansasii pulmonary disease

INH 300 mg/dRifampin 600 mg/dEthambutol 15 mg/dUntil culture negative for 1 year.

Treatment for M abscessus pulmonary disease

No drug regimen. Clarithromycin 1000 mg/d and multidrug regSurgical resection of localized disease

Treatment of nonpulmonary disease by RGM (M abscessus, M chelonae, M

fortuitum)Based on in vitro susceptibilities. M absessus: a macrolide regimen is often

used.

Treatment of NTM cervical adenitis

Mostly due to MACSurgical resection with >90% cure rateA macrolide-based regimen for extensive

MAC lymphadenitis.

Epidemiology on NTM

Widely distributed in the environment.Organisms found in soil and water, both

natural and treated water sources.M kansasii, M xenopi, M simiae almost

exclusively from municipal water sources. No evidence of animal-to-human or human-

to-human transmission of NTM. Human disease acquired from environ

exposures.

Epidemiology

NTM diseases in most industrialized countries: 1.0-1.8 cases per 100,000.

CDC report of NTM: 75% pulmonary, 5% blood, 2% skin and soft tis, 0.4% lymph n.

1 mil population: MAC 29-36 isol, M fortuitum 4.6 to 6 isol, M kansasii 2-3.1 isol

Southeastern US: higher isolation rates

Pathogenesis

HIV: disseminated NTM infection typically occurred only after CD4 T-lymphocyte is <50/microliter.

In non-HIV, disseminated NTM infection assoc with specific mutation in INF gamma and IL-12 synthesis and response path. IFN-gamma receptor 1, IFN-gamma receptor 2, IL-12 receptor beta1 subunit, IL-12 subunit p40. the signal transducer and activator of transcription 1, and the nuclear factor-kappa beta essential modulator.

An association between bronchiectasis, nodular pulmonary NTM infection and particular body habitus in postmenopausal woman: pectus excavatum, scoliosis, mitral valve prolapse.

Host Defense

Mycobacteria phagocytosed by macrophages, which produce IL-12, which up-regulates IFN-gamma. INF-gamma activates neutrophils and macrophages to kills intracellular pathogens.

Positive feed back loop between INF-gamma and IL-12. Disseminated NTM is manifestation of immunologic defect.

Pulmonary Disease with NTM

Predisposing lung diseasesCOPDBronchiectasis (NTM often coexist)CFPneumoconiosisPrior TBPulmonary alveolar proteinosisEsophageal motility disorders

Body Morphotype

Woman with nodular NTM pulmonary infections associated with bronchiectasis have similar clinical characteristics and body type. So called Lady Windermere’s

Scoliosis, pectus excavatum, mitral valve prolapse and joint hypermobility

Hypersensitivity-like Lung Disease

MAC exposure associated with hot tub use (“hot tub lung”)

MAC has predisposition for growth in indoor hot tubs.

Mycobacteria are relatively resistant to disinfectants and wide range of temp.

Metal working fluids may cause similar dis-M. immunogenus, a rapidly growing M.

Hot Tub Lung

Subacute onset of dyspnea, cough, feverOccas hypoxemic respiratory failureNon-smokersChest HRCT: diffuse nodular all overCulture from sputum, bronchial washing,

tissue biopsy isolating MACTreatment: removal, antimicrobials,

corticosteroids.

Tumor Necrosis Factor Inhibition

NTF-alpha blocking agents, blocking antibodies infliximab and adalimumab and the soluble receptor etanercept lead to relatively high rate of active TB in latent infection.

Relevance to NTM unknown