Nontuberculous Mycobacterium Diseases

Chapter: Nontuberculous Mycobacterium Diseases
McMaster Section Editor(s): Paul M. O’Byrne
Section Editor(s) in Interna Szczeklika: Ewa Niżankowska-Mogilnicka, Filip Mejza
McMaster Author(s): Lori Whitehead
Author(s) in Interna Szczeklika: Iwona Grzelewska-Rzymowska, Maria Korzeniewska-Koseła, Katarzyna Kruczak, Zofia Zwolska, Ewa Augustynowicz-Kopeć
Additional Information

Definition, EtiologyTop

Mycobacterioses are caused by atypical mycobacteria: nontuberculous mycobacteria (NTM) and mycobacteria other than tuberculosis (MOTT). NTM species include Mycobacterium avium complex (MAC) (this comprises Mycobacterium avium and Mycobacterium intracellulare), Mycobacterium fortuitum complex, Mycobacterium xenopi, and Mycobacterium kansasii. Some species are associated with clinical disease, while others are rarely associated with disease. These strains are widely present in the environment, particularly in soil and water reservoirs. Geologic factors account for regional variability in incidence and speciation. At-risk groups include human immunodeficiency virus–positive individuals, patients treated with anti–tumor necrosis factor alpha agents, individuals with a history of tuberculosis (TB), and patients with pneumoconiosis, cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, or alcohol dependence. Clinical syndromes can also occur in patients with no preexisting lung disease or apparent indicators of immune dysfunction. NTM infection is not transmitted between humans and therefore is not a disease that requires reporting to public health authorities. Although NTM disease is not caused by infection with M tuberculosis complex, it is often considered in conjunction with TB since both diseases (1) overlap with respect to several clinical presenting features and therapeutic agents; (2) have specimens processed at a common mycobacteriology laboratory with expertise in acid-fast bacillus (AFB) smear, culture, drug-sensitivity testing, and speciation; (3) are often treated in a TB clinic setting by a health-care team with expertise in mycobacteriosis.

Clinical FeaturesTop

The clinical features are similar to TB and typically include chronic, productive cough, sputum production (with or without hemoptysis), asthenia, and less frequently fever and sweating. The NTM diseases also yield specimens with similar laboratory characteristics to TB, including positive AFB stain and necrotizing granuloma formation. Nucleic acid amplification tests are a rapid method of differentiation between the two conditions; however, the gold standard for identification is culture.

The lesions are predominantly located in the lungs, although other sites include lymph nodes, skin, and bone/joint. In some cases, multiple organs are involved. In patients who are not significantly immunocompromised, pulmonary NTM may be associated with 2 patterns. One pattern is of multiple small nodules, bronchiectasis, and tree-in-bud densities (mainly in the right middle lobe or lingula) visible on high-resolution computed tomography (HRCT) of the chest, often found in middle-aged women without preexisting lung disease. The second pattern with cavitation in the upper lobes often occurs in the setting of preexisting lung disease such as chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, and other abnormalities in pulmonary structure and mucus clearance. Patients with a single nodule or few nodules have no symptoms.

DiagnosisTop

NTM organisms can be isolated from pulmonary specimens due to contamination, colonization, or disease. Clinical, radiographic, and microbiologic criteria are all equally important and all 3 must be met in order to make a diagnosis of NTM disease.

1. Clinical criteria:

1) Pulmonary symptoms (cough, sputum, hemoptysis, chest pain, dyspnea) and/or systemic symptoms (fever, weight loss, fatigue), and

2) Exclusion of other potential causes (such as M tuberculosis complex, other respiratory infections, sarcoidosis, malignancy).

3) Progressive symptoms, which increase the likelihood of an NTM disease.

2. Radiology:

1) Chest radiograph: Nodular or cavitary opacities, or

2) Computed tomography (CT) of the chest: Bronchiectasis with multiple small nodules or lung cavitation, or airspace disease (consolidation with ground-glass opacification).

3. Microbiological criteria:

1) Positive culture result from at least 2 sputum samples collected on separate occasions, or

2) Positive culture result from at least 1 bronchial wash or lavage, or

3) Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture of NTM, or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and 1 or more sputum or bronchial washings that are culture-positive for NTM.

TreatmentTop

Drug therapy for NTM lung diseases is not recommended for all patients. The decision to treat should be based on an individual assessment of the risks and benefits of therapy. Progression of clinical symptoms with compatible radiographic findings increases the likelihood of disease and may be an indication for a stronger recommendation for drug therapy. The long treatment period required to achieve a clinical effect is often poorly tolerated due to adverse effects and/or toxicities. Clinical outcomes for pulmonary NTM are suboptimal compared with treatment outcomes for M tuberculosis complex. Consultation with an expert in NTM disease is suggested, especially in complex cases where there is uncertainty about diagnosis of the disease, treatment indications, or management of drug therapy.

General principles of treatment:

1) Asymptomatic patients with a single or small number of randomly distributed incidental lung nodules due to NTM generally should not be treated unless there is significant radiographic progression with the development of symptoms.Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Behr M, Jarand J, Marras T. Nontuberculous Mycobacteria. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:273-91. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf.

2) Combination therapy with 3 or more drugs is recommended for the treatment of NTM disease. Macrolides are an important component included in drug regimens for many of the common NTM species. Patients with repeated isolation of NTM should not receive macrolide monotherapy for treatment of bacterial infections or for treatment of NTM, as this may foster resistance to this class of drugs, thereby limiting efficacy of future NTM treatment.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Behr M, Jarand J, Marras T. Nontuberculous Mycobacteria. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:273-91. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Griffith D, Aksamit T, Winthrop K, et al. An official ATS/ISDA statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. http://www.atsjournals.org/doi/pdf/10.1164/rccm.200604-571ST. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. Review. Erratum in: Am J Respir Crit Care Med. 2007 Apr 1;175(7):744-5. Dosage error in article text. PubMed PMID: 17277290.

3) Drug choices are generally species-specific (Table 13.18-1). Evidence to support the recommended treatment regimens to target the various NTM species is weak to moderate. Data to correlate results from drug-susceptibility testing with clinical response to treatment is lacking, except for identification of macrolide resistance in MAC and rifampin (INN rifampicin) resistance in M kansasii.

4) The duration of treatment is ≥12 months from the first negative culture result; and when mycobacteriosis is diagnosed based on cultures of a material other than sputum, up to 18 months. Isolated pulmonary lesions and involved lymph nodes may be treated by surgical resection.

5) Monitoring while on drug therapy is important to assess clinical response, adverse effects, and drug toxicities. Medication schedules and regimens require frequent modifications if treatment is poorly tolerated or ineffective. Practices regarding regular monitoring for specific adverse reactions, such as liver toxicity (rifampin), optic neuritis (ethambutol), or nerve VIII and renal injury (aminoglycosides), are variable. Most clinicians recommend at least monthly monitoring of parameters appropriate to drug selection, which may include transaminases, visual assessment with an ophthalmologist or optometrist, audiograms, and/or creatinine levels.

TablesTop

Table 13.18-1. Recommended treatment of nontuberculous mycobacterial disease1

Organism

Drugs

Duration

Mycobacterium avium complex lung disease (macrolide susceptible)

– Daily: clarithromycin 500 mg bid or azithromycin 250 mg; EMB 15 mg/kg (may use 25 mg/kg for initial 2 months); RMP (450-600 mg) or RBT (150-300 mg) ± aminoglycosides (SM or amikacin) intermittently (conditional recommendation, based on moderate evidence)

– Thrice weekly2 (may be considered for nonadvanced, nodular bronchiectatic pulmonary MAC): clarithromycin 500 mg bid or azithromycin 500 mg; EMB 25 mg/kg; RMP 600 mg (conditional recommendation, based on moderate evidence)

– Clofazimine and FQNs may be useful (conditional recommendation, based on moderate evidence)

12 months after culture conversion to negative (conditional recommendation, based on moderate evidence)

MAC lymphadenitis (macrolide susceptible)

If antibacterial therapy is being considered: daily or thrice weekly clarithromycin or azithromycin plus EMB ± RMP (conditional recommendation, based on very weak evidence)

3-9 months (conditional recommendation, based on very weak evidence)

M xenopi lung disease

– Azithromycin or clarithromycin plus RMP plus EMB

– Consider, in addition, moxifloxacin (or other FQNs), INH, SM, amikacin

(conditional recommendation, based on very weak evidence)

12 months after culture-negative (conditional recommendation, based on very weak evidence)

M abscessus complex lung disease

Clarithromycin or azithromycin + amikacin, cefoxitin or imipenem (± tigecycline, linezolid, clofazimine) (conditional recommendation, based on moderate evidence)

2-6 months of combination IV and PO therapy (conditional recommendation, based on weak evidence)

M kansasii lung disease

– Daily RMP, EMB, INH

– Consider clarithromycin or azithromycin, moxifloxacin, sulfamethoxazole, and aminoglycosides

(strong recommendation, based on moderate evidence)

12 months after culture-negative (conditional recommendation, based on weak evidence)

M fortuitum lung disease

Based on in-vitro sensitivity testing: azithromycin or clarithromycin and RMP or EMB (± doxycycline, amikacin, imipenem, FQNs, sulfonamides, cefoxitin) (conditional recommendation, based on very weak evidence)

12 months after culture-negative for lung disease (conditional recommendation, based on very weak evidence)

M fortuitum skin/soft tissue

Based on in-vitro sensitivity testing: azithromycin or clarithromycin and RMP or EMB (± doxycycline, amikacin, imipenem, FQNs, sulfonamides, cefoxitin) (conditional recommendation, based on very weak evidence)

4 months for skin/soft tissue (6 months for severe disease) (conditional recommendation, based on weak evidence)

M marinum skin/soft tissue

Clarithromycin, EMB ± RMP (conditional recommendation, based on weak evidence)

3-6 months (consider longer if deep structures involved) (conditional recommendation, based on weak evidence)

Disseminated MAC in HIV-infected patients

Treatment

Clarithromycin 500 mg PO daily + EMB 15 mg/kg PO daily ± RBT 300 mg PO daily3 (strong recommendation, based on very strong evidence)

Lifelong or until control of HIV viremia with rise of CD4 to >100 × 106/L for at least 6 months and 12 months after culture-negative (strong recommendation, based on strong evidence)

Disseminated MAC in HIV-infected patients

Prophylaxis

Patients with CD4 <50 × 106/L

Azithromycin 1200 mg weekly

or

RBT 300 mg a day

or

Clarithromycin 500 mg bid

(strong recommendation, based on very strong evidence)

Lifelong or until control of HIV viremia with rise of CD4 to >100 × 106/L for ≥6 months and 12 months after culture-negative (strong recommendation, based on strong evidence)

Suggested regimens for initial therapy of NTM disease should be modified, if needed, depending upon clinical circumstances such as drug intolerance, the presence of macrolide-resistant MAC, and lack of efficacy.

1 More detailed recommendations and treatment guidance regarding other NTM species may be found elsewhere.

2 Although directly observed therapy is recommended for intermittent therapy of TB, this is not so in NTM disease, because there is no public health consideration of contagion. Intermittent therapy for pulmonary NTM has been suggested to reduce toxic effects and sometimes costs of therapy and has been shown to be effective in many cases.

3 Doses may need to be adjusted according to interactions with concurrent antiretroviral therapy.

Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016.

EMB; ethambutol; FQNs, fluoroquinolones; HIV, human immunodeficiency virus; INH, isoniazid; IV, intravenous; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacterium; PO, oral; RBT, rifabutin; RMP, rifampin (INN rifampicin); SM, streptomycin.

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