Nontuberculous Mycobacterial Infections
By Dylan Tierney, MD, MPH , Instructor, Harvard Medical School; Associate Physician, Division of Global Health Equity, Brigham and Women’s Hospital
Edward A. Nardell, MD, Professor of Medicine and Global Health and Social Medicine, Harvard Medical School; Associate Physician, Divisions of Global Health Equity and Pulmonary and Critical Care Medicine, Brigham & Women’s Hospital
Mycobacteria other than the tubercle bacillus sometimes infect humans. These organisms (called nontuberculous mycobacteria) are commonly present in soil and water and are much less virulent in humans than is Mycobacterium tuberculosis. Infections with these organisms have been called atypical, environmental, and nontuberculous mycobacterial infections.
Most exposures and infections by these organisms do not cause disease, which usually requires a defect in local or systemic host defenses; the frail elderly and immunocompromised people are at the highest risk. M. avium complex (MAC)—the closely related species of M. avium and M. intracellulare—accounts for most diseases. Other causative species are M. kansasii, M. xenopi, M. marinum, M. ulcerans, M. fortuitum, M. abscessus, and M. chelonae. Person-to-person transmission has not been documented.
The lungs are the most common site of disease; most of these lung infections involve MAC but may be due to M. kansasii, M. xenopi, or M. abscessus. Occasional cases involve lymph nodes, bones and joints, the skin, and wounds. However, incidence of disseminated MAC disease is increasing in HIV-infected patients, and resistance to anti-TB drugs is the rule (except for M. kansasii and M. xenopi).
Diagnosis of nontuberculous mycobacterial infections is typically made via acid-fast stain and culture of samples.
Nontuberculous mycobacterial infections are best managed by a specialist with particular expertise in that area. The American Thoracic Society publishes updated diagnostic and therapeutic guidelines on the diagnosis and management of these challenging infections.
The typical patient is a middle-aged or elderly woman with bronchiectasis, scoliosis, pectus excavatum, or mitral valve prolapse but without known underlying lung abnormalities. MAC also causes pulmonary disease in middle-aged or older white men with previous lung problems such as chronic bronchitis, emphysema, healed TB, bronchiectasis, or silicosis. Whether MAC causes bronchiectasis or bronchiectasis leads to MAC is not always clear. In older, thin women with chronic nonproductive cough, this syndrome is often called Lady Windermere syndrome; it appears to be increasing in frequency for unknown reasons.
Cough and expectoration are common, often associated with fatigue, weight loss, and low-grade fever. The course may be slowly progressive or stable for long periods. Respiratory insufficiency and persistent hemoptysis may develop. Fibronodular infiltrates on chest x-ray resemble those of pulmonary TB, but cavitation tends to be thin-walled, and pleural effusion is rare. So-called tree-and-bud infiltrates, seen on chest CT, are also characteristic of MAC disease.
Sputum examination and culture are done to diagnosis MAC and to distinguish MAC infection from tuberculosis.
Determination of drug susceptibility may be helpful for certain organism/drug combinations but can be done only in highly specialized laboratories. For MAC, susceptibility to clarithromycin is a predictor of therapeutic response.
For moderately symptomatic disease due to MAC with positive sputum smears and cultures, clarithromycin 500 mg po bid or azithromycin 600 mg po once/day, rifampin (RIF) 600 mg po once/day, and ethambutol (EMB) 15 to 25 mg/kg po once/day should be used for 12 to 18 mo or until cultures are negative for 12 mo.
For progressive cases unresponsive to standard drugs, combinations of 4 to 6 drugs that include clarithromycin 500 mg po bid or azithromycin 600 mg po once/day, rifabutin 300 mg po once/day, ciprofloxacin 250 to 500 mg po or IV bid, clofazimine 100 to 200 mg po once/day, and amikacin 10 to 15 mg/kg IV once/day may be tried.
Resection surgery is recommended in exceptional cases involving well-localized disease in young, otherwise healthy patients.
M. kansasii and M. xenopi infections respond to isoniazid, rifabutin, and EMB, with or without streptomycin or clarithromycin, given for 18 to 24 mo. M. abscessus infections are treated with 3 drugs: amikacin, cefoxitin or imipenem, and an oral macrolide.
All nontuberculous mycobacteria are resistant to pyrazinamide.
In children 1 to 5 yr, chronic submaxillary and submandibular cervical lymphadenitis is commonly due to MAC or M. scrofulaceum. It is presumably acquired by oral ingestion of soil organisms.
Diagnosis is usually by excisional biopsy.
Usually, excision is adequate treatment, and chemotherapy is not required.
Swimming pool granuloma is a protracted but self-limited superficial granulomatous ulcerating disease usually caused by M. marinum contracted from swimming in contaminated pools or from cleaning a home aquarium. M. ulcerans and M. kansasii are occasionally involved. Lesions, reddish bumps, enlarging and turning purple, most frequently occur on the upper extremities or knees. Healing may occur spontaneously, but minocycline or doxycycline 100 to 200 mg po once/day, clarithromycin 500 mg po bid, or RIF plus EMB for 3 to 6 mo have been effective against M. marinum.
Buruli ulcer, caused by M. ulcerans, occurs in rural areas of > 30 tropical and subtropical countries; most cases occur in West and Central Africa. It starts as a painless subcutaneous nodule, a large painless area of induration, or a diffuse painless swelling of the legs, arms, or face. The infection progresses to cause extensive destruction of the skin and soft tissue; large ulcers may form on the legs or arms. Healing may result in a severe contracture, scarring, and deformity. For diagnosis, PCR should be used. The WHO recommends 8 wk of once/day combination therapy with rifampin 10 mg/kg po plus either streptomycin 15 mg/kg IM, clarithromycin 7.5 mg/kg po (preferred during pregnancy), or moxifloxacin 400 mg po.
Nontuberculous mycobacteria form biofilms; they can survive in water systems in residential, office, and health care facilities. They are difficult to eradicate with common decontamination practices (eg, using chlorine, organomercurials, or alkaline glutaraldehyde).
Rapidly growing nontuberculous mycobacteria (M. fortuitum complex, M. chelonae, M. abscessus complex) can cause nosocomial outbreaks of infections, usually due to injection of contaminated solutions, wound contamination with nonsterile water, use of contaminated instruments, or implantation of contaminated devices. These infections may also develop after cosmetic procedures, acupuncture, or tattooing.M. fortuitum complex has caused serious infections of penetrating wounds in the eyes and skin (especially feet), in tattoos, and in patients receiving contaminated materials (eg, porcine heart valves, breast implants, bone wax).
In the US, outbreaks of M. abscessus infection occurred in Georgia (2015) and California (2016). They occurred in children when water contaminated with M. abscessus biofilm was used to irrigate the tooth’s pulp chamber during a root canal; severe infection resulted.
Treatment usually requires extensive debridement and removal of the foreign material. Useful drugs include
- Imipenem 1 g IV q 6 h
- Levofloxacin 500 mg IV or po once/day
- Clarithromycin 500 mg po bid
- Trimethoprim/sulfamethoxazole 1 double-strength tablet po bid
- Doxycycline 100 to 200 mg po once/day
- Cefoxitin 2 g IV q 6 to 8 h
- Amikacin 10 to 15 mg/kg IV once/day
Combination therapy with at least 2 drugs that have in vitro activity is recommended. Duration of therapy averages 24 mo and may be longer if the infected foreign body remains in the body. Amikacin is usually included for the first 3 to 6 mo of therapy. Infections caused by M. abscessus and M. chelonae are usually resistant to most antibiotics, have proved extremely difficult or impossible to cure, and should be referred to an experienced specialist.
MAC causes disseminated disease commonly in patients with advanced AIDS and occasionally in those with other immunocompromised states, including organ transplantation and hairy cell leukemia. In AIDS patients, disseminated MAC usually develops late (unlike TB, which develops early), occurring simultaneously with other opportunistic infections.
Disseminated MAC disease causes fever, anemia, thrombocytopenia, diarrhea, and abdominal pain (features similar to Whipple disease).
Diagnosis of disseminated MAC infection can be confirmed by cultures of blood or bone marrow or by biopsy (eg, percutaneous fine-needle biopsy of liver or necrotic lymph nodes). Organisms may be identified in stool and respiratory specimens, but organisms from these specimens may represent colonization rather than true disease.
Combination therapy to clear bacteremia and alleviate symptoms usually requires 2 or 3 drugs; one is clarithromycin 500 mg po bid or azithromycin 600 mg po once/day, plus EMB 15 to 25 mg/kg once/day. Sometimes rifabutin 300 mg once/day is also given. After successful treatment, chronic suppression with clarithromycin or azithromycin plus EMB is necessary to prevent relapse.
HIV-infected patients who were not diagnosed before presenting with disseminated MAC should receive 2 wk of antimycobacterial treatment before starting antiretroviral therapy to decrease the risk of developing the immune reconstitution inflammatory syndrome(IRIS).
HIV-infected patients with a CD4 count <100 cells/µL require prophylaxis for disseminated MAC with azithromycin 1.2 g po once/week or clarithromycin 500 mg po bid.