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Nontuberculous Mycobacterial Infections

By

Edward A. Nardell

, MD, Harvard Medical School

Last full review/revision Jul 2022| Content last modified Sep 2022
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There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections do not cause disease. Disease usually requires a defect in local or systemic host defenses. People with chronic lung disease (particularly cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis ), frail older people, and immunocompromised people are at highest risk, but others with less obvious defects can have progressive disease. New species and infections are reported regularly. (The mycobacterial infection tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Tuberculosis (TB) is discussed elsewhere.)

Mycobacteria other than Mycobacterium tuberculosis can be human pathogens, and the incidence of infection appears to be increasing. These organisms are commonly present in soil and water and are much less virulent for humans than M. tuberculosis. Infections caused by these organisms have been called atypical, environmental, and nontuberculous mycobacterial (NTM) infections. These organisms also cause a wider range of disease manifestations among people who have HIV infection or are otherwise immunocompromised, but those manifestations are not discussed here.

NTM infections are generally noncommunicable (ie, they are usually acquired from the environment rather than from infected people), so they are not reportable public health diseases and it is difficult to accurately determine the incidence of NTM infection. Also, isolation of an NTM organism does not necessarily mean it is the cause of disease. Nonetheless, the number of patients presenting with NTM infection that requires treatment appears to be increasing. It is unclear how much of this apparent increase is due to greater awareness and improved diagnostic testing and how much is an actual increased incidence of infection. Longer survival of patients with cystic fibrosis and patients with other predisposing lung diseases may be a factor. Because NTM organisms are rather resistant to routine levels of chlorine in public water (1 General reference There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more ), greater exposure to aerosolized water sources through routine showering, water misters, decorative water displays could be playing a role. Environmental climate change also may play a role because a warmer, wetter climate extends the areas that NTM can inhabit. Worldwide, there is considerable geographic diversity in the prevalence of NTM in clinical specimens and environmental sources. In the US, warmer, wet southern climates generally have more NTM isolates than do colder, drier northern climates.

Mycobacterium avium complex (MAC)—the closely related species of M. avium and M. intracellulare—accounts for most NTM disease, but M. abscessus is increasingly becoming common. Other causative species are M. kansasii, M. xenopi, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae (M. fortuitum and M. chelonae are related to M. abscessus). Although person-to-person transmission of most NTM infections is generally not thought to occur, M. abscessus may be transmitted among patients with cystic fibrosis.

The lungs Pulmonary disease There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more are the most common site of infection; most of these lung infections are caused by MAC but could also be caused by M. kansasii, M. xenopi, or M. abscessus. Occasional cases involve lymph nodes Lymphadenitis There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more , bones and joints, skin Cutaneous disease There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more , and wounds Wound and foreign body infections There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more . However, incidence of disseminated MAC disease Disseminated disease There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more 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. Although nucleic acid amplification tests (NAATs) exist for the most common NTM organisms, in the US speciation is increasingly done in state public health laboratories using molecular and other methods.

Nontuberculous mycobacterial infections are best managed by a specialist with particular expertise in that area. For updated diagnostic and therapeutic information on the diagnosis and management of these challenging infections, see the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America's 2020 practice guideline on the treatment of nontuberculous mycobacterial pulmonary disease.

General reference

Pulmonary disease

The typical patient is a middle-aged or older woman with bronchiectasis, scoliosis, pectus excavatum, or mitral valve prolapse but without known underlying lung abnormalities. Mycobacterium avium complex (MAC) also causes pulmonary disease in middle-aged or older White men with previous lung problems such as chronic bronchitis Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disease (COPD) , emphysema Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disease (COPD) , healed TB, bronchiectasis Bronchiectasis Bronchiectasis is dilation and destruction of larger bronchi caused by chronic infection and inflammation. Common causes are cystic fibrosis, immune defects, and recurrent infections, though... read more Bronchiectasis , or silicosis Silicosis Silicosis is caused by inhalation of unbound (free) crystalline silica dust and is characterized by nodular pulmonary fibrosis. Chronic silicosis initially causes no symptoms or only mild dyspnea... read more Silicosis . Whether MAC causes bronchiectasis or bronchiectasis leads to MAC is not always clear in any given patient; both phenomena occur. 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.

Another important population subject to NTM infection and disease is patients with cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis . With better management of CF, patients are living longer and therefore are more likely to develop complications such as NTM disease.

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 orally 2 times a day or azithromycin 600 mg orally once/day, rifampin (RIF) 600 mg orally once/day, and ethambutol (EMB) 15 to 25 mg/kg orally once/day should be used for 12 to 18 months or until cultures are negative for 12 months.

For progressive cases unresponsive to standard drugs, combinations of 4 to 6 drugs that include clarithromycin 500 mg orally 2 times a day or azithromycin 600 mg orally once/day, rifabutin 300 mg orally once/day, ciprofloxacin 250 to 500 mg orally or IV 2 times a day, clofazimine 100 to 200 mg orally 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 months. M. abscessus is a multidrug-resistant organism. Its isolates have in vitro resistance to most oral antibiotics but generally are susceptible to a limited number of parenteral antibiotics, including tigecycline, imipenem, cefoxitin, and amikacin; treatment with at least 3 active drugs is recommended (see the 2020 practice guideline on the treatment of nontuberculous mycobacterial pulmonary disease).

All nontuberculous mycobacteria are resistant to pyrazinamide.

Lymphadenitis

In children 1 to 5 years of age, chronic submaxillary and submandibular cervical lymphadenitis is commonly due to MAC or Mycobacterium 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.

Cutaneous disease

Swimming pool granuloma is a protracted but self-limited superficial granulomatous ulcerating disease usually caused by Mycobacterium 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 orally once/day, clarithromycin 500 mg orally 2 times a day, or RIF plus EMB for 3 to 6 months 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, polymerase chain reaction should be used.

The World Health Organization (WHO) recommends 8 weeks of once/day combination therapy with rifampin 10 mg/kg orally plus either streptomycin 15 mg/kg IM, clarithromycin 7.5 mg/kg orally (preferred during pregnancy), or moxifloxacin 400 mg orally. However, streptomycin is problematic because it is parenteral and toxic. The WHO states that a recent study suggests the combination of rifampicin (10 mg/kg once/day) and clarithromycin (7.5 mg/kg 2 times a day) is now the recommended treatment (1 Cutaneous infection reference There are over 170 recognized species of mycobacteria, mostly environmental. Environmental exposure to many of these organisms is common, but most exposures do not cause infection and many infections... read more ).

Cutaneous infection reference

Wound and foreign body infections

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 (Mycobacterium 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). These outbreaks 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 every 6 hours

  • Levofloxacin 500 mg IV or orally once/day

  • Clarithromycin 500 mg orally 2 times a day

  • Trimethoprim/sulfamethoxazole 1 double-strength tablet orally 2 times a day

  • Doxycycline 100 to 200 mg orally once/day

  • Cefoxitin 2 g IV every 6 to 8 hours

  • 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 months and may be longer if the infected foreign material remains in the body. Amikacin is usually included for the first 3 to 6 months 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.

Disseminated disease

Mycobacterium avium complex (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 patients with AIDS, disseminated MAC usually develops late (unlike tuberculosis, which develops early), occurring simultaneously with other opportunistic infections.

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 combination is clarithromycin 500 mg orally 2 times a day or azithromycin 600 mg orally once/day, plus ethambutol (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.

Patients with HIV infection who were not diagnosed before presenting with disseminated MAC should receive 2 weeks of antimycobacterial treatment before starting antiretroviral therapy to decrease the risk of developing the immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome (IRIS) Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more Immune reconstitution inflammatory syndrome (IRIS) (IRIS).

Patients with HIV infection and a CD4 count < 100 cells/mcL (0.01 × 109/L) require prophylaxis for disseminated MAC with azithromycin 1.2 g orally once/week or clarithromycin 500 mg orally 2 times a day.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Drugs Mentioned In This Article

Drug Name Select Trade
BIAXIN
ZITHROMAX
RIFADIN, RIMACTANE
MYAMBUTOL
MYCOBUTIN
CILOXAN, CIPRO
No US brand name
No US brand name
LANIAZID
No US brand name
TYGACIL
MEFOXIN
No US brand name
MINOCIN
VIBRAMYCIN
AVELOX
LEVAQUIN
BACTRIM, SEPTRA
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