Nontuberculous Mycobacterial Infections

One common clinical scenario of Mycobacterium avium complex (MAC) infection is in immunocompetent, middle-aged or older, White women with a low BMI who have middle lobe bronchiectasis, scoliosis, pectus excavatum, or mitral valve prolapse. This patient population typically presents with a chronic nonproductive cough and no other lung abnormalities. This pattern is often called Lady Windermere syndrome, and it appears to be increasing in frequency, especially among women in resource-rich countries. The reasons for this increase are not fully understood, but it may be due to the ubiquity of NTM organisms in the environment and increased host susceptibility. Both of these factors lead to higher rates of infection in people with no prior lung disease, particularly older, immunocompetent women (1). The pattern seen in Lady Windermere syndrome seems to have been incidentally reported in a handful of older men as well.

MAC also causes pulmonary disease in middle-aged or older White men with previous pulmonary conditions such as chronic bronchitis, emphysema, healed TB, bronchiectasis, or silicosis.

Whether MAC causes bronchiectasis or bronchiectasis leads to MAC is not always clear in any given patient; both phenomena occur.

Another important population subject to NTM infection is patients with cystic fibrosis (CF). With better management of CF, patients are living longer and therefore are more likely to develop complications such as NTM disease.

Common symptoms are cough and expectoration, 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 radiographs resemble those of pulmonary TB, but cavitation is typically 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 performed to diagnose MAC infection and to distinguish it from TB.

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.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.

Treatment of pulmonary disease in adults is tailored to the specific NTM species, disease severity, and drug susceptibility results (2). A 3-drug regimen, typically azithromycin or clarithromycin, rifampin (rifampicin) or rifabutin, and ethambutol, is recommended, sometimes with the addition of parenteral amikacin or streptomycin. Treatment should continue for at least 12 months after culture conversion. Because of the long duration of treatment, adherence and the potential for adverse effects (including drug interactions) must be factored into management decisions. Treatment of pulmonary disease (usually due to MAC) is based on clinical severity. ). A 3-drug regimen, typically azithromycin or clarithromycin, rifampin (rifampicin) or rifabutin, and ethambutol, is recommended, sometimes with the addition of parenteral amikacin or streptomycin. Treatment should continue for at least 12 months after culture conversion. Because of the long duration of treatment, adherence and the potential for adverse effects (including drug interactions) must be factored into management decisions. Treatment of pulmonary disease (usually due to MAC) is based on clinical severity.

For noncavitary nodular or bronchiectatic disease due to MAC, azithromycin 500 mg, ethambutol 25 mg/kg, and rifampin 600 mg orally 3 times/week is an acceptable regimen (For noncavitary nodular or bronchiectatic disease due to MAC, azithromycin 500 mg, ethambutol 25 mg/kg, and rifampin 600 mg orally 3 times/week is an acceptable regimen (2).

For severe bronchiectatic or cavitary disease due to MAC infection with positive sputum smears and cultures, clarithromycin 500 mg orally 2 times a day or azithromycin 250 to 500 mg orally once/day, rifampin 600 mg or rifabutin 5 mg/kg (300 mg) orally once/day, and ethambutol 15 mg/kg orally once/day (or 25 mg/kg 3 times/week) should be used for 12 to 18 months or until cultures are negative for 12 months (For severe bronchiectatic or cavitary disease due to MAC infection with positive sputum smears and cultures, clarithromycin 500 mg orally 2 times a day or azithromycin 250 to 500 mg orally once/day, rifampin 600 mg or rifabutin 5 mg/kg (300 mg) orally once/day, and ethambutol 15 mg/kg orally once/day (or 25 mg/kg 3 times/week) should be used for 12 to 18 months or until cultures are negative for 12 months (2).

For patients with persistent pulmonary MAC infection despite 6 months of therapy, amikacin liposome inhalation suspension, if available, or inhaled amikacin should be added (For patients with persistent pulmonary MAC infection despite 6 months of therapy, amikacin liposome inhalation suspension, if available, or inhaled amikacin should be added (2). For patients with macrolide-resistant MAC infection or cavitary lung disease, parenteral amikacin or streptomycin should be added to the initial regimen for 2 to 3 months.

M. kansasii and M. xenopi infections respond to isoniazid, rifabutin, and ethambutol, with or without streptomycin or clarithromycin, given for 18 to 24 months. infections respond to isoniazid, rifabutin, and ethambutol, with or without streptomycin or clarithromycin, given for 18 to 24 months.

Pulmonary M. abscessus complex disease is particularly challenging to treat because some subspecies are resistant to macrolides. Treatment requires 3 to 4 antibiotics with activity based on susceptibility testing. Therapy may include a combination of amikacin, imipenem/cilastatin, cefoxitin, clofazimine, linezolid, bedaquiline, or omadacycline. complex disease is particularly challenging to treat because some subspecies are resistant to macrolides. Treatment requires 3 to 4 antibiotics with activity based on susceptibility testing. Therapy may include a combination of amikacin, imipenem/cilastatin, cefoxitin, clofazimine, linezolid, bedaquiline, or omadacycline.

All nontuberculous mycobacteria are resistant to pyrazinamide.

Pulmonary resection surgery is recommended in exceptional cases involving well-localized disease in young, otherwise healthy patients.

In children 1 to 5 years of age, chronic submaxillary and submandibular cervical lymphadenitis is commonly due to MAC or M. scrofulaceum. It is presumably acquired by oral ingestion of NTM organisms in soil or water.

Lymphadenitis (Submandibular)

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Diagnosis is usually by excisional biopsy.

Usually, excision is adequate treatment, and chemotherapy may not be required; however, antibiotics (eg, macrolides) may be needed for recurrent or recalcitrant cases (1).

Swimming pool granuloma or fish tank granuloma is a protracted but self-limited superficial granulomatous ulcerating disease usually caused by M. marinum contracted from, for example, swimming in a contaminated pool or cleaning a home aquarium. M. ulcerans and M. kansasii are occasionally involved.

Erythematous lesions that enlarge and become violaceous nodules 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 rifampin (rifampicin) plus ethambutol for 3 to 6 months have been effective against Healing may occur spontaneously, but minocycline or doxycycline 100 to 200 mg orally once/day, clarithromycin 500 mg orally 2 times a day, or rifampin (rifampicin) plus ethambutol for 3 to 6 months have been effective againstM. marinum.

Buruli ulcer (also known as Bairnsdale or Daintree ulcer) is caused by M. ulcerans and occurs in rural areas of > 30 tropical and subtropical countries; most cases occur in West and Central Africa, and areas in Victoria province, Australia, have seen an increase in cases (1). 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, molecular methods such as polymerase chain reaction testing should be performed.

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, 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 study suggests the combination of rifampin (10 mg/kg once/day) and clarithromycin (7.5 mg/kg 2 times a day) is the recommended treatment (is problematic because it is parenteral and toxic. The WHO states that a study suggests the combination of rifampin (10 mg/kg once/day) and clarithromycin (7.5 mg/kg 2 times a day) is the recommended treatment (2). An ongoing randomized trial is being done to evaluate whether the addition of amoxicillin/clavulanate to this regimen may offer better efficacy and tolerability (). An ongoing randomized trial is being done to evaluate whether the addition of amoxicillin/clavulanate to this regimen may offer better efficacy and tolerability (3).

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 medical 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 United States, 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 during pulpotomy (a dental procedure); severe infection resulted.

Treatment usually requires extensive debridement and removal of the foreign material.

Several medications have been efficacious when used for the treatment for nontuberculous mycobacterial skin and soft-tissue infections (1, 2). Useful medications include:

• Imipenem 1 g IV every 6 hours

• Levofloxacin 500 mg IV or orally once/dayLevofloxacin 500 mg IV or orally once/day

• Clarithromycin 500 mg orally 2 times a dayClarithromycin 500 mg orally 2 times a day

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

• Doxycycline 100 to 200 mg orally once/dayDoxycycline 100 to 200 mg orally once/day

• Cefoxitin 2 g IV every 6 to 8 hoursCefoxitin 2 g IV every 6 to 8 hours

• Amikacin 10 to 15 mg/kg IV once/day Amikacin 10 to 15 mg/kg IV once/day

Combination therapy with at least 2 medications 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 (including macrolides), have proved extremely difficult or impossible to cure, and should be referred to an experienced specialist (3).

Mycobacterium avium complex (MAC) commonly causes disseminated disease in patients with advanced HIV infection and occasionally in those with other immunocompromised states, including organ transplantation and hairy cell leukemia. In patients with advanced HIV infection, disseminated MAC infection usually develops late (unlike TB, which develops early), occurring simultaneously with other opportunistic infections (1).

Disseminated MAC infection 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 medications; 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 orally once/day. Sometimes rifabutin 300 mg orally once/day is also given. After successful treatment, chronic suppression with Combination therapy to clear bacteremia and alleviate symptoms usually requires 2 or 3 medications; 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 orally once/day. Sometimes rifabutin 300 mg orally once/day is also given. After successful treatment, chronic suppression withclarithromycin or azithromycin plus EMB is necessary to prevent relapse.

Patients with HIV infection who were not diagnosed before presenting with disseminated MAC infection may receive up to 2 weeks of antimycobacterial treatment before starting antiretroviral therapy (ART) to decrease the risk of developing immune reconstitution inflammatory syndrome (IRIS).

Primary prophylaxis for MAC is not recommended for patients with HIV infection who immediately start ART (1). MAC prophylaxis is indicated for patients with a CD4 count < 50 cells/mcL who are not receiving ART, who have persistent viremia on ART, or who cannot be fully suppressed because of resistance. Before prophylaxis is started, disseminated MAC infection should be ruled out clinically or by doing a blood culture to check for acid-fast bacilli.