Mycobacterium avium Complex Disease
Publish date: April 2014
Mycobacterium avium complex (MAC) disease is an opportunistic infection caused by species of Mycobacterium that can produce severe illness in people with advanced AIDS but rarely affects others. The risk of disseminated MAC (DMAC) is directly related to the severity of immunosuppression. DMAC typically occurs in persons with CD4 counts of <50 cells/µL, and its frequency increases as the CD4 count declines. In the absence of antibiotic prophylaxis, DMAC occurs in up to 40% of AIDS patients with CD4 counts of <50 cells/µL. Antimicrobial therapy, especially if given in conjunction with antiretroviral therapy (ART) that achieves immune reconstitution, can be successful in treating MAC disease. Specific antimicrobial prophylaxis and effective ART also may be used to prevent MAC in patients with advanced AIDS (see chapter Opportunistic Infection Prophylaxis).
MAC organisms are common in the environment. They are found worldwide and have been isolated from soil, water, animals, birds, and foods. They usually enter the body through the respiratory or gastrointestinal tract and disseminate to cause multisystem infection, typically manifested by nonspecific symptoms and signs such as fever, sweats, weight loss, abdominal pain, fatigue, chronic diarrhea, and anemia and other cytopenias. MAC also can cause local disease such as central nervous system infection, lymphadenitis, soft-tissue or bone infections, and rarely, isolated pulmonary disease. Focal MAC disease is more common among patients on ART, whereas DMAC is the more common manifestation among those with low CD4 cell counts who are not on ART. Unlike Mycobacterium tuberculosis, Mycobacterium avium is not thought to be transmitted via person-to-person contact. In patients with subclinical or incompletely treated MAC who have recently started ART, an immune reconstitution inflammatory syndrome (IRIS) may occur with localized lymphadenitis or paradoxically worsening symptoms (see chapter Immune Reconstitution Inflammatory Syndrome).
The patient complains of one or more of the following symptoms:
- Persistent or cyclic fever
- Night sweats
- Unintentional weight loss
- Chronic diarrhea
- Abdominal pain
- Lymph node enlargement
When taking the history, ask about the following:
- Any symptoms as described above, including duration and intensity; other symptoms of infection
- Whether the patient is taking MAC prophylaxis or ART
Perform a full physical examination with particular attention to the following:
- Vital signs (temperature, heart rate, blood pressure, respiratory rate)
- Weight (compare with previous measurements)
- General appearance (cachexia, wasting, signs of chronic illness, jaundice, pallor)
- Lymph nodes (lymphadenopathy)
- Abdomen (hepatosplenomegaly, tenderness)
Review previous laboratory values, particularly the CD4 count (usually <50 cells/µL).
Rule out other infectious or neoplastic causes of constitutional symptoms, anemia, or organomegaly. A partial differential diagnosis would include the following:
- M. tuberculosis infection
- Cytomegalovirus infection
- Disseminated fungal infection
- Pyogenic abscess
- Other septicemia
Definitive diagnosis requires identification of MAC in blood or other normally sterile body fluids or tissues (M. avium cultured from sputum, bronchial washing, or stool may represent colonization rather than infection). Send blood for acid-fast bacilli (AFB) culture (sensitivity of a single blood culture for MAC bacteremia is 91%, sensitivity increases to 98% if two samples [drawn at different times] are sent). Because MAC may take weeks to grow in culture, ancillary studies should be performed. The following are not specific, but may be helpful in reaching a presumptive diagnosis:
- AFB smear
- Complete blood count (CBC) for anemia, lymphopenia, and thrombocytopenia
- Serum alkaline phosphatase (often elevated in DMAC)
- Computed tomography (CT) scan of the chest and abdomen (intraabdominal and mediastinal lymphadenopathy or hepatosplenomegaly often are present)
If blood cultures are negative and MAC is suspected (or if results of blood cultures are pending), consider biopsy of the lymph nodes, bone marrow, liver, or bowel (via endoscopy) to detect DMAC by microscopic examination for AFB and culture. If the evidence suggests pulmonary MAC, consider bronchoscopy and bronchoalveolar lavage. Note that in MAC IRIS, MAC bacteremia usually is absent and a tissue-based diagnosis is required.
Perform additional studies as indicated to rule out other causes of the patient's symptoms, including bacterial blood cultures, sputum for M. tuberculosis, Bartonella studies, lymph node cytology for lymphoma, and stool cultures, as appropriate.
Because antimicrobial resistance develops quickly with single-drug therapy, multidrug regimens must be administered for DMAC.
- Clarithromycin 500 mg BID + ethambutol 15 mg/kg QD
- Azithromycin 500-600 mg QD + ethambutol 15 mg/kg QD (see below)
Clarithromycin is the preferred cornerstone of MAC therapy, as it has been studied more extensively and is associated with more rapid clearance of MAC bacteremia. If clarithromycin cannot be tolerated or if there is concern regarding drug interactions, azithromycin may be substituted for clarithromycin, as above. Clarithromycin dosages should not exceed 1 g per day, as high-dose clarithromycin has been associated with excess mortality.
Some experts recommend including a third agent for patients with more advanced HIV disease or higher MAC burden in blood cultures, and for those who are not receiving effective ART. The addition of rifabutin (300 mg QD) has been associated with a mortality benefit in one study and with reduced emergence of mycobacterial resistance in two other trials; however, these studies were done before potent ART was available; the possible benefit of rifabutin in patients treated with effective ART has not been established. A fluoroquinolone (e.g., levofloxacin, moxifloxacin), amikacin, or streptomycin may be used instead of rifabutin as a third agent, or in addition to rifabutin as a fourth agent; however, studies have not confirmed the clinical benefit of these medications.
Because immune reconstitution is essential for controlling MAC, all patients who are not already receiving ART should begin ART, if possible. Current guidelines recommend initiation of ART after 2 weeks of MAC treatment, for patients who are not already on ART. This strategy may decrease the risk IRIS and it serves to forestall interactions between DMAC and ARV drugs and the additive toxicities of those medications. Patients who are receiving suboptimal ART should be changed to suppressive regimens, if possible.
Potential ARV Interactions
Clarithromycin and rifabutin have a number of significant drug interactions, including interactions with some commonly prescribed ARVs. These interactions should be reviewed prior to initiation of MAC therapy. Dosage adjustments or alternative medications may be required. Azithromycin does not have significant interactions with ARVs.
Interactions of concern include the following:
- Atazanavir may raise clarithromycin levels by 90%; some experts recommend using azithromycin in place of clarithromycin, or dosage reduction of clarithromycin by 50%.
- Darunavir increases clarithromycin levels; alternative agent (azithromycin) or dosage reduction of clarithromycin is recommended for patients with renal impairment.
- Lopinavir/ritonavir and other protease inhibitors may increase clarithromycin levels; alternative agent (azithromycin) or dosage reduction of clarithromycin is recommended for patients with renal impairment.
- Efavirenz may lower clarithromycin levels; avoid this combination if possible.
- Etravirine may lower clarithromycin levels, while clarithromycin may in turn increase etravirine levels. Avoid this combination, if possible.
- Nevirapine may decrease clarithromycin levels and increase levels of its active metabolite. Avoid this combination, if possible.
- Elvitegravir/cobicistat may increase clarithromycin levels. Dosage reduction of clarithromycin is required for patients with renal insufficiency.
Protease inhibitor-based ART (e.g., lopinavir or darunavir) or integrase inhibitor-based ART may be the preferred HIV treatment for patients on MAC therapy, because of limited drug interactions associated with those ARV classes.
Rifabutin has significant interactions with many drugs, including nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and elvitegravir/cobicistat; therefore, dosage adjustments or alternative agents may be needed (for further information, see chapter Mycobacterium tuberculosis).
The patient should show clinical improvement within the first weeks of treatment. If there is not a response to treatment after 2-4 weeks, assess adherence, consider adding one or more drugs, and consider evaluation for other or additional causes of the patient's symptoms. Repeat a blood culture with antimicrobial sensitivities for patients whose clinical status has not improved after 4-8 weeks of treatment. Interpretation of MAC drug susceptibility testing should be undertaken in consultation with an infectious disease or HIV specialist, because laboratory evidence of drug resistance does not always correlate with clinical drug resistance.
If immune reconstitution inflammatory reactions are suspected, consider adding antiinflammatory medications, including corticosteroids if moderate to severe MAC IRIS symptoms do not improve with NSAIDs (see chapter Immune Reconstitution Inflammatory Syndrome).
Treatment of MAC generally is required for the remainder of the patient's life in the absence of immune reconstitution with effective ART. It may be reasonable to discontinue MAC therapy if patients complete at least 12 months of MAC treatment, have no further symptoms, and demonstrate immune restoration in response to ART (an increase in CD4 counts to >100 cells/µL for at least 6 months). If MAC treatment is discontinued, the patient must be monitored carefully for any decrease in CD4 cell count or recurrence of MAC symptoms. Treatment should be resumed if the CD4 count drops to <100 cells/µL or if symptoms recur.
Primary prevention using azithromycin or clarithromycin should be initiated in persons with CD4 cell counts of <50 cells/µL. See chapter Opportunistic Infection Prophylaxis.
- Advise patients that antimycobacterial therapy alone will not eradicate MAC infection, but should decrease symptoms and improve quality of life. A response to treatment may take up to 4 weeks. If medications are discontinued, the disease almost always recurs, unless the CD4 count has increased to >50-100 cells/µL in response to ART.
- Patients must take all medicines exactly as prescribed. If doses are missed, or if the medication is stopped and restarted, MAC can develop resistance to the medications. If patients are having trouble taking the medications on schedule, they should contact their health care provider promptly.
- Advise patients that MAC IRIS is a common complication of effective ART and MAC therapy, and its occurrence in the course of treatment should be anticipated.
- Urge patients to contact the clinic immediately if they notice worsening of existing symptoms or the development of new symptoms.
- DMAC is an opportunistic infection of late-stage HIV and it is indicative of profound immunosuppression. Some patients may not respond to MAC treatment or to ART. Because this is a life-threatening disease, clinicians should discuss advance directives and durable power of attorney with patients. Referral to a social worker, mental health clinician, or chaplain experienced in such issues may facilitate the discussion.
- Benson CA, Williams PL, Currier JS, et al.; AIDS Clinical Trials Group 223 Protocol Team. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis. 2003 Nov 1;37(9):1234-43.
- Cabié A, Abel S, Brebion A, et al. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis. 1998 Nov;17(11):812-3.
- Gordin FM, Sullam PM, Shafran SD, et al. A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis. 1999 May;28(5):1080-5.
- Horsburgh CR Jr, Gettings J, Alexander LN, et al. Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency virus, 1985-2000. Clin Infect Dis. 2001 Dec 1;33(11):1938-43.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed December 1, 2013.
- Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and longterm follow-up. Clin Infect Dis. 2005 Nov 15;41(10):1483-97.
- Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet. 1998 Jan 24;351(9098):252-5.
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Abbreviations for Dosing Terminology
- twice daily
- twice weekly
- intramuscular (injection), intramuscularly
- intravenous (injection), intravenously
- oral, orally
- Q2H, Q4H, etc.
- every 2 hours, every 4 hours, etc.
- every morning
- once daily
- every hour
- every night at bedtime
- four times daily
- every other day
- every evening
- three times daily
- three times weekly