Mycobacterium avium complex (MAC) 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).
Mycobacterium 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, M. 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:
When taking the history, ask about the following:
Perform a full physical examination with particular attention to the following:
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:
MAC from the 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:
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.
Because antimicrobial resistance develops quickly with single-drug therapy, multidrug regimens must be administered for DMAC.
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 500-600 mg once daily may be substituted for clarithromycin. Clarithromycin dosages should not exceed 1 g per day, as high-dose clarithromycin has been associated with excess mortality.
Ethambutol is the recommended second agent, to be given with a macrolide.
Some experts recommend including a third agent for more advanced disease and for patients who are not receiving effective ART. The addition of rifabutin (300 mg daily) has been associated with a mortality benefit in one study and with reduced emergence of mycobacterial resistance in two other trials. A fluoroquinolone (e.g., ciprofloxacin, levofloxacin) or amikacin 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. Patients who are receiving suboptimal ART should be evaluated for enhancement of their regimens. The optimal timing of ART initiation in relation to MAC treatment is unclear. Because immune reconstitution from effective ART may cause a paradoxical inflammatory response if started during active DMAC infection, some experts recommend treating DMAC for at least 2 weeks before adding antiretroviral (ARV) medications (see chapter Immune Reconstitution Inflammatory Syndrome). This strategy also helps to avoid or forestall interactions between DMAC and ARV drugs and the additive toxicities of those medications.
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. Interactions of concern include the following:
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 and protease inhibitors, and 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. Consider repeating 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 MAC IRIS is moderate to severe (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. Some clinicians verify negative AFB cultures before discontinuing therapy. 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 <50 cells/µL. See chapter Opportunistic Infection Prophylaxis.