Ward 86 Management Recommendations
updated April 2016
Contributors: Mark A. Jacobson, MD
Katerina Christopolous, MD
Diane Havlir, MD
Among AIDS patients with CD4 counts of <50 cells/µL who are not receiving antiretroviral therapy (ART) or antimycobacterial prophylaxis, disseminated Mycobacterium avium complex infection (dMAC) is so common that we often manage unexplained fever in such patients by initiating empiric therapy for dMAC while awaiting mycobacterial blood culture results.
dMAC occurs in approximately half of AIDS patients with CD4 counts of <50 cells/µL who are not receiving ART or antimycobacterial prophylaxis. This opportunistic infection typically presents with fever, often high, but without other signs of sepsis, unless the patient is dehydrated. Weight loss, diarrhea, and abdominal pain (caused by enlarged retroperitoneal lymph nodes) are common. However, mycobacteria are slow-growing organisms, and the time to culture positivity is on the order of 2-4 weeks. Hence, if clinical suspicion for dMAC is high, we initiate therapy (see Table 1 for dosing details), which can be discontinued if subsequent cultures are negative.
The diagnosis of dMAC should be confirmed by culture of MAC from blood or other normally sterile tissue.
Of note, MAC growth from respiratory secretions or stool may simply represent colonization rather than invasive, disseminated infection. A single mycobacterial blood culture is 90% sensitive and 100% specific for making the diagnosis of dMAC. Obtaining a second blood culture on a separate day can improve sensitivity to 95%. dMAC can be presumptively diagnosed in a high-risk patient if acid-fast stain of a lymph node, bone marrow, liver, or bowel specimen reveals mycobacteria and if tuberculosis can be excluded.
First-line treatment for patients with dMAC should include a macrolide (clarithromycin or azithromycin) chosen on the basis of a patient's likely tolerance of these drugs' common adverse effects (anorexia and nausea for clarithromycin; diarrhea for azithromycin) PLUS either ethambutol, rifabutin, or both of these latter agents (see Table for dosing details)
In AIDS patients with dMAC, the only antimycobacterial agents with proven clinical efficacy (ie, those that eliminate or quantitatively reduce mycobacteremia or improve survival) are clarithromycin, azithromycin, ethambutol, and rifabutin. In a treatment trial initiated before the modern antiretroviral era that randomized patients with newly diagnosed dMAC to receive clarithromycin in combination with ethambutol, rifabutin, or both agents, survival was significantly longer in the 3-drug arm.(1) However, it is not clear that this finding is generalizable to patients with newly diagnosed dMAC who will initiate ART imminently and are likely to adhere to their regimen. We generally reserve the 3-drug regimen for individuals who have severe clinical manifestations of dMAC or are not likely to adhere to ART. In patients for whom tuberculosis is also in the differential diagnosis, isoniazid and pyrazinamide can be added to the 3-drug regimen while awaiting culture results.
We manage treatment failure (defined as persistent symptoms consistent with dMAC and a persistent positive culture from blood or other normally sterile tissue obtained after at least 4 weeks of antimycobacterial therapy) either by increasing the rifabutin dosage to tolerance or by increasing the ethambutol dosage from the standard 15 mg/kg/day to 25 mg/kg/day, or both.
Rifabutin tolerance is primarily limited by the development of eye, joint, or mouth pain. The uveitis, arthralgias/arthritis, or stomatitis that can be caused by high-dose rifabutin is reversible with dosage reduction. With high-dose ethambutol, visual acuity must be monitored biweekly and the drug stopped if visual acuity deteriorates, as ethambutol-induced optic neuritis, a rare adverse effect, may not be reversible. There are other agents with in vitro activity against MAC, but randomized trials in patients with AIDS have demonstrated no benefit and only increased toxicity (amikacin) or increased mortality (clofazimine).(2,3) Higher than standard dosages of clarithromycin also have been reported to increase mortality in 2 separate randomized trials. There is no efficacy data from randomized trials regarding quinolones. Unfortunately, the results of treatment studies in HIV-negative patients with invasive MAC infection (primarily those with pulmonary infection in the setting of underlying chronic lung disease) are not generalizable to AIDS patients with dMAC, in whom the disease has a very different pathogenesis. Because there have been 4 multicenter, randomized treatment trials for dMAC in which agents with better in vitro activity against MAC caused more harm than benefit, we are reluctant to use agents with unproven clinical efficacy in patients who are failing first-line therapy.
With patients on treatment for dMAC, clinicians should be alert for the possible occurrence of immune reconstitution inflammatory syndrome (IRIS) after ART is initiated. MAC IRIS is the most common form of IRIS in the United States, occurring in 30% of patients with dMAC who initiate ART. Because dMAC causes minimal, if any, tissue damage until ART-induced immune reconstitution occurs, symptoms and signs of dMAC are usually nonspecific but can become localizing with MAC-associated IRIS (eg, necrotizing lymphadenitis, pulmonary infiltrates, osteomyelitis). (See section on Diagnosis and Management of Immune Reconstitution Inflammatory Syndrome for more information.)
Duration of therapy. dMAC involves a high body burden of organisms and is not curable with available antimycobacterial drugs; eventually, drug resistance occurs, leading to microbiologic relapse and clinical deterioration. However, with ART-associated immune reconstitution, dMAC can be cured in the vast majority of patients. In those who initiate ART after being diagnosed with dMAC, antimycobacterial therapy can be discontinued 12 months after the CD4 count rises to >50 cells/µL (assuming the patient no longer has symptoms of dMAC and a repeat mycobacterial blood culture is negative). Suppressive therapy should be reinitiated if the CD4 count subsequently decreases to <50 cells/µL.
Prophylaxis with clarithromycin, azithromycin, or rifabutin is highly effective in preventing dMAC in at-risk AIDS patients and should be given to all HIV-infected patients with an absolute CD4 count of <50 cells/µL. We generally choose the once-weekly azithromycin alternative to reduce pill burden.(4) Another option should be considered for those who have severe diarrhea, which can worsen with azithromycin (see Table 1 for dosing details). Prophylaxis can be discontinued 6 months after ART-induced recovery of the CD4 count to >50 cells/µL but should be reinitiated if the CD4 count subsequently decreases to <50 cells/µL.
- 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.
- Parenti D, Williams PL, Hafner R, et al. A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS Clinical Trials Group Protocol 135 Study Team. AIDS. 1998 Dec 24;12(18):2439-46.
- Chaisson RE, Keiser P, Pierce M, et al. Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS. 1997 Mar;11(3):311-7.
- Havlir DV, Dubé MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin or both. California Collaborative Treatment Group. N Engl J Med. 1996 Aug 8;335(6):392-8.
Table 1. Treatment and Prophylaxis for Disseminated Mycobacterium avium Complex Infection