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Management Recommendations > Disseminated MAC

Ward 86 Management Recommendations

Diagnosis and Management of Disseminated Mycobacterium avium Complex Infection

updated September 2017

Contributors: Mark A. Jacobson, MD
Katerina Christopolous, MD
Diane Havlir, MD

  1. 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.

  2. 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.

  3. 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.

  4. Disseminated MAC treatment failure can be diagnosed if both:

    1. Symptoms consistent with dMAC (fever, weight loss, diarrhea, abdominal pain) recur after an initial clinical response, and
    2. A blood culture obtained after at least 4 weeks of antimycobacterial therapy is positive for MAC.

    Antimicrobial susceptibility testing is of little clinical utility in this situation. We concur with the following American Thoracic Society/IDSA/National Committee for Clinical Laboratory Standards Statement regarding this issue.(2) Because no correlation between in vitro susceptibility results for MAC and clinical response for agents other than macrolides has been established, clarithromycin is the only drug for which susceptibility testing for MAC isolates is recommended.

  5. We manage treatment failure by either 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. However, randomized trials in patients with AIDS and dMAC have demonstrated no clinical benefit and increased toxicity with amikacin and increased mortality with clofazimine.(3,4) Higher-than-standard dosages of clarithromycin (ie, 1,000 mg BID) were reported to increase mortality in a randomized trial. It is unclear whether continuing standard clarithromycin or azithromycin dosing is beneficial if susceptibility testing demonstrates macrolide resistance. Quinolones have in vitro activity vs MAC, but there are no efficacy data from randomized trials regarding this antimicrobial class. Moxifloxacin is the quinolone with the greatest in vitro activity vs MAC, and adding this drug may be considered for patients who are slow to clear mycobacteremia or in whom there is concern about resistance. On the other hand, some of us are reluctant to use an agent with unproven clinical efficacy given the risk of harm that might occur. 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 necessarily generalizable to AIDS patients with dMAC, in whom the disease has a very different pathogenesis.

  6. 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.)

  7. Timing for initiation of ART in patients with disseminated MAC: There are competing risk considerations when determining the optimal time to initiate ART for HIV patients with dMAC. Earlier ART initiation may increase the risk of IRIS, and later initiation can increase the risks of AIDS-related opportunistic infections and mortality. Some centers have observed particularly severe and prolonged cases of MAC IRIS in patients who had entered care without known MAC infection. These patients generally had absolute CD4 counts of <50 cells/µL and were initiated on ART and weekly azithromycin MAC prophylaxis after blood was sent for mycobacterial culture. These patients were discovered several weeks later to have a positive blood culture for MAC, indicating disseminated infection and--with the already-initiated ART--had prolonged courses of MAC IRIS.(5) In light of this phenomenon, the NIH/IDSA/CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents were recently revised to suggest that ART "should be started as soon as possible after the first 2 weeks of initiating antimycobacterial therapy in patients with dMAC disease who have not been treated previously with or are not receiving effective ART." We consider this a reasonable recommendation to balance risks and benefits, but also suggest that clinicians initiate empiric therapy for dMAC whenever patients with absolute CD4 counts of <50 cells/µL, who are not taking ART, enter care with symptoms (eg, fever, marked weight loss) or signs (eg, diffuse nonfluctuant adenopathy, hepatosplenomegaly, diarrhea) that suggest dMAC infection. Empiric MAC therapy can be discontinued and MAC prophylaxis instituted once mycobacterial blood cultures are reported as negative.

  8. 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.

  9. 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.(6) 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.

References

  1. 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.
  2. Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175:367-416.
  3. 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.
  4. 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.
  5. Smibert OC, Trubiano JA, Cross GB, et al. Mycobacterium avium complex infection and immune reconstitution inflammatory syndrome remain a challenge in the era of effective antiretroviral therapy. AIDS Res Hum Retroviruses. 2017 Sep 6. doi: 10.1089/AID.2017.0030. [Epub ahead of print]
  6. 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

Treatment

Combination therapy with:
Clarithromycin 500 mg PO BID or azithromycin 600 mg PO daily
AND
Ethambutol 15 mg/kg PO daily or rifabutin 150-600 mg PO daily (dosage depends on concomitant drug interactions) or both ethambutol and rifabutin

Prophylaxis

Options include:
a. Azithromycin 1,200 mg PO once a week
b. Clarithromycin 500 mg PO BID
c. Rifabutin 150-450 mg PO daily (dosage depends on concomitant drug interactions)