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Disseminated Mycobacterium avium Complex Disease
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Epidemiology

Organisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment (398Inderlied CB: Microbiology and minimum inhibitory concentration testing for Mycobacterium avium complex prophylaxis. Am J Med 1997;102:2-10., 399Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289-97., 400Benson CA, Williams PL, Currier JS, et al. 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;37:1234-43.). M. avium is the etiologic agent in >95% of patients with AIDS who acquire disseminated MAC disease (398Inderlied CB: Microbiology and minimum inhibitory concentration testing for Mycobacterium avium complex prophylaxis. Am J Med 1997;102:2-10., 401Kemper CA, Havlir D, Bartok AE, et al. Transient bacteremia due to Mycobacterium avium complex in patients with AIDS. J Infect Dis 1994;170:488-93., 402Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997;176:126-32., 403Benson CA, Ellner JJ. Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis 1993;17:7-20., 404Havlik JA, Jr., Horsburgh CR, Jr., Metchock B, et al. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. J Infect Dis 1992;165:577-80., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22.). An estimated 7%-12% of adults have been previously infected with MAC, although rates of disease vary in different geographic locations (398Inderlied CB: Microbiology and minimum inhibitory concentration testing for Mycobacterium avium complex prophylaxis. Am J Med 1997;102:2-10., 402Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997;176:126-32., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22.). Although epidemiologic associations have been identified, no environmental exposure or behavior has been consistently linked to a subsequent risk for developing MAC disease.

The mode of transmission is thought to be through inhalation, ingestion, or inoculation via the respiratory or gastrointestinal tract. Household or close contacts of those with MAC disease do not appear to be at increased risk for disease, and person-to-person transmission is unlikely.

In the absence of effective ART or chemoprophylaxis in those with AIDS-associated immunosuppression, the incidence of disseminated MAC disease is 20%-40% (407Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165:1082-5., 408Chaisson RE, Moore RD, Richman DD, Keruly J, Creagh T. Incidence and natural history of Mycobacterium avium-complex infections in patients with advanced human immunodeficiency virus disease treated with zidovudine. Am Rev Respir Dis 1992;146:285-9.). For persons with a CD4+ count <100 cells/µL who are receiving effective prophylaxis or have responded to ART with a sustained increase in CD4+ count to levels >100-200 cells/µL, the overall incidence has been estimated at 2 cases per 100 person-years. MAC disease typically occurs among persons with CD4+ counts <50 cells/µL. Other factors that are associated with increased susceptibility to MAC disease are high plasma HIV RNA levels (>100,000 copies/mL), previous OIs, previous colonization of the respiratory or gastrointestinal tract with MAC, and reduced in vitro lymphoproliferative immune responses to M. avium antigens, possibly reflecting defects in T-cell repertoire.

Clinical Manifestations

In persons with AIDS not on ART, MAC disease is typically a disseminated multi-organ infection (409Barbaro DJ, Orcutt VL, Coldiron BM. Mycobacterium avium-Mycobacterium intracellulare infection limited to the skin and lymph nodes in patients with AIDS. Rev Infect Dis 1989;11:625-8., 410Hellyer TJ, Brown IN, Taylor MB, Allen BW, Easmon CS. Gastro-intestinal involvement in Mycobacterium avium-intracellulare infection of patients with HIV. J Infect 1993;26:55-66., 411Owen RL, Roth RI, St. Hilaire RJ, Keren DF. Pseudo Whipple's disease: intestinal infection with Mycobacterium avium-intracellulare (M.avium) in acquired immune deficiency syndrome (AIDS). Gastroenterology 1984;84:1267., 412Torriani FJ, McCutchan JA, Bozzette SA, Grafe MR, Havlir DV. Autopsy findings in AIDS patients with Mycobacterium avium complex bacteremia. J Infect Dis 1994; 170:1601-5.). Early symptoms might be minimal and might precede detectable mycobacteremia by several weeks. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain (402Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997;176:126-32.).

Localized manifestations of MAC disease have been reported most frequently among persons who are receiving and have responded to ART. Localized syndromes include cervical or mesenteric lymphadenitis, pneumonitis, pericarditis, osteomyelitis, skin or soft tissue abscesses, genital ulcers, or CNS infection.

Laboratory abnormalities particularly associated with disseminated MAC disease include anemia (often out of proportion to that expected for the stage of HIV disease) and elevated liver alkaline phosphatase (398Inderlied CB: Microbiology and minimum inhibitory concentration testing for Mycobacterium avium complex prophylaxis. Am J Med 1997;102:2-10., 399Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289-97., 401Kemper CA, Havlir D, Bartok AE, et al. Transient bacteremia due to Mycobacterium avium complex in patients with AIDS. J Infect Dis 1994;170:488-93., 402Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997;176:126-32., 403Benson CA, Ellner JJ. Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis 1993;17:7-20., 404Havlik JA, Jr., Horsburgh CR, Jr., Metchock B, et al. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. J Infect Dis 1992;165:577-80., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22., 407Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165:1082-5.408Chaisson RE, Moore RD, Richman DD, Keruly J, Creagh T. Incidence and natural history of Mycobacterium avium-complex infections in patients with advanced human immunodeficiency virus disease treated with zidovudine. Am Rev Respir Dis 1992;146:285-9., 413Inderlied CB, Kemper CA, Bermudez LE. The Mycobacterium avium complex. Clin Microbiol Rev 1993;6:266-310., 414Packer SJ, Cesario T, Williams JH, Jr. Mycobacterium avium complex infection presenting as endobronchial lesions in immunosuppressed patients. Ann Intern Med 1988;109:389-93.). Hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, para-aortic, or less commonly peripheral) might be identified on physical examination or by radiographic or other imaging studies. Other focal physical findings or laboratory abnormalities might occur in the context of localized disease.

IRIS, initially characterized by focal lymphadenitis with fever, has subsequently been recognized as a systemic inflammatory syndrome with signs and symptoms that are clinically indistinguishable from active MAC infection. Its occurrence with MAC disease is similar to IRIS or paradoxical reactions observed with TB disease (415Phillips P, Kwiatkowski MB, Copland M, Craib K, Montaner J. Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:122-8., 416Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005;41:1483-97., 417Race 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;9098:252-5., 418Cabie A, Abel S, Brebion A, et al. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 1998;17:812-3.). Bacteremia is absent. The syndrome has been described among patients with subclinical ("unmasking IRIS") or established MAC disease and advanced immunosuppression who begin ART and have a rapid and marked increase in CD4+ count (≥100 cells/µL). As with TB, the syndrome might be benign and self-limited or might result in severe unremitting symptoms that are improved with the use of systemic anti-inflammatory therapy or corticosteroids in doses similar to those described for TB-associated IRIS.

Diagnosis

A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms coupled with the isolation of MAC from cultures of blood, lymph node, bone marrow, or other normally sterile tissue or body fluids (408Chaisson RE, Moore RD, Richman DD, Keruly J, Creagh T. Incidence and natural history of Mycobacterium avium-complex infections in patients with advanced human immunodeficiency virus disease treated with zidovudine. Am Rev Respir Dis 1992;146:285-9., 411Owen RL, Roth RI, St. Hilaire RJ, Keren DF. Pseudo Whipple's disease: intestinal infection with Mycobacterium avium-intracellulare (M.avium) in acquired immune deficiency syndrome (AIDS). Gastroenterology 1984;84:1267., 419Shanson DC, Dryden MS. Comparison of methods for isolating Mycobacterium avium-intracellulare from blood of patients with AIDS. J Clin Pathol 1988;41:687-90., 420Hafner R, Inderlied CB, Peterson DM, et al. Correlation of quantitative bone marrow and blood cultures in AIDS patients with disseminated Mycobacterium avium complex infection. J Infect Dis 1999;180:438-47.). Species identification should be performed using specific DNA probes, high performance liquid chromatography, or biochemical tests.

Other ancillary studies provide supportive diagnostic information, including AFB smear and culture of stool or tissue biopsy material, radiographic imaging, or other studies aimed at isolation of organisms from focal infection sites.

Preventing Exposure

MAC organisms commonly contaminate environmental sources (e.g., food and water). Available information does not support specific recommendations regarding avoidance of exposure.

Preventing Disease
Initiating Primary Prophylaxis

HIV-infected adults and adolescents should receive chemoprophylaxis against disseminated MAC disease if they have a CD4+ count of <50 cells/µL (AI). Azithromycin (421Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392-8.) or clarithromycin (399Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289-97., 422Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 1996;335:384-91.) are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis, is associated with a higher rate of adverse effects than either drug alone, and should not be used (EI) (399Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289-97.). The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a survival difference compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI) (421Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392-8.). Azithromycin and clarithromycin also each confer protection against respiratory bacterial infections (BII). If azithromycin or clarithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease, although drug interactions might complicate the use of this agent (BI) (423CDC. TB/HIV Drug Interactions. www.cdc.gov/tb/tb_hiv_Drugs/rifabutin.htm. Last accessed December 22, 2008., 424US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://AIDSinfo.nih.gov.). Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC. Because treatment with rifabutin could result in RIF resistance among persons who have active TB, active TB also should be excluded before rifabutin is used for prophylaxis.

Although detecting MAC organisms in the respiratory or gastrointestinal tract might predict disseminated MAC infection, no data are available regarding efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin, or other drugs among asymptomatic patients harboring MAC organisms at these sites in the presence of a negative blood culture. Therefore, routine screening of respiratory or gastrointestinal specimens for MAC is not recommended (DIII).

Discontinuing Primary Prophylaxis

Primary MAC prophylaxis should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >100 cells/µL for ≥3 months (AI). Two randomized, placebo-controlled trials and observational data have demonstrated that such patients can discontinue primary prophylaxis with minimal risk for acquiring MAC disease (126, 425El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000; 342:1085-92., 426Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:493-503., 427Furrer H, Telenti A, Rossi M, Ledergerber B. Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy: the Swiss HIV Cohort Study. AIDS 2000;14:1409-12., 428Brooks JT, Song R, Hanson DL, et al. Discontinuation of primary prophylaxis against Mycobacterium avium complex infection in HIV-infected persons receiving antiretroviral therapy: observations from a large national cohort in the United States, 1992-2002. Clin Infect Dis 2 005;41:549-53.). Discontinuing primary prophylaxis among patients who meet these criteria is recommended to reduce pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Primary prophylaxis should be reintroduced if the CD4+ count decreases to <50 cells/µL (AIII).

Treatment of Disease

Initial treatment of MAC disease should consist of two or more antimycobacterial drugs to prevent or delay the emergence of resistance (AI) (400Benson CA, Williams PL, Currier JS, et al. 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;37:1234-43., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22., 429Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994;121:905-11., 430May T, Brel F, Beuscart C, et al. Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium. Clin Infect Dis 1997;25:621-9., 431Gordin 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 (MAC). Clin Infect Dis 1999;28:1080-5., 432Dube MP, Sattler FR, Torriani FJ, et al. A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. J Infect Dis 1997;176:1225-32., 433Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999;29:125-33., 434Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis 1998;178:1446-9., 435Ward TT, Rimland D, Kauffman C, et al. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Clin Infect Dis 1998;27:12 78-85., 436Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis 2000;31:1245-52.). Clarithromycin is the preferred first agent (AI); it has been studied more extensively than azithromycin in patients with AIDS and appears to be associated with more rapid clearance of MAC from the blood (400Benson CA, Williams PL, Currier JS, et al. 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;37:1234-43., 429Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994;121:905-11., 431Gordin 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 (MAC). Clin Infect Dis 1999;28:1080-5., 435Ward TT, Rimland D, Kauffman C, et al. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Clin Infect Dis 1998;27:12 78-85., 436Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis 2000;31:1245-52., 437Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996;335:377-83.). However, azithromycin can be substituted for clarithromycin when drug interactions or clarithromycin intolerance preclude the use of clarithromycin (AII). Testing MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for all patients (BIII) (438Griffith DE, Aksamit T, Brown-Elliott BA, et al. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416., 439Gardner EM, Burman WJ, DeGroote MA, et al. Conventional and molecular epidemiology of macrolide resistance among new Mycobacterium avium complex isolates recovered from HIV-infected patients. Clin Infect Dis 2005;41:1041-4.).

EMB is the recommended second drug (AI). Some clinicians add rifabutin as a third drug (CI). One randomized clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and EMB improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance (400Benson CA, Williams PL, Currier JS, et al. 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;37:1234-43., 431Gordin 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 (MAC). Clin Infect Dis 1999;28:1080-5.) in persons with AIDS and disseminated MAC disease. These studies were completed before the availability of effective ART. The addition of a third or fourth drug should be considered in persons with advanced immunosuppression (CD4+ count <50 cells/µL), high mycobacterial loads (>2 log10 colony forming units/mL of blood), or in the absence of effective ART, settings in which mortality is increased and emergence of drug resistance is most likely (CIII). On the basis of data in non-HIV-infected patients, the third or fourth drug might include an injectable agent such as amikacin or streptomycin (CIII) (438Griffith DE, Aksamit T, Brown-Elliott BA, et al. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416.).

Patients who have disseminated MAC disease and have not been treated previously with or are not receiving effective ART should generally typically have ART withheld until after the first 2 weeks of antimycobacterial therapy have been completed to reduce risk for drug interactions, pill burden, and complications associated with the occurrence of IRIS (CIII). If ART has already been instituted, it should be continued and optimized unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

A repeat blood culture for MAC should be obtained 4-8 weeks after initiating antimycobacterial therapy only for patients who fail to have a clinical response to their initial treatment regimen. Improvement in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within 2-4 weeks after initiation of appropriate therapy; however, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed.

Adverse effects with clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. Doses of clarithromycin >1 g/day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used (EI) (440Abbot Laboratories: Clarithromycin (biaxin) (package insert). Abbot Park, IL: Abbot Laboratories, 1995.). Rifabutin doses of ≥450 mg/day have been associated with higher risk for adverse drug interactions when used with clarithromycin or other drugs that inhibit cytochrome P450 isoenzyme 3A4 and might be associated with a higher risk for experiencing uveitis, arthralgias, or other adverse drug reactions (441Shafran SD, Deschenes J, Miller M, Phillips P, Toma E. Uveitis and pseudojaundice during a regimen of clarithromycin, rifabutin, and ethambutol. N Engl J Med 1994;330:438-9., 442Hafner R, Bethel J, Power M, et al. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin in human immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother 1998;42:631-9.).

Persons who develop moderate to severe symptoms typical of IRIS during ART, should receive initial treatment with nonsteroidal, anti-inflammatory agents (CIII). If IRIS symptoms do not improve, short-term (4-8 weeks) systemic corticosteroid therapy, in doses equivalent to 20-40 mg of oral prednisone daily, has been successful in reducing symptoms and morbidity (CIII) (416Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005;41:1483-97., 443Graves M, Salvato P, Thompson C. MAIC and the effect of prednisone on disease progression in AIDS patients. Presented at the 11th International Conference on AIDS, Vancouver, Canada: July 7-12, 1996., 444Wormser GP, Horowitz H, Dworkin B. Low-dose dexamethasone as adjunctive therapy for disseminated Mycobacterium avium complex infections in AIDS patients. Antimicrob Agents Chemother 1994;38:2215-7.).

Rifabutin should not be administered to patients receiving certain PIs and NNRTIs because the complex interactions have been incompletely studied and the clinical implications of those interactions are unclear (423CDC. TB/HIV Drug Interactions. www.cdc.gov/tb/tb_hiv_Drugs/rifabutin.htm. Last accessed December 22, 2008., 424US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://AIDSinfo.nih.gov.). PIs can increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or PIs can be made on the basis of existing data. Efavirenz can induce metabolism of clarithromycin. This can result in reduced serum concentration of clarithromycin but increased concentration of the 14-OH active metabolite of clarithromycin. Although the clinical significance of this interaction is unknown, the efficacy of clarithromycin for MAC prophylaxis could be reduced because of this interaction. Azithromycin metabolism is not affected by the cytochrome P450 (CYP450) system; azithromycin can be used safely in the presence of PIs or NNRTIs without concerns of drug interactions.

Management of Treatment Failure

Treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia after 4-8 weeks of treatment. Repeat testing of MAC isolates for susceptibility to clarithromycin or azithromycin is recommended for patients who relapse after an initial response. The majority of patients who experience failure of clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time MAC disease was detected (400Benson CA, Williams PL, Currier JS, et al. 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;37:1234-43., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22., 429Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994;121:905-11., 445Heifets L, Lindholm LP, Libonati J. Radiometric broth macrodilution method for determination of minimal inhibitory concentrations (MIC) with Mycobacterium avium complex isolates: proposed guidelines. Denver, CO:National Jewish Center for Immunology and Respiratory Medicin e, 1993., 446Heifets L, Mor N, Vanderkolk J. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother 1993;37:2364-70.).

Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multi-drug regimen. The regimen should consist of at least two new drugs not used previously, to which the isolate is susceptible and selected from among the following: EMB, rifabutin, amikacin, or a quinolone (moxifloxacin, ciprofloxacin, or levofloxacin), although data supporting a survival or microbiologic benefit when these agents are added have not been compelling (CIII) (33Masur H. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. N Engl J Med 1993; 329:898-904., 405Benson CA. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1994;18(Suppl 3):S237-42., 406Benson CA. Disease due to the Mycobacterium avium complex in patients with AIDS: epidemiology and clinical syndrome. Clin Infect Dis 1994;18(Suppl 3):S218-22., 430May T, Brel F, Beuscart C, et al. Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium. Clin Infect Dis 1997;25:621-9., 431Gordin 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 (MAC). Clin Infect Dis 1999;28:1080-5., 432Dube MP, Sattler FR, Torriani FJ, et al. A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. J Infect Dis 1997;176:1225-32., 433Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999;29:125-33., 434Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis 1998;178:1446-9., 437Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996;335:377-83., 447Kemper CA, Meng TC, Nussbaum J, et al. Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen: rifampin, ethambutol, clofazimine, and ciprofloxacin. Ann Intern Med 1992;116:466-72., 448Chaisson 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;11:311-7., 449Chiu J, Nussbaum J, Bozzette S, et al. Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. Ann Intern Med 1990;113:358-61., 450Rodriguez Diaz JC, Lpez M, Ruiz M, Royo G. In vitro activity of new fluoroquinolones and linezolid against non-tuberculous mycobacteria. Int J Antimicrobial Agents 2003;21:585-8.). On the basis of data related to non-HIV-infected patients being treated for MAC, an injectable agent such as amikacin or streptomycin should be considered (CIII) (438Griffith DE, Aksamit T, Brown-Elliott BA, et al. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416.). Whether continuing clarithromycin or azithromycin despite resistance provides additional benefit is unknown. Clofazimine should not be used because randomized trials have demonstrated lack of efficacy and an association with increased mortality (EII) (430May T, Brel F, Beuscart C, et al. Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium. Clin Infect Dis 1997;25:621-9., 432Dube MP, Sattler FR, Torriani FJ, et al. A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. J Infect Dis 1997;176:1225-32., 448Chaisson 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;11:311-7.). Other second-line agents (e.g., ethionamide, thiacetazone [not available in the United States], or cycloserine) have been anecdotally combined with clarithromycin and azithromycin as salvage regimens. However, their role in this setting is not well defined. Among patients whose initial treatment for MAC disease has not been successful or who have antimycobacterial drug-resistant MAC disease, optimizing ART is an important adjunct to second-line or salvage therapy for MAC disease (AIII).

Adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for use (DIII).

Preventing Recurrence

Adult and adolescent patients with disseminated MAC disease should receive lifelong secondary prophylaxis (chronic maintenance therapy) (AII), unless immune reconstitution occurs as a result of ART (425El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000; 342:1085-92., 426Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:493-503.).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Patients are at low risk for recurrence of MAC when they have completed a course of ≥12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase (e.g., >6 months) in their CD4+ counts to >100 cells/µL after ART. Although the numbers of patients who have been evaluated remain limited and recurrences could occur, based on the limited number of patients who have been evaluated and the inferences from more extensive data indicating the safety of discontinuing secondary prophylaxis for other OIs, discontinuing chronic maintenance therapy is reasonable (BII) (121El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998;339:1889-95., 426Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:493-503., 434Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis 1998;178:1446-9., 451Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex. J Infect Dis 2003;187:1046-52.). Secondary prophylaxis should be reintroduced if the CD4+ count decreases to <100 cells/µL (AIII).

Special Considerations During Pregnancy

Chemoprophylaxis for MAC disease should be administered to pregnant women the same as for nonpregnant women and adolescents (AIII). Because of an increased risk for birth defects evident in certain animal studies, clarithromycin is not recommended as the first-line agent for prophylaxis or treatment of MAC in pregnancy (DIII). Two studies, each with slightly more than 100 women with first-trimester exposure to clarithromycin, did not demonstrate an increase in or specific pattern of defects, although an increased risk for spontaneous abortion was noted in one study (452Einarson A, Phillips E, Mawji F, et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15:523-5., 453Drinkard CR, Shatin D, Clouse J. Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations. Pharmacoepidemiol Drug Saf 2000;9:549-56.). Azithromycin did not produce defects in animal studies, but experience for use in humans during the first trimester is limited. Azithromycin is recommended for primary prophylaxis in pregnancy (BIII). For secondary prophylaxis (chronic maintenance therapy), azithromycin plus EMB are the preferred drugs (BIII).

Diagnostic considerations and indications for treatment of pregnant women are the same as for nonpregnant women. On the basis of animal data discussed previously, azithromycin is preferred over clarithromycin as the second agent with EMB (BIII). Use of EMB should minimize concerns regarding drug interactions, allowing initiation of ART as soon as possible during pregnancy to decrease the risk for perinatal transmission of HIV. Pregnant women whose treatment failed on their primary regimen should be managed in consultation with infectious disease and obstetrical specialists.

Prophylaxis to prevent first episode of opportunistic disease: Disseminated Mycobacterium avium complex (MAC) disease
IndicationFirst choiceAlternative
Excerpted from Table 1
Definitions of abbreviations: PO = by mouth; bid = twice daily
CD4+ count <50 cells/µL - after ruling out active MAC infection (AI)Azithromycin 1,200 mg PO once weekly (AI); or

Clarithromycin 500 mg PO bid (AI); or

Azithromycin 600 mg PO twice weekly (BIII)

transparent gifgrey bulletRFB 300 mg PO daily (BI) (dosage adjustment based on drug-drug interactions with ART); rule out active TB before starting RFB
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Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Disseminated Mycobacterium avium complex (MAC) disease
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Definitions of abbreviations: PO = by mouth; bid = twice daily; IM = intramuscular; IV = intravenous
Preferred therapy for disseminated MAC
At least 2 drugs as initial therapy with
transparent gifgrey bulletClarithromycin 500 mg PO bid (AI) + ethambutol 15 mg/kg PO daily (AI)
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Addition of rifabutin may also be considered:
transparent gifgrey bulletRifabutin 300 mg PO daily (dosage adjusted may be necessary based on drug-drug interactions) (CI)
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Alternative therapy for disseminated MAC (e.g., when drug interactions or intolerance precludes the use of clarithromycin)
transparent gifgrey bulletAzithromycin 500-600 mg + ethambutol 15 mg/kg PO daily (AII)
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Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4+ count <50 cells/µL), high mycobacterial loads (>2 log CFU/mL of blood), or in the absence of effective ART (CIII)
transparent gifgrey bulletAmikacin 10-15 mg/kg IV daily; or
transparent gif
transparent gifgrey bulletStreptomycin 1 gm IV or IM daily; or
transparent gif
transparent gifgrey bulletCiprofloxacin 500-750 mg PO bid; or
transparent gif
transparent gifgrey bulletLevofloxacin 500 mg PO daily; or
transparent gif
transparent gifgrey bulletMoxifloxacin 400 mg PO daily
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Testing of susceptibility to clarithromycin and azithromycin is recommended (BIII)

In ART-naïve patients, may consider withholding initiation of ART until after 2 weeks of MAC treatment to lessen drug interactions, reduce pill burden, and potentially lower occurrence of IRIS (CIII)

NSAIDs may be used for patients who experience moderate to severe symptoms attributed to ART-associated IRIS (CIII)

If immune reconstitution inflammatory syndrome (IRIS) symptoms persist, short term (4-8 weeks) of systemic corticosteroid (equivalent to 20-40 mg of prednisone) can be used (CIII)

Chronic maintenance therapy (secondary prophylaxis)
transparent gifgrey bulletSame as treatment drugs and regimens
transparent gif
Duration: Lifelong therapy (AII), unless in patients with sustained immune recovery on ART (BII)

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