Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Disseminated Mycobacterium avium Complex Disease Epidemiology      Organisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment.  M. avium is the etiologic agent in >95% of patients with AIDS who develop disseminated MAC disease . An estimated 7%--12% of adults have been previously infected with MAC, although rates of disease vary in different geographic locations .Although certain epidemiologic associations have been identified, no environmental exposure or behavior has been consistently associated with the subsequent development of MAC disease in susceptible persons. The mode of transmission for MAC infection is thought to be through inhalation, ingestion, or inoculation through respiratory or gastrointestinal tract portals of entry. Household or close contacts of those with MAC disease do not appear to be at increased risk for experiencing disease, and person-to-person transmission is unlikely. In the absence of effective combination ART or chemoprophylaxis in those with advanced immunosuppression, the incidence of disseminated MAC disease among persons with AIDS ranges from 20%--40% . For those with a CD4+ T lymphocyte count <100 cells/µL who are receiving effective prophylaxis or those who have responded to ART with a sustained increase in CD4+ T lymphocyte count to levels >100--200 cells/µL, the overall incidence rate has been estimated at 2 cases per 100 person-years. Most cases of MAC disease occur among persons with CD4+ T lymphocyte counts <50 cells/µL. Other factors that are associated with increased susceptibility to MAC disease are high plasma HIV-1 RNA levels (>100,000 copies/mL), previous opportunistic infections (particularly CMV disease), 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 MAC disease among patients with AIDS, in the absence of ART, is generally a disseminated multiorgan infection . Early symptoms might be minimal and might precede detectable intermittent or continuous mycobacteremia by several weeks. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain. Immune reconstitution inflammatory syndrome, characterized by focal lymphadenitis with fever, is a systemic inflammatory response with signs and symptoms that are clinically indistinguishable from active infection and is similar to paradoxical reactions observed with TB disease . Bacteremia is absent. The syndrome has been described among patients with subclinical or established MAC disease and advanced immunosuppression who begin ART and have a rapid and marked increase in CD4+ T lymphocyte count (>100 cells/µL). This syndrome might be benign and self-limited or might be severe and require systemic anti-inflammatory therapy to alleviate clinical symptoms. Other localized manifestations of MAC disease have been reported most commonly among persons who are receiving and who 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 stage of HIV-1 disease) and elevated liver alkaline phosphatase .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 those localized disease syndromes previously described.   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, bone marrow, or other normally sterile tissue or body fluids . Use of an Isolator® (Wampole Laboratories, Cranbury, New Jersey) or a similar blood culture system and inoculation of blood into Bactec 12B liquid medium, or direct inoculation of specimens into Bactec 13A bottles (Bactec; Becton Dickinson, Sparks, Maryland), followed by radiometric detection of growth, are recommended . 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 biopsy material obtained from tissues or organs, radiographic imaging of the abdomen or mediastinum for detection of lymphadenopathy, or other studies aimed at isolation of organisms from focal infection sites.   Treatment Recommendations Initial treatment of MAC disease should consist of two antimycobacterial drugs to prevent or delay the emergence of resistance (AI). Clarithromycin is the preferred first agent (AI); it has been studied more extensively than azithromycin and appears to be associated with more rapid clearance of MAC from the blood . However, azithromycin can be substituted for clarithromycin when drug interactions or clarithromycin intolerance preclude the use of clarithromcyin (AII). Ethambutol is the recommended second drug  (AI). Some clinicians would add rifabutin as a third drug (CI). One randomized clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and ethambutol for the treatment of disseminated MAC disease improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance.    These studies were completed before the availability of effective ART. The addition of rifabutin should be considered in persons with advanced immunosuppression (CD4+ T lymphocyte 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 are most likely (CIII). If rifabutin cannot be used because of drug interactions or intolerance, a third or fourth drug may be selected from among either the fluoroquinolones (ciprofloxacin or levofloxacin) or parenteral amikacin, although data supporting a survival or microbiologic benefit when these agents are added have not been compelling  (CIII). Patients who have had disseminated MAC disease diagnosed and who have not previously been treated with or are not receiving potent ART should generally have ART initiated simultaneously or within 1-2 weeks of initiation of antimycobacterial therapy for MAC disease (CIII). If ART has already been instituted, it should be continued and optimized for patients with disseminated MAC disease, unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs (CIII). Persons who have symptoms of moderate-to-severe intensity because of an immune recovery inflammatory syndrome in the setting of ART should receive treatment initially with nonsteroidal, anti-inflammatory agents (CIII). If symptoms fail to improve, short-term (4--8 weeks) systemic corticosteroid therapy, in doses equivalent to 20--40 mg of oral prednisone QD, has been successful  (CIII).   Monitoring and Adverse Events 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. A repeat blood culture for MAC should be obtained 4-8 weeks after initiation of antimycobacterial therapy for patients who fail to have a clinical response to their initial treatment regimen (i.e., little or no reduction in fever or systemic symptoms). 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 per day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used  (EI). 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 or other adverse drug reactions (259,260).   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. Testing of MAC isolates for susceptibility to clarithromycin and azithromycin is recommended for patients who fail to microbiologically respond to initial therapy, relapse after an initial response, or develop MAC disease while receiving clarithromycin or azithromycin for prophylaxis; testing for susceptibility to clarithromycin, azithromycin, ethambutol, and rifabutin might be helpful in this setting, although the predictive value for ethambutol and rifabutin with regard to response to therapy has not been established. The majority of patients who failed clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time MAC disease was detected . Bactec® radiometric broth macrodilution is the recommended method for testing M. avium for susceptibility to antimicrobial agents . Minimum inhibitory concentrations (MICs) of >32 µg/mL for clarithromycin or >256 µg/mL for azithromycin are the suggested thresholds for determination of resistance based on the Bactec® method for radiometric susceptibility testing . Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multidrug regimen consisting of at least two new drugs not previously used and to which the isolate is susceptible from among the following: ethambutol, rifabutin, ciprofloxacin or levofloxacin, or amikacin (CIII). Whether continuing clarithromycin or azithromycin in the face of resistance provides additional benefit is unknown (CIII). Clofazimine should not be used on the basis of the lack of efficacy demonstrated in randomized trials and the association with increased mortality  (EII). Other second-line agents (e.g., ethionamide, thiacetazone [not available in the United States], or cycloserine) have been anecdotally combined with these drugs as salvage regimens. However, their role in this setting is not well defined. Among patients who have failed initial treatment for MAC disease 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). Interferon-gamma, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, and interleukin-12, either alone or in combination with other cytokines, appear to inhibit intracellular replication or enhance in vitro intracellular killing of M. avium. Use of these immunomodulators would be a logical adjuvant treatment for those who fail conventional antimycobacterial therapy.   Prevention of 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 . 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+ T lymphocyte counts to >100 cells/µL after ART. Although the numbers of patients who have been evaluated remain limited and recurrences could occur, on the basis of these observations and on inference from more extensive data indicating the safety of discontinuing secondary prophylaxis for other opportunistic infections during advanced HIV-1 disease, discontinuing chronic maintenance therapy among such patients is reasonable  (BII). Certain health-care providers recommend obtaining a blood culture for MAC, even for asymptomatic patients, before discontinuing therapy to substantiate that disease is no longer active, but it is not clear how often a positive culture will be obtained in such patients. Secondary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100 cells/µL (AIII).   Special Considerations During Pregnancy Diagnostic considerations and indications for treatment are the same as among nonpregnant adults. Azithromycin is preferred over clarithromycin as the second agent with ethambutol or rifabutin because of the occurrence of birth defects in mice and rats associated with clarithromycin  (BIII). Limited data among humans do not indicate an increased risk for defects among 122 women taking clarithromycin during the first trimester, although an increased rate of spontaneous abortions was noted. Limited data are available on the use of azithromycin during the first trimester in humans .