The patient in this case had blood cultures that turned positive for Mycobacterium avium complex (MAC) 8 days after they were drawn, and the patient was started on clarithromycin (Biaxin) and ethambutol (Myambutol). The following discussion will focus on the clinical features, diagnosis, and treatment of disseminated MAC. The epidemiology, transmission, and primary prevention of MAC are discussed in detail in the case Prophylaxis for Mycobacterium avium complex.
Clinical and Laboratory Features of Disseminated MAC
Mycobacterium avium complex organisms enter through the lung or gastrointestinal tract and can rapidly disseminate in persons with advanced immune suppression.[,] Patients at risk for MAC have a weak immune response to the organisms and experience minimal tissue destruction and MAC-related clinical manifestations result from the huge burden of organisms, which interfere with tissue function and alter cytokine production. Patients with disseminated MAC typically have CD4 counts less than 50 cells/mm3 and present with non-specific clinical features, including fatigue, fever, fatigue, weight loss, diarrhea, and abdominal pain (Figure 1).[,] Less frequently, patients develop diarrhea or symptoms of extrahepatic obstruction. Common abnormal laboratory studies include anemia, increased alkaline phosphatase (often with normal bilirubin, normal hepatic transaminases levels), and increased serum lactate dehydrogenase level.[,,] The anemia associated with disseminated MAC predominantly results from a failure in the maturation of red blood cell precursors, presumably mediated by a soluble factor in the serum that suppresses erythroid progenitor cells. Other factors may play a role in the MAC-associated anemia. Abdominal computed tomographic (CT) scan abnormalities may include multiple large retroperitoneal and mesenteric lymph nodes, hepatomegaly, splenomegaly, and thickened small bowel wall. Although disseminated MAC is rarely a direct cause of death, it is an independent predictor of increased mortality. A normal abdominal CT scan does not rule out the diagnosis of disseminated MAC.
Diagnosis of Disseminated MAC
The definitive diagnosis of disseminated MAC is usually made by isolating the organism from a normally sterile body site. Use of mycobacterial blood cultures (BACTEC or DuPont isolator system) to isolate MAC has become the preferred method of diagnosis, with most studies showing a greater than 90% yield with two blood cultures. With disseminated MAC, the laboratory will usually detect mycobacterial growth by day 14, at which point it can rapidly identify the species using DNA probes. Although there are rare reports in which a MAC was diagnosed by culture of a bone marrow aspirate after blood culture failed to grow MAC, performing a bone marrow aspirate or biopsy is unnecessary in most cases. Stained bone marrow samples can rapidly reveal the presence of acid-fast bacilli, but this test is not specific for MAC. Although a positive culture from stool or respiratory system indicates an increased risk of developing disseminated infection, it is not diagnostic of disseminated infection.
Treatment for Disseminated MAC Infection
Treatment of disseminated MAC consists of combination therapy with at least two agents with potent activity against MAC. Combinations therapy that includes either clarithromycin (Biaxin) or azithromycin (Zithromax) improves response rates when compared with therapies without a macrolide. The 2013 guidelines for the prevention and treatment of opportunistic infections recommends treating disseminated MAC disease with either clarithromycin plus ethambutol or azithromycin plus ethambutol; adding a third agent (rifabutin, an aminoglycoside, or fluoroquinolone) should be considered in patients who have advanced immunosuppression (CD4 count less than 50 cells/mm3), a high mycobacterial load (greater than 2 log CFU/ml blood), or the absence of antiretroviral therapy as part of the overall treatment plan (Figure 2). Initial treatment regimens should not include either clofazimine or amikacin. There are no clear guidelines regarding the management of clarithromycin- or azithromycin-resistant MAC, and expert advice should be obtained in this situation. In an early study clarithromycin monotherapy sterilized blood in most patients, but relapse with clarithromycin-resistant MAC was common. In a randomized trial that clearly established the importance of macrolides in the treatment of MAC, Canadian investigators treated 229 patients with disseminated MAC and found the 3-drug regimen of clarithromycin, ethambutol, and rifabutin (Mycobutin) led to more frequent and more rapid resolution of bacteremia than the 4-drug regimen of ethambutol, rifampin, clofazimine (Lamprene), and ciprofloxacin (Cipro). Several studies have shown good overall response rates with azithromycin-containing regimens.[,] In a comparative trial of azithromycin and clarithromycin as part of combined therapy for MAC, there was a trend toward better response rates and fewer relapses with clarithromycin, but these differences were not statistically different (Figure 3). Most regimens for disseminated MAC have also included ethambutol after a clinical trial showed lower relapse relates with inclusion of ethambutol in a treatment regimen. In a trial of clarithromycin plus clofazimine, with or without ethambutol, patients who received ethambutol had much lower relapse rates (Figure 4). Whether rifabutin provides significant benefit remains unclear based on conflicting results from two trials.[,] In one trial, patients who received clarithromycin, ethambutol, and rifabutin had better survival than those who received clarithromycin and ethambutol. In the other trial, in which patients received clarithromycin and ethambutol with or without rifabutin, the use of rifabutin did not improve bacterial response or survival, but did decrease the risk of developing clarithromycin-resistant MAC. Clofazimine does not provide any benefit when added to a standard regimen of clarithromycin plus ethambutol and may increase mortality.[,] Similarly, amikacin (Amikin) does not improve responses.
Management of Immune Reconstitution-Associated MAC
Multiple reports have described patients who developed fever and localized MAC infection (with negative MAC blood cultures) after starting antiretroviral therapy.[,,] These patients generally have a very low CD4 cell count that rapidly increases in response to antiretroviral therapy; clinical manifestations may include mesenteric lymphadenitis, focal soft tissue lymphadenitis, osteomyelitis, pneumonitis.[,,,] Biopsies typically demonstrate a marked localized inflammatory response with a paucity of organisms. Some of these cases likely represent an unmasking of a subclinical infection caused by an upregulation in immunity following antiretroviral therapy. In the setting of symptomatic localized disease, clinicians have used corticosteroids along with standard MAC therapy, but rapid tapering of the corticosteroids has proven difficult. The effectiveness and optimal dosing of corticosteroids in this setting has not clearly been established. Nevertheless, based on small reports and expert opinion, a suggested approach is to use prednisone at a dose of 1.0 to 1.5 mg/kg per day for 2 weeks, followed by 0.75 mg/kg for 2 weeks, with a gradual taper in the dose as tolerated during the final 2 weeks. Some patients will require a more prolonged taper.
Chronic Maintenance Therapy (Secondary Prophylaxis)
Chronic maintenance therapy to prevent recurrence of disseminated MAC consists of the same recommended regimen used to treat acute disseminated MAC, given at the same doses (Figure 2). Several studies have shown that patients on treatment for disseminated MAC who have a sustained response to antiretroviral therapy have a low risk of developing recurrent disseminated MAC if they discontinue maintenance therapy for MAC.[,,] In a retrospective, multi-center Canadian study, 52 patients who had received therapy for disseminated MAC discontinued therapy following immunologic recovery with antiretroviral therapy and at a median of 20 months after stopping therapy, only 1 of 52 patients had recurrence of MAC; at the time MAC therapy was stopped, most patients had a CD4 count greater than 100 cells/mm3 (median 230 cells/mm3), all had suppressed HIV RNA levels in response to antiretroviral therapy, and all had received extensive therapy for MAC (median 32 months). In a prospective, non-randomized ACTG study, 48 patients with immunologic responses to antiretroviral therapy subsequently discontinued MAC therapy and 47 of the 48 remained free of MAC; at the time of discontinuation of MAC therapy, the patients were asymptomatic for MAC, had received at least 16 weeks of antiretroviral therapy, and had CD4 counts greater than 100 cells/mm3 (median CD4 count was 240 cells/mm3). In a retrospective French study, 26 patients with a history of disseminated MAC discontinued maintenance therapy, and 4 of the 26 relapsed. The relapse rate for MAC was higher in this study, but the median CD4 count at the time MAC therapy was discontinued was lower (105 cells/mm3) than in other studies and fewer than 50% of the patients had undetectable HIV RNA levels. Based on these studies, the 2013 guidelines for prevention and treatment of opportunistic infections recommend that it is reasonable to discontinue chronic maintenance MAC therapy if the patient has (1) completed at least 12 months of treatment for MAC, (2) they have no signs or symptoms to suggest active MAC infection, and (3) the CD4 count has increased above 100 cells/mm3 for at least 6 months in response to antiretroviral therapy.