DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX INFECTION
Before the AIDS era, disease caused by Mycobacterium avium and Mycobacterium intracellulare was relatively rare. Infection occurred in patients who presented with chronic, slowly progressive, cavitary pulmonary disease. Disseminated disease was even rarer (<100 cases reported) and was seen in those with underlying defects in cellular immunity. Since the beginning of the AIDS epidemic, Mycobacterium avium-intracellulare complex (MAC) infection has been seen in 23% of patients infected with HIV. This percentage reflects underdiagnosis, as MAC disease has been noted at autopsy in more than 50% of patients with HIV disease.
The organism has been recovered from soil, water, air, and animals such as poultry. The portal of entry of the organism is likely the gastrointestinal or respiratory tract. Because the organism is ubiquitous, methods to prevent its acquisition are not likely to be found. The major risk factor predisposing patients to infection is a low CD4-cell count. Disseminated MAC infection occurs with CD4-lymphocyte counts below 100/mm3. Evidence suggests that MAC disease results from primary acquisition rather than reactivation. When dissemination occurs, the main sites affected are the blood, bone marrow, liver, spleen, and lymph nodes; however, the organism has been recovered from almost every site in the body. Pathologically, the tissue reveals massive numbers of acid-fast bacilli (1010 colony-forming units per gram) with a minimal inflammatory response or evidence of tissue destruction. Granulomas, if present, are poorly formed. Phagocytosis of the organisms occurs, but there appears to be little macrophage-mediated killing.
Most laboratories are unable to distinguish M. avium from M. intracellulare and report the isolates as MAC. However, nucleic acid probes show that the majority of isolates infecting AIDS patients are M. avium. There are also nucleic acid probes for Mycobacterium tuberculosis complex, which consists of M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti. Unlike M. tuberculosis, which is niacin-positive, MAC is niacin-negative. When the BACTEC system is used, the growth of isolates of the M. tuberculosis complex are inhibited by a compound, p-nitro-a-acetylamino-b-hydroxypropiophenone (NAP), in contrast to isolates of MAC, which are not inhibited by its presence. Mycobacteria can be recovered from blood cultures by using a lysis-centrifugation system (Isolator) or the radiometric blood culture system (BACTEC). With the BACTEC system, the time to culture positivity is usually 5 to 30 days, depending on the magnitude of the bacteremia. The number of colony-forming units of mycobacteria in the blood usually ranges between 101 and 104/mL, whereas in tissue, up to 1010/g have been noted.
Disseminated MAC infection should be suspected in any HIV patient with a CD4-cell count below 100/mm3 and systemic symptoms of fever, malaise, and weight loss. Anemia is present, and an increased need for blood transfusions is reported. In one study, disseminated MAC infection (31.9%) was the most frequent cause of fever of unknown origin, followed by M. tuberculosis infection (26.2%) and Pneumocystis carinii infection (9.5%). Chronic diarrhea and abdominal pain occur when organisms invade the colon. Chronic malabsorption has been described, with pathologic changes in the small intestine resembling those of Whipple's disease. Extrahepatic biliary obstruction secondary to periportal lymphadenopathy also occurs. The lungs can be involved, but the symptoms are usually not prominent. On physical examination, hepatosplenomegaly is often present. Abdominal computed tomography in patients with MAC infection shows lymphadenopathy (86%), hepatic (45%) and splenic (23%) enlargement, and diffuse thickening of the jejunal wall (18%).
The diagnosis of disseminated MAC infection depends on detecting the organism by culture of blood, bone marrow, or any other sterile body site. The diagnosis may also be established by obtaining a culture from the liver, spleen, or a lymph node. Positive cultures of sputum and stool may indicate disseminated disease or reflect colonization. Similarly, a smear of sputum, bronchial washings, or stool that is positive for acid-fast bacilli may indicate disseminated disease or colonization. In patients with disseminated disease, two blood cultures will detect 70% to 98% of cases. Occasionally, a buffy coat smear for acid-fast bacilli will be positive for mycobacteria. In a patient with pulmonary disease, a smear that is positive for acid-fast bacilli is more likely to represent M. tuberculosis than MAC. In patients with unexplained fever, a liver or bone marrow biopsy may yield a diagnosis more rapidly than a blood culture by demonstrating acid-fast bacilli on smear (Table 87-1).
Table 87-1. Interpretation of positive test results for Mycobacterium avium-intracellulare complex
The median survival of untreated patients with MAC infection was 4 months, compared with 11 months for matched controls. In another study of the natural history of MAC infection, severe anemia and death were associated with disseminated MAC infection.
Therapy of MAC infection is difficult because the organisms are resistant to the first-line agents: isoniazid, rifampin, pyrazinamide, and streptomycin. Drugs capable of inhibiting the organisms include rifabutin, ethambutol, clarithromycin, ciprofloxacin, ofloxacin, azithromycin, and amikacin. Various combinations of these drugs have been used, including regimens containing three or four drugs. To date, the preferred regimen consists of 500 mg of clarithromycin given orally twice daily plus 15 mg of ethambutol per kilogram once daily with or without 300 mg of rifabutin once daily or 500 to 750 mg of ciprofloxacin twice daily. Azithromycin can be given as 500 mg once daily instead of clarithromycin. Also, amikacin can be added to the two- or three-drug regimen in a dose of 10 to 15 mg/kg per day given intramuscularly in two divided doses. A dose of clarithromycin greater than 1 g daily has been associated with increased mortality. Rifabutin was more effective in a higher dose (600 mg/d) than in a lower dose (300 mg/d), but the higher dose was associated with the development of reversible uveitis in half the patients. Clofazimine is no longer recommended, as it has been associated with increased mortality. Aspirin or nonsteroidal antiinflammatory drugs can be administered for relief of symptoms. Survival after a diagnosis of MAC infection has increased from 4.5 months without therapy to about 9 months with the macrolide combination therapy. To prevent recurrences, the drugs used for initial therapy should be given as lifelong therapy.
In untreated patients, MAC bacteremia occurred in nearly 20% of patients with CD4-cell counts below 50/mm3 and in only 6% of those with an initial CD4-cell count above 100/mm3. Chemoprophylaxis for MAC infection is now strongly recommended as a standard of care. Before initiation of prophylaxis, patients should be assessed with a tuberculin skin test, chest roentgenography, and one blood culture to exclude active disease caused by M. tuberculosis or MAC.
Azithromycin (1,200 mg given orally once weekly) or clarithromycin (500 mg given orally twice daily) is preferred for chemoprophylaxis. Rifabutin (300 mg orally once daily) can be given as an alternative agent. Either macrolide is superior to rifabutin. In a study, the combination of azithromycin plus rifabutin was superior to either agent alone, but adverse effects, compliance issues, and possible drug interactions limit the use of both drugs together for chemoprophylaxis. One issue is the development of macrolide-resistant isolates in patients taking azithromycin or clarithromycin for prophylaxis. This has not been a serious problem with the use of macrolides because prophylaxis failures are rare. I prefer using azithromycin once weekly for prophylaxis. (N.M.G.)
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