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Pathogen:
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Sites of Infection:
When MAC occurs in non-immunocompromised people, it usually causes infection in the respiratory tract. In patients with AIDS, MAC is frequently disseminated (disseminated MAC or DMAC). Almost any organ system can be involved, especially those with many mononuclear phagocytes (e.g., the liver, spleen and bone marrow).
Nightingale et al. prospectively monitored 1,006 patients with AIDS for the development of MAC bacteremia (culture of MAC from blood; no symptoms of MAC disease). Among patients who survived for 2 years after an AIDS diagnosis, 43% developed MAC bacteremia. The risk of developing MAC bacteremia increased as the CD4 count fell, and most cases occurred in patients with CD4 counts below 100/mm3.
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Diagnosis:
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Treatment
Results:
While few data are available, the Public Health Service recommends that the guidelines outlined above also be applied to children with disseminated MAC.
Interim results from an open, randomized study, of two clarithromycin combination treatments for MAC bacteremia were recently reported (May et al.). Data were available in 123/132 patients enrolled. Patients were randomized to receive either clarithromycin (2,000 mg qd for two months, then 1,000 mg qd) and clofazamine (200 mg qd, then 100 mg qd) or clarithromycin (2,000 mg qd for two months, then 1000 mg qd), rifabutin (450 mg qd), and ethambutol (1,200 mg qd). The median CD4+ count was 14 cells/mm3. At 2 months, the success rate (defined as alive with decreased fever and negative blood cultures) was 36/49 (53%) for patients in the clarithromycin and clofazimine group and 32/46 (70%) in the triple combination group (P =0.51). At 6 months, the success rate was 7/25 (28%) and 12/26 (46%), respectively (P <0.51). Eighteen patients experienced relapse (Positive for MAC bacteremia) between months 2 and 6 in the two drug combination group (14 with resistance to clarithromycin) versus 6 relapses in the triple combination group (2 resistant to clarithromycin) (P <0.01). There was no difference in survival distribution between the two groups.
Chaisson et al. has concluded that the addition of clofazimine to a combination of clarithromycin and ethambutol does not contribute to clinical response and is associated with higher mortality. A total of 106 patients with MAC bacteremia were randomized to receive clarithromycin (500 mg bid) and ethambutol (15 mg/kg/day) either with or without clofazimine (100 mg daily). There was no significant difference in the proportion of patients becoming culture negative. 65% turned negative in the 2-drug combination (median time 58 days) and 54% in the 3-drug combination (median time 63 days). Of concern, however, 38% of patients in the 2-drug combination and 61% of patients in the 3-drug combination died during follow-up (P = 0.03), and time to death was shorter in patients treated with 3 drugs (P <0.01).
A 3-drug combination of ethambutol (800 mg daily), clarithromycin (1,000 mg bid) and clofazimine (100 mg daily) has been shown to be more effective than a 2-drug combination of clarithromycin and clofazimine for the prevention of relapse of MAC bacteremia (Dube et al.). Of 80 patients with positive baseline MAC cultures, 24/35 (69%) receiving the 2-drug combination and 31/45 (69%) in the 3-drug combination responded. Time to microbiologic responses were similar in both groups. There were 8 relapses in the 2-drug arm and 2 relapses in the 3- drug arm. Estimated risk of relapse at 26 weeks were 68% and 5%, respectively (P =0.004). All10 relapse isolates were resistant to clarithromycin. The median time to development of clarithromycin resistance was16 weeks with two drugs and 40 weeks with three drugs (P =0.004). The number of adverse events were similar in the two groups (GI disturbances).
Shafran et al. recently reported the final results of a 16 week open-label trial conducted by the Canadian MAC Study Group. 229 HIV-positive patients with MAC bacteremia were randomized to receive either ciprofloxacin 750 mg twice daily, ethambutol 15 mg/kg/day, rifampin 600 mg/day and clofazimine100 mg/day or clarithromycin 1000 mg twice daily, rifabutin 600 mg/qd and ethambutol 15 mg/kg/day. The rifabutin dose was halved to 300 mg/day after125 patients were randomized, due to the development of uveitis at the 600 mg dose. Data were available in187/229 patients. Proportions of MAC bacteremia clearance at15 weeks were 67/97 (69%) on the 3-drug arm and 26/90 (30%) on the 4-drug 4 arm (P <0.001 ). The proportion clearing was higher in the 3-drug than 4-drug 61% arm at the higher dose of rifabutin (79% vs 22%, P <0.001) and at the lower 4 dose (58% vs 36%, P <0.05). The median survival times were 8.7 months in the 3-drug arm and 5.2 months in the 4-drug arm (P <0.001).The authors concluded that the 3-drug combination was superior terms of clearing bacteremia and survival. The higher dose of rifabutin was more effective than the lower but caused more uveitis. Parenti et al. treated 79 symptomatic HIV patients with disseminated MAC in a randomized study of rifampin 600 mg/day, ciprofloxacin 500 mg bid, clofazimine 100 mg/day and ethambutol 15 mg/kg/day with or without amikacin 10 mg/kg/day. After a 1-2 week observation period, 37 patients were randomized to receive amikacin and 37 patients to matching placebo. The mean CD4+ counts at entry were10 cells/mm3. Median duration of treatment was 12 weeks with a median follow up of 23 weeks. Patients were classified as complete or partial responders on the basis of decreases in clinical symptoms of fever, diarrhea and antipyretic use after 4, 8, and 12 weeks of treatment. At 4 weeks, 33% of patients were randomized to amikacin had a complete or partial response, versus 35% in the placebo group; at 8 weeks reported responses were 62% and 65%, respectively. Quantitative cultures showed no significant difference between the two groups in the decrease of mean CFUs relative to baseline at any visit. There was no statistical difference between the two groups in survival distribution.
Dautzenberg et al. reported results from a twelve week, double-blind placebo controlled trial of rifabutin in combination with ethambutol, clofazimine and isoniazid. 200 patients with disseminated MAC and a median CD4+ count of 10 cells/mm3 were randomized to ethabutol, clofazimine and isoniazid with either placebo or rifabutin (600 mg daily). In the intent-to-treat analysis, MAC bacteremia declined in 46/100 (46%) patients in the rifabutin combination group and in 30/100 (30%) patients in the placebo group.
Chaisson et al. enrolled 154 patients with disseminated MAC in ACTG 157, a dose-comparison study of monotherapy (500, 1,000, or 2,000 mg twice daily) for twelve weeks, The main outcome measure was the median number of colony forming units (CFU) per milliliter of blood. Clarithromycin decreased mycobacterial CFUs from 2.7 to 2.8 log 10/mL of blood at baseline to less than 0 log10/mL during follow-up (P <0.0001). After 2 weeks, patients receiving 500 mg twice daily were less likely to be culture negative than were patients receiving 1,000 or 2,000 mg twice daily (11% compared with 33% or 29%; P =0.08). At 6 weeks, the median number of CFUs of M. avium complex/mL of blood was 0 or 1 for all three groups. Clarithromycin resistant isolates of M. avium complex developed in 46% of patients at a median of 16 weeks. Median survival was longer in patients assigned to 500 mg twice daily (median, 249 days) than in patients assigned to 1,000 mg or 2,000 mg. Death in the first 12 weeks was lowest in the 500 mg group (P =0.007). Symptoms of M. avium complex disease were prominent at enrollment and decreased substantially with all three doses of clarithromycin. Gastrointestinal intolerance was observed in some patients, causing 20-30% of participants to voluntarily withdraw from the study. Fifty-five patients relapsed. 52/55 of these patients had resistant MAC strains at the time of relapse. Resistance was not seen before 8 weeks of treatment but usually occurred before week 12. While clarithromycin strains remained susceptible to other anti-mycobacterial drugs, cross-resistance to azithromycin was observed.
A dose-escalation study of the combination of clarithromycin and AZT in HIV-positive people found that the maximum tolerated dose of clarithromycin was 2,000 mg bid; higher doses caused severe abdominal pain. Additionally, clarithromycin altered the pharmacokinetics of AZT, interfering with absorption and reducing peak concentrations by approximately 20%. The investigators suggested that people taking clahthromycin and AZT may need to take AZT several hours before or after a clarithromycin dose.
Nightingale et al. enrolled 21 patients with AIDS and disseminated MAC (median entry CD4+ count 6/mm3) in a phase I/II dose-ranging trial of TLCG-65 (liposome-encapsulated gentamycin). Patients received TLC G-65 (1.7, 3.4 or 5.1 mg/kg) IV twice weekly for 4 weeks. One patient at the highest dose developed reversible renal failure; no other toxicities were observed. All doses of TLC G-65 gave serum levels above the in vitro inhibitory concentration. A one-log reduction in MAC colony-forming units in the blood was observed after treatment, and 4/6 evaluable patients on the highest dose reported reduced symptoms and night sweats. A phase II study of TLC G-65 in combination with clarithromycin and ethambutol is underway.
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Ongoing Treatment
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Prophylaxis:
Rifabutin (300 mg PO daily) and clarithromycin (500 mg PO bid) have been approved as prophylaxis for MAC in HIV-positive patients with CD4+ counts below 200/mm3.
Two studies found that rifabutin effectively delays or prevents MAC bacteremia compared to placebo in AIDS patients with CD4 counts under 200/mm3 (Nightingale et al.). The first study enrolled 590 patients. The mean baseline CD4 count was 66 in the rifabutin group and 56 in the placebo group. 24/292 (8%) of rifabutin recipients and 51/298 (17%) of placebo recipients developed MAC bacteremia (P <0.001). The second study enrolled 556 patients. The mean baseline CD4 count was 61 in the rifabutin group and 55 in the placebo group. 24/274 (9%) of rifabutin recipients and 51/282 (18%) of placebo recipients developed MAC bacteremia (P <0.002). 'There was no survival difference between the MAC and placebo groups in either study. The frequency of adverse reactions was similar in the rifabutin and placebo groups, with discolored urine occurring more frequently in the rifabutin group. Uveitis (eye pain, inflammation and vision loss) has been reported in some patients receiving rifabutin (Frank et al., Fuller et al. and Havlir et al.), particularly in patients receiving high doses (>300 mg/day) and in patients receiving concomitant fluconazole, which increases serum levels of rifabutin. If symptoms of uveitis develop in patients receiving rifabutin, the drug should be stopped immediately and an ophthalmologic examination should be performed.
Chaisson et al. recently conducted Cox proportional hazards analyses for survival from the two prophylaxis clinical trials of rifabutin originally reported in 1993 (Nightingale et al., 1993). Data from 1145 patients with CD4+ counts <200 cells/mm3 were assessed. The risk of death at 12 and 18 months was evaluated. At 12 months, the relative risk of death in patients receiving rifabutin was 20%, compared to 28% in those not receiving rifabutin. At 18 months the risk of death in the two treatment groups was 28% and 45%, respectively.
Pierce et al. reported results of a double-blind, multicenter trial of daily prophylaxis treatment with either clarithromycin (500 mg bid) or placebo in HIV-positive people with CD4+ cell counts 100 cells/mm3 or less. 682 patients (341 clarithromycin, 341 placebo) were enrolled and followed for a median of 10.2 months. MAC bacteremia developed in 19/341 (5.7%) of the clarithromycin group and 53/341 (15.9%) of the placebo group (P <0.001). In those who developed MAC bacteremia, clarithromycin resistant isolates were recovered from 11 out of 19 patients in the clarithromycin group. 106 patients in the clarithromycin group died compared to 136 patients in the placebo group. Median survival was 700 days for those who received clarithromycin versus 573 days in the placebo group. Placebo recipients who developed MAC culture positively had an increased relative risk of death of 2.6 compared to those who were MAC negative (P <0.001). Discontinuation due to adverse events was 4% and 6%, respectively. A randomized, double-blind study (ACTG 196/CPCRA 009) has been completed comparing rifabutin, clarithromycin, and the combination of rifabutin/clarithromycin for the prevention of MAC bacteremia or disease in 1178 patients (Benson et al.). The median CD4+ count upon entry was 28 cells/mm3. During the median follow-up of 589 days, 35/398 (9%) developed MAC in the clarithromycin group, 59/339 (15%) developed MAC in the rifabutin group, and 26/389 (7%) developed MAC in the combination group (P =0.001). A preliminary analysis of 75% of the break-through patients indicated a similar frequency of resistance in the clarithromycin group (29%) and the combination groups (25%). No clarithromycin resistant isolates (MIC>32mcg/mL) were seen in the rifabutin group. Survival time did not differ among the three treatment groups (515 deaths total).
Two studies of azithromycin as MAC prophylaxis have been completed.Oldfield et al. compared azithromycin (1200 mg once weekly) to placebo in 182 HIV-positive patients with a mean CD4+ count of 44 cells/mm3. Mean duration of time on treatment was 400 days in the azithromycin group and 340 days in the placebo group. MAC bacteremia developed in 7/85 (10.6%) patients receiving azithromycin and 20/86 (24.7%) patients receiving placebo (P =0.002). There was no statistical difference in the time to death or number of deaths in either the treatment or control groups (11 and 10 deaths, respectively). The major type of toxicity was gastrointestinal (83.3% in the azithromycin group and 44% in the placebo group). The investigators conclude that azithromycin is effective in preventing MAC bacteremia.
In a second recently reported study,
Havlir et al.
studied 669 HIV-positive patients with fewer than 100 CD4+
cells/mm3
to receive either azithromycin (1200 mg once weekly) or rifabutin (300
mg daily)
or a combination of both. In the primary analysis, which included
endpoints
occurring up to 30 days after discontinuation of drugs (mean time on
study drug
was 318 days), 5/199 (2.5%) in the combination group, 18/204 (8.8%) in
the
azithromycin group, and 25/207 (12.1%) in the rifabutin group developed
MAC
bacteremia. In pairwise comparisons of the treatments, no statistical
difference
was found between azithromycin and rifabutin monotherapies. However,
statistically significant differences were reported when comparing the
combination group to either azithromycin monotherapy
(P =0.01) and
rifabutin monotherapy (P <0.001). Survival time did not
differ
significantly between the three treatment groups. Of 44 breakthrough
isolates of
MAC tested, only 2 (both in the azithromycin monotherapy arm) were
resistant (to
both drugs). The investigators conclude that weekly azithromycin is an
effective
alternative to daily rifabutin and combination treatment is more
effective that
either drug alone.
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Centers for Diseases Control. USPHS/IDSA guidelines for the Prevention
of
Opportunistic Infections in Persons Infected with Human
Immunodeficiency Virus.
MMWR 44:1-24,1995.
Chaisson RE et al. Survival analysis of two controlled trials of
rifabutin
prophylaxis against Mycobacterium avium complex in AIDS. 35th ICAAC,
Abstract
1204, San Francisco, 1995.
Chaisson RE et al. Clarithromycin therapy for bacteremic Mycobacterium
avium
complex disease. Ann lnt Med 121: 905-911, 1994.
Chaisson RE et al. Controlled trial of clarithromycin/ethambutol with
or without
clofazimine for MAC bacteremia in AIDS. Abstract #LB 17, 3rd Conf on
Human Retro
and Opport infect Washington DC, 1996.
Frank MO et al. Rifabutin and uveitis. NEJM 330:868,1994.
Fuller JD et al. Rifabutin prophylaxis and uveitis. NEJM 330:1315-6,
1994.
Dautzenberg et al. Rifabutin vs placebo in combination therapy for the
treatment
of disseminated MAC in HIV+ patients. Abstract #A/l, 34th ICAAC,
Orlando, 1994.
Dube M et al. Prevention of relapse of MAC bacteremia in AIDS: A
randomized
study of clarithromycin, plus clofazimine, with or without ethambutol.
Abstract
#206, 3rd Conference on Retroviruses and Opportunistic Infections,
Washington DC,
1996.
Gordin F and Masur H. Prophylaxis of Mycobacterium avium complex
bacteremia in
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Havlir D et al. Uveitis associated with rifabutin prophylaxis. Ann
Intern Med
121: 510-512,1994.
Havlir DV et al. A double-blind, randomized study of weekly
azithromycin,
daily rifabutin, and combination azithromycin and rifabutin for the
prevention of
MAC in AIDS patients. Abstract #204, 3rd Conf on Human Retro and
Opport Infect,
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Horsburgh CR et al. Clinical presentation of disseminated M. avium
complex
(MAC) disease: A case-controlled analysis. 35th ICAAC, Abstract 192,
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Jacobson et al. Randomized, placebo-controlled trial of rifampin,
ethambutol,
and ciprofloxacin for AIDS patients with disseminated Mycobacterium
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May T et al. A French randomized open trial of 2 clarithromycin
combination
therapies for MAC bacteremia: First results. 35th ICAAC, Abstract
LB-19, San
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Morrissey AM et al. Changes in quantitative blood cultures, colonial
morphology and susceptibility of Mycobacterium avium during therapy.
Abstract 11
24, 33rd ICAAC, New Orleans, 1993.
Nightingale SD et al. Incidence of Mycobacterium
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Nightingale S et al. Phase I/II study of TLC-G-65
(liposome-encapsulated
gentamicin) for treatment of Mycobacterium avium complex disease. 32nd
ICAAC,
abstract 898, Anaheim, 1992.
Nightingale SD et al. Two controlled trials of rifabutin prophylaxis
against
Mycobacterium avium complex infection in AIDS. NEJM 329:828-33, 1993.
Oldfield EC et al. One weekly azithromycin for the prevention of MAC
infection
in AIDS patients. Abstract #203, 3rd Conf on Humm Retro and Opport
Infect,
Washington DC, 1996.
Parenti D et al. A Phase II/III trial of rifabutin, ciprofloxacin,
clofazimine, ethambutol with or without amikacin in the treatment of
disseminated
MAC. 2nd Natl Conf Human Retroviruses and Rel Infect, Abstract 6,
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Pierce M et al. The effect of MAC and its prevention on survival in
patients
with advanced HIV infection. 35th ICAAC, Abstract LB-18, San Francisco,
1995.
Shafran SD et al. The Canadian randomized open-label trial of
combination
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Kallenius et al. Human immunodeficiency virus type I enhances
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Kerlikowske KM et al. Antimycobacterial therapy for disseminated
Mycobacterium
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Kolonoski PT et al. Therapeutic efficacy of WIN 57273 (WIN) and
sparfloxacin
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beige mice.
Abstract1247, 30th ICAAC, 1990.
Newman GW et al. Interlukin-12 enhances antigen-specific
proliferation of
peripheral
blood mononuclearcells from HIV-positive and negative donors in
response to
Mycobacterium
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Opravil M et al. Dapsone-pyrimethamine might prevent mycobacterial
disease in
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aggravates
impairment in tumor necrosis factor- secretion and increases
mycobacterial load
in macrophages from AIDS patients with disseminated Mycobacterium
avium-intracellulare complex infection. J infect Dis 170: 484487, 1994.
Rastogi N et al. Potential drug targets for Mycobacterium avium
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REFERENCES:
Benson CA et al. A phase III prospective, randomized, double-blind
study of the
safety and efficacy of clarithromycin vs. rifabutin vs.
clarithromycin/rifabutin
for the prevention of MAC disease in HIV-positive patients with CD4+
counts <100
cells/mm3. Abstract #205, 3rd Conf on Human Retro and Opport
Infect,
Washington DC, 1996.
OTHER REPORTS:
Benson C et al. Treatment of disseminated disease due to the
Mycobacterium avium
complex in patients with AIDS. Clin Inf Dis 18:S23742, 1994.
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