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

The optimal regimen for treatment of Mycobacterium avium complex (MAC) disease has not been established. Eighty-five AIDS patients with disseminated MAC disease were randomized to receive a three-drug regimen of clarithromycin, rifabutin or clofazimine, and ethambutol. Two dosages of clarithromycin, 500 or 1,000 mg twice daily (b.i.d.), were compared. The Data and Safety Monitoring Board recommended discontinuation of the clarithromycin dosage comparison and continuation of the rifabutin vs. clofazimine comparison. After a mean follow-up of 4.5 months, 10 (22%) of 45 patients receiving clarithromycin at 500 mg b.i.d. had died (70 deaths per 100 person-years) compared with 17 (43%) of 40 patients receiving clarithromycin at 1,000 mg b.i.d. (158 deaths per 100 person-years) (relative risk, 2.43; 95% confidence interval, 1.11-5.34; P = .02). After 10.4 months, 20 (49%) of 41 patients receiving rifabutin had died (81 deaths per 100 person-years) compared with 23 (52%) of 44 patients receiving clofazimine (94 deaths per 100 person-years) (relative risk, 1.20; 95% confidence interval, 0.65-2.19; P = .56). Bacteriologic outcomes were similar among treatment groups. In treating MAC disease in AIDS patients, the maximum dose of clarithromycin should be 500 mg b.i.d.

[1]  J. Coffin,et al.  HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy , 1995, Science.

[2]  R. Chaisson,et al.  Clarithromycin Therapy for Bacteremic Mycobacterium avium Complex Disease , 1994, Annals of Internal Medicine.

[3]  B. Dautzenberg,et al.  Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium. ANRS Trial 033 Curavium Group. Agence Nationale de Recherche sur le Sida. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  L. Heifets,et al.  Clarithromycin minimal inhibitory and bactericidal concentrations against Mycobacterium avium. , 1992, The American review of respiratory disease.

[5]  J. Ellner,et al.  Mycobacterium avium infection and AIDS: a therapeutic dilemma in rapid evolution. , 1991, The Journal of infectious diseases.

[6]  Increased Plasma Rifabutin Levels with Concomitant Fluconazole Therapy in HIV-Infected Patients , 1996, Annals of Internal Medicine.

[7]  H. Masur.  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. , 1993, The New England journal of medicine.

[8]  R. Reves,et al.  A retrospective comparison of clarithromycin versus rifampin in combination treatment for disseminated Mycobacterium avium complex disease in AIDS: clarithromycin decreases transfusion requirements. , 1997, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[9]  J. Singer,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. Canadian HIV Trials Network Protocol 010 Study Group. , 1996, The New England journal of medicine.

[10]  J P Matts,et al.  Primary prophylaxis with pyrimethamine for toxoplasmic encephalitis in patients with advanced human immunodeficiency virus disease: results of a randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS. , 1994, The Journal of infectious diseases.

[11]  Mark A. Miller,et al.  Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group. , 1998, The Journal of infectious diseases.

[12]  C. Kemper,et al.  Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen. Rifampin, ethambutol, clofazimine, and ciprofloxacin. The California Collaborative Treatment Group. , 1992, Annals of internal medicine.

[13]  D. Armstrong,et al.  Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. , 1986, Annals of internal medicine.

[14]  C. Kemper,et al.  The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS. , 1994, The Journal of infectious diseases.

[15]  G. Drusano,et al.  Tolerance and Pharmacokinetic Interactions of Rifabutin and Clarithromycin in Human Immunodeficiency Virus-Infected Volunteers , 1998, Antimicrobial Agents and Chemotherapy.

[16]  C. Horsburgh,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. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  S. Morikawa,et al.  Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro , 1994, Antimicrobial Agents and Chemotherapy.

[18]  H. Masur,et al.  Clarithromycin Therapy for Mycobacterium avium Complex Disease in Patients with AIDS: Potential and Problems , 1994, Annals of Internal Medicine.

[19]  R. Chaisson,et al.  Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic: Mycobacterium avium complex disease in patients with HIV infection , 1997, AIDS.

[20]  E. Vittinghoff,et al.  The impact of Mycobacterium avium complex bacteremia and its treatment on survival of AIDS patients--a prospective study. , 1994, The Journal of infectious diseases.

[21]  C. Horsburgh,et al.  Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. , 1997, The Journal of infectious diseases.

[22]  C. Horsburgh,et al.  Survival of patients with acquired immune deficiency syndrome and disseminated Mycobacterium avium complex infection with and without antimycobacterial chemotherapy. , 1991, The American review of respiratory disease.

[23]  J. McCutchan,et al.  Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. California Collaborative Treatment Group. , 1990, Annals of internal medicine.

[24]  S. Naik,et al.  In vitro activities of several new macrolide antibiotics against Mycobacterium avium complex , 1989, Antimicrobial Agents and Chemotherapy.

[25]  J. Currier,et al.  Impact of clarithromycin and azithromycin on patterns of treatment and survival among AIDS patients with disseminated Mycobacterium avium complex , 1995, AIDS.

[26]  C. Kemper,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. California Collaborative Treatment Group. , 1997, The Journal of infectious diseases.

[27]  Horsburgh Cr.  Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. , 1991, The New England journal of medicine.

[28]  L. Grayson,et al.  Quadruple-drug therapy for Mycobacterium avium-intracellulare bacteremia in AIDS patients. , 1990, The Journal of infectious diseases.

[29]  F. Gordin,et al.  Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. The Rifabutin Treatment Group. , 1994, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  P. Nassos,et al.  Antimicrobial synergism against Mycobacterium avium complex strains isolated from patients with acquired immune deficiency syndrome , 1988, Antimicrobial Agents and Chemotherapy.

[31]  Jerald F. Lawless,et al.  Statistical Models and Methods for Lifetime Data. , 1983 .

[32]  L. Heifets,et al.  Quantitation of mycobacteria in blood specimens from patients with AIDS. , 1994, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[33]  D. Sassella,et al.  Clinical experience with rifabutin in the treatment of mycobacterial infections. , 1995, Scandinavian journal of infectious diseases. Supplementum.

[34]  S. Morikawa,et al.  Modulatory effect of antibiotics on cytokine production by human monocytes in vitro , 1996, Antimicrobial agents and chemotherapy.

[35]  M. Cynamon,et al.  Rapid broth macrodilution method for determination of MICs for Mycobacterium avium isolates , 1993, Journal of clinical microbiology.

[36]  B. Dautzenberg,et al.  Activity of clarithromycin against Mycobacterium avium infection in patients with the acquired immune deficiency syndrome. A controlled clinical trial. , 1991, The American review of respiratory disease.

[37]  L. Heifets,et al.  Susceptibility testing of Mycobacterium avium complex isolates , 1996, Antimicrobial agents and chemotherapy.

[38]  P M Southern,et al.  Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. , 1992, The Journal of infectious diseases.

[39]  F. Raffi,et al.  Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. Study Group. , 1995, The Journal of infectious diseases.