Correspondence

Fluconazole and Enhanced Effect of Rifabutin Prophylaxis

N Engl J Med 1994; 330:1316-1317May 5, 1994

Article

To the Editor:

The results of two double-blind, randomized, placebo-controlled trials published in the Journal (Sept. 16 issue)1 have shown that prophylactic treatment with rifabutin (300 mg per day) significantly reduces the incidence of Mycobacterium avium complex bacteremia. A Special Report in the same issue2 further recommends rifabutin prophylaxis in adults and adolescents with human immunodeficiency virus infection and CD4+ counts of 100 cells or less per cubic millimeter and suggests that effective primary prophylaxis could improve the patients' quality of life and survival.

Fluconazole, a potent inhibitor of cytochrome P-450, significantly (P<0.01) increases both the maximal concentration and the area under the curve of rifabutin and LM565 (d-acetyl metabolite) by at least 80 percent3. In a retrospective analysis of the data from the two double-blind trials,1 we examined whether higher levels of rifabutin enhanced its prophylactic effect against M. avium complex. A total of 150 patients had M. avium complex bacteremia: 102 of the 580 patients receiving placebo and 48 of the 566 patients receiving rifabutin. Fluconazole was given concomitantly to 239 patients in the placebo group and 272 patients in the rifabutin group. The base-line median CD4+ counts were similar in those receiving rifabutin and fluconazole and those not receiving fluconazole (18 cells per cubic millimeter vs. 25 cells per cubic millimeter, P>0.8). Patients who had positive cultures before treatment was initiated or 15 or more days after fluconazole was discontinued were included in the group that received rifabutin alone. Safety was assessed on the basis of the incidence of common signs or symptoms thought to be associated with rifabutin (leukopenia, nausea and vomiting, rash, abdominal pain, and diarrhea).

Table 1Table 1Effect of Concomitant Fluconazole Therapy on the Incidence of M. avium Complex Bacteremia during Rifabutin Prophylaxis. shows that patients receiving rifabutin and fluconazole had a lower incidence of M. avium complex bacteremia than those receiving rifabutin alone (P<0.033). In patients receiving placebo, fluconazole had no effect on the incidence of M. avium complex bacteremia. The group receiving rifabutin and fluconazole had a higher incidence of leukopenia than the group given rifabutin alone (17 percent vs. 7 percent, P<0.01), but there were no differences between groups in the incidence of the other adverse effects.

We conclude that the prophylactic effect of rifabutin is enhanced by concomitant treatment with fluconazole, possibly as a result of higher systemic levels of the active antimycobacterial agent. Therefore, daily doses of more than 300 mg of rifabutin may prove more effective in the prevention of disseminated M. avium complex disease but should not be used until the safety and efficacy are confirmed in clinical trials. Additional studies are needed.

Prem K. Narang, Ph.D.
Pharmacia-Adria, Columbus, OH 43017

Carol Braun Trapnell, M.D.
Food and Drug Administration, Rockville, MD 20892

John R. Schoenfelder, Ph.D.
Pharmacia-Adria, Columbus, OH 43017

James P. Lavelle, M.D.
Georgetown University, Washington, DC 20007

Joseph R. Bianchine, M.D., Ph.D.
Pharmacia-Adria, Columbus, OH 43017

3 References

1. 1

   Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med 1993;329:828-833
   Full Text | Web of Science | Medline

2. 2

   Masur H, Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. N Engl J Med 1993;329:898-904
   Full Text | Web of Science | Medline

3. 3

   Trapnell CB, Narang PK, Li R, et al. Fluconazole increases rifabutin (RIF) absorption in HIV(+) patients on stable zidovudine (ZDV) therapy. In: Proceedings of the Ninth International Conference on AIDS, Berlin, Germany, June 6-11, 1993. London: Wellcome Foundation, 1993:504. abstract.
   

Citing Articles (15)

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   G. Krishna, A. Parsons, B. Kantesaria, T. Mant. (2007) Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men. Current Medical Research and Opinion 23:3, 545-552
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   Jeffrey J. Kuper, Michelle D??Aprile. (2000) Drug-Drug Interactions of Clinical Significance in the Treatment of Patients with Mycobacterium avium Complex Disease. Clinical Pharmacokinetics 39:3, 203-214
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