Correspondence
Oral Azole Drugs as Systemic Antifungal Therapy
N Engl J Med 1994; 330:1759-1760June 16, 1994
- Article
To the Editor:
The review of oral azole drugs for systemic antifungal therapy, by Como and Dismukes (Jan. 27 issue),1 was informative but lacked a discussion of the use of these agents in children. Clinicians who treat children have long been seeking an alternative to amphotericin B and have started using azole agents despite the lack of data on the pharmacokinetics, safety, and efficacy of these drugs in children. Ketoconazole is the azole most familiar to clinicians caring for children and is currently the only oral agent for which there is an established dose for children (5 to 10 mg per kilogram of body weight given once daily). Although there are suggested doses for the newer agents (fluconazole, 3 to 6 mg per kilogram per day, and itraconazole, 5 to 10 mg per kilogram per day), these doses are based on limited data.
The other obstacle to the use of these drugs in children is the lack of a commercially prepared oral liquid formulation. Ketoconazole can be formulated as a liquid preparation but has a limited shelf life. For the other agents, clinicians must resort to crushing tablets and instructing parents in the art of disguising medication to ensure its delivery. The use of such extemporaneous formulations may reduce the efficacy of the drugs, since such preparations may not be well tolerated and are not standardized. Until there is more information about accepted dosages for children and standardized preparations are available, these agents should have a limited role in the treatment of systemic fungal diseases in children.
1 ReferencesGordon E. Schutze, M.D.
Arkansas Children's Hospital, Little Rock, AR 72202-35911
Como JA ,Dismukes WE . Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263-272
Full Text | Web of Science | Medline
To the Editor:
Como and Dismukes state, “A loading dose of 200 mg of itraconazole three times daily for three days is recommended in patients with serious infections to reduce the time until steady-state concentrations are attained.” The belief that loading doses allow a steady state to be achieved more rapidly appears to be a common misconception. The time that is required for a drug to accumulate to a steady-state serum concentration is dependent on the drug's elimination half-life.1 The serum concentration will be between 95 percent and 99 percent of the steady-state concentration only after a constant dose has been administered for a period of five half-lives.1
Itraconazole has an elimination half-life of up to 42 hours; therefore, a steady-state concentration will not be achieved until the drug has been administered for approximately eight or nine days (5 × 42 hours = 210 hours). A loading dose of a drug is given not to achieve a steady state more rapidly but rather to attain rapidly a high enough serum concentration to exert an immediate pharmacologic effect.1 Thereafter, steady-state concentrations will be achieved when subsequent maintenance doses of the drug are given for a period exceeding five half-lives.
1 ReferencesJoseph V. Etzel, Pharm.D.
St. John's University, Jamaica, NY 11439Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Schutze's comments about the use of azole antifungal drugs in children. The same pharmacologic and microbiologic properties that make this class of drugs attractive for use in adults apply to its use in children. The paucity of published data and controlled clinical trials in children, however, precluded us from considering the use of azoles in children in our review.
We accept Dr. Etzel's point that administration of a loading dose of itraconazole does not shorten the time required to achieve a steady-state serum concentration. Our emphasis should have been that the benefit of a loading dose of a drug such as itraconazole is the rapid achievement of a therapeutic serum concentration.
Jackson A. Como, Pharm.D.
William E. Dismukes, M.D.
University of Alabama, Birmingham, AL 35294-0012- Citing Articles (1)
Citing Articles
1
Lytt I. Gardner, Shannon H. Harrison, Craig W. Hendrix, Stephen P. Blatt, Kenneth F. Wagner, Ray C. Y. Chung, Richard W. Harris, David L. Cohn, Donald S. Burke, Douglas L. Mayers. (1998) Size and Duration of Zidovudine Benefit in 1003 HIV-Infected Patients: U.S. Army, Navy, and Air Force Natural History Data. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 17:4, 345-353
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