Correspondence

More on Continuous-Infusion Acyclovir for Severe Varicella

N Engl J Med 1997; 337:203-204July 17, 1997

Article

To the Editor:

In their letter reporting the use of a continuous infusion of acyclovir to treat severe hemorrhagic varicella (March 6 issue),1 Kakinuma and Itoh describe serologically confirmed infection with varicella-zoster virus in a patient with leukemia who had no response to the conventional regimen of therapy. However, the conventional-regimen dose of 250 mg of intravenous acyclovir every eight hours that was used in this 40-year-old woman is well below the dose of acyclovir recommended to treat varicella-zoster virus infection in immunocompromised patients -- namely, 10 mg per kilogram of body weight every eight hours.2

From the stated continuous-infusion dose of 2 mg per kilogram per hour, totaling 2250 mg per day, that the patient then received, one can infer that the patient weighed 47 kg. The difference in response to the two regimens described in the report may well be related to the higher dose administered during the continuous infusion (2250 vs. 750 mg) rather than to the mode of administration of the drug.

The emergence of acyclovir-resistant varicella-zoster virus is seen mostly in severely immunocompromised patients with AIDS.3 In such patients the high viral burden, together with multiple recurrences and exposures to acyclovir, allows the selection of resistant strains.3,4 In this case, there is no convincing evidence that the involved strain was resistant to acyclovir at the recommended dose.

Alejandro J. Krolewiecki, M.D.
Michael Braffman, M.D.
Thomas Jefferson University, Philadelphia, PA 19107

4 References

1. 1

   Kakinuma H, Itoh E. A continuous infusion of acyclovir for severe hemorrhagic varicella. N Engl J Med 1997;336:732-733
   Full Text | Web of Science | Medline

2. 2

   Hayden FG. Antiviral agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 4th ed. Vol. 1. New York: Churchill Livingstone, 1995:411-50.
   

3. 3

   Chatis PA, Crumpacker CS. Resistance of herpesviruses to antiviral drugs. Antimicrob Agents Chemother 1992;36:1589-1595
   Web of Science | Medline

4. 4

   Balfour HH Jr, Benson C, Braun J, et al. Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr 1994;7:254-260
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The recommended dose of intravenous acyclovir for immunocompromised patients is 10 mg per kilogram every eight hours, as Drs. Krolewiecki and Braffman indicate. The development of new vesicles continues for more than five days in immunocompromised patients.1 Acyclovir therapy substantially decreases the number of lesions and accelerates crusting and healing. Our evaluation of efficacy was made on day 5 of treatment and was based on the development of new vesicles.

There are two differences between continuous infusion and intermittent infusion -- in the peak serum concentration and its duration. The serum acyclovir concentration on day 3 of treatment was 5.2 micrograms per milliliter, and it was thought to remain roughly the same during treatment.2 On the other hand, the peak serum concentration even with an infusion of 5 mg of acyclovir per kilogram, the dose we used at first, has been variously reported as 7.45±1.59 and 9.8±2.6 micrograms per milliliter. The concentration then decreases rapidly because of the short half-life of acyclovir in serum (2.2 to 3.1 hours).3,4 The peak serum concentration achieved with an intermittent infusion is higher than that achieved with a continuous infusion.

Although there were no convincing data indicating in vitro resistance of the virus to acyclovir in our patient, the median infective dose of varicella-zoster virus is 0.46 to 4.6 microgram per milliliter.5 With intermittent infusion, the serum concentration is above that level for about two hours. The duration of a high serum concentration of acyclovir with a continuous infusion, although the concentration is lower than the peak achieved with an intermittent infusion, appears to be another important factor. The highest intravenous doses have the potential for nephrotoxicity induced by acyclovir-related crystalluria.2 The possibility of nephrotoxicity with a continuous infusion may be less than that with an intermittent infusion. The optimal dose of acyclovir and its duration require further study.

Hiroshi Kakinuma, M.D.
Kawaguchi Municipal Medical Center, Saitama 333, Japan

Eisuke Itoh, M.D.
Nihon University Itabashi Hospital, Tokyo 173, Japan

5 References

1. 1

   Balfour HH Jr. Varicella zoster virus infections in immunocompromised hosts: a review of the natural history and management. Am J Med 1988;85:Suppl 2A:68-73
   CrossRef | Web of Science | Medline

2. 2

   Spector SA, Hintz M, Wyborny C, Connor JD, Keeney RE, Liao S. Treatment of herpes virus infections in immunocompromised patients with acyclovir by continuous intravenous infusion. Am J Med 1982;73:Suppl 1A:275-280
   CrossRef | Web of Science | Medline

3. 3

   de Miranda P, Whitley RJ, Blum MR, et al. Acyclovir kinetics after intravenous infusion. Clin Pharmacol Ther 1979;26:718-728
   Web of Science | Medline

4. 4

   Barry DW, Blum MR. Antiviral drugs: acyclovir. In: Turner P, Shand D, eds. Recent advances in clinical pharmacology. London: Churchill Livingstone, 1983:57-80.
   

5. 5

   Burgess ED, Gill MJ. Intraperitoneal administration of acyclovir in patients receiving continuous ambulatory peritoneal dialysis. J Clin Pharmacol 1990;30:997-1000
   Web of Science | Medline