Correspondence

A Continuous Infusion of Acyclovir for Severe Hemorrhagic Varicella

N Engl J Med 1997; 336:732-733March 6, 1997

Article

To the Editor:

Severe infections with varicella–zoster virus are common in immunocompromised hosts.1 Hemorrhagic varicella is serious and frequently fatal. We describe a case of hemorrhagic varicella that was resistant to a conventional regimen of acyclovir but was successfully treated by a continuous infusion of acyclovir.

A 40-year-old woman with leukemia treated with various chemotherapies was admitted with fever, general fatigue, and generalized hemorrhagic bullae without a dermatomic distribution (Figure 1AFigure 1Generalized Hemorrhagic Bullae on the Back of the Patient. and Figure 1B). A Tzanck smear of the bullae was positive. The patient had had varicella in childhood. An intravenous infusion of 250 mg of acyclovir over a one-hour period every eight hours for five days (the conventional regimen) in combination with 2.5 g of immune globulin twice daily for four days did not prevent the development of new vesicles. Therefore, treatment was changed to a continuous infusion of acyclovir at a rate of 2 mg per kilogram of body weight per hour (2250 mg per day). This regimen markedly improved the clinical features by day 9 without any adverse effects or laboratory abnormalities. Treatment was stopped on day 14, and the patient was discharged. One month after admission, the diagnosis of varicella was confirmed by a test for complement-fixing antibody to varicella–zoster virus, which had been negative at the time of admission. The patient died of Pneumocystis carinii pneumonia two months later.

Acyclovir therapy is standard for herpesvirus infections, but it has three major drawbacks: the drug is poorly absorbed orally, it has a short half-life in serum, and acyclovir-resistant strains of virus have emerged.2 There is little doubt that in our patient the organism was resistant to the conventional regimen, although thymidine kinase activity was not examined because of a failure to isolate the virus. The action of acyclovir appears to be more complicated in immunocompromised patients than in normal hosts, and higher doses and improved regimens of acyclovir may be necessary in these patients. In reported cases of herpes simplex virus infection that was resistant to the conventional acyclovir regimen but cured with a continuous infusion, the virus was shown to be resistant to acyclovir in vitro.3-5 The case we describe of varicella–zoster virus infection shows the clinical superiority of a continuous acyclovir infusion over the conventional regimen. These observations and serial measurements of the serum drug concentrations over time in both regimens suggest that the duration of continuous exposure to acyclovir at levels that are near or exceed the median inhibitory concentration is important in inhibiting viral DNA replication. This method, with appropriate monitoring of serum acyclovir concentrations, may help overcome some of the deficiencies of acyclovir therapy. A continuous infusion of acyclovir may be beneficial for severe, life-threatening varicella–zoster virus infections that are resistant to treatment with the conventional regimen, and perhaps even acyclovir-resistant herpesvirus infections.

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

Eisuke Itoh, M.D.
Itabashi Hospital, Tokyo, Japan

5 References

1. 1

   Wagstaff AJ, Faulds D, Goa KL. Aciclovir: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994;47:153-205
   CrossRef | Web of Science | Medline

2. 2

   Field AK, Biron KK. “The end of innocence“ revisited: resistance of herpesviruses to antiviral drugs. Clin Microbiol Rev 1994;7:1-13
   Web of Science | Medline

3. 3

   Fletcher CV, Englund JA, Bean B, Chinnock B, Brundage DM, Balfour HH Jr. Continuous infusion of high-dose acyclovir for serious herpesvirus infections. Antimicrob Agents Chemother 1989;33:1375-1378
   Web of Science | Medline

4. 4

   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

5. 5

   Engel JP, Englund JA, Fletcher CV, Hill EL. Treatment of resistant herpes simplex virus with continuous-infusion acyclovir. JAMA 1990;263:1662-1664
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   (1997) More on Continuous-Infusion Acyclovir for Severe Varicella. New England Journal of Medicine 337:3, 203-204
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