Acyclovir: An overview
- Kimon C Zachary, MD
Kimon C Zachary, MD
- Assistant Professor of Medicine
- Harvard Medical School
Acyclovir is widely used in the treatment of herpesvirus infections, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). An overview of the mechanisms of action of and resistance to acyclovir and its major clinical uses will be provided here.
Dosing and treatment of the specific clinical syndromes are described in greater detail on the appropriate topic reviews.
MECHANISM OF ACTION
Acyclovir (9-[2-hydroxymethyl]guanine) is a nucleoside analog that selectively inhibits the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and varicella-zoster virus (VZV). After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase. This step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymes.
Acyclovir triphosphate competitively inhibits viral DNA polymerase by acting as an analog to deoxyguanosine triphosphate (dGTP). Incorporation of acyclovir triphosphate into DNA results in chain termination since the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides. Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio [1,2].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med 1992; 327:782.
- Hirsch MS, Swartz MN. Drug therapy: antiviral agents (second of two parts). N Engl J Med 1980; 302:949.
- Amjad M, Gillespie MA, Carlson RM, Karim MR. Flow cytometric evaluation of antiviral agents against human herpesvirus 6. Microbiol Immunol 2001; 45:233.
- Coen N, Duraffour S, Topalis D, et al. Spectrum of activity and mechanisms of resistance of various nucleoside derivatives against gammaherpesviruses. Antimicrob Agents Chemother 2014; 58:7312.
- Chatis PA, Crumpacker CS. Resistance of herpesviruses to antiviral drugs. Antimicrob Agents Chemother 1992; 36:1589.
- Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 2004; 39 Suppl 5:S248.
- Englund JA, Zimmerman ME, Swierkosz EM, et al. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med 1990; 112:416.
- Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 320:293.
- Hardy WD. Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial. Am J Med 1992; 92:30S.
- Boivin G, Edelman CK, Pedneault L, et al. Phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. J Infect Dis 1994; 170:68.
- Laskin OL. Clinical pharmacokinetics of acyclovir. Clin Pharmacokinet 1983; 8:187.
- Adair JC, Gold M, Bond RE. Acyclovir neurotoxicity: clinical experience and review of the literature. South Med J 1994; 87:1227.
- Sitavig (acyclovir) buccal tablets prescribing information. Farmea, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203791s000lbl.pdf (Accessed on December 09, 2014).
- Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009; 29:562.
- Acyclovir tablet, capsule, and oral suspension United States Prescribing information (revised July, 2013); available at US National Library of Medicine DailyMed website http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f94a46a2-2e86-4d98-ec89-9483a41d290a.
- Acyclovir sodium injection; United States prescribing information (revised May, 2014); available at US National Library of Medicine DailyMed website available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=badf347b-eeee-4239-9c74-966f262925aa.
- Hernandez JO, Norstrom J, Wysock G. Acyclovir-induced renal failure in an obese patient. Am J Health Syst Pharm 2009; 66:1288.
- Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J Clin Pharm Ther 2014; 39:584.
- Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis 1997; 25:112.
- Drugs for non-HIV viral infections. Treat Guidel Med Lett 2007; 5:59.
- Sawyer MH, Webb DE, Balow JE, Straus SE. Acyclovir-induced renal failure. Clinical course and histology. Am J Med 1988; 84:1067.
- Perazella MA. Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 2003; 325:349.
- Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis 1988; 157:385.
- Davenport A, Goel S, Mackenzie JC. Neurotoxicity of acyclovir in patients with end-stage renal failure treated with continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1992; 20:647.
- Stathoulopoulou F, Almond MK, Dhillon S, Raftery MJ. Clinical pharmacokinetics of oral acyclovir in patients on continuous ambulatory peritoneal dialysis. Nephron 1996; 74:337.
- Almond MK, Fan S, Dhillon S, et al. Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis. Nephron 1995; 69:428.
- Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA 2010; 304:859.
- pregnancyregistry.gsk.com/acyclovir.html (Accessed on September 25, 2012).
- American Academy of Pediatrics. Red Book Online News. Shortage of intravenous acyclovir. http://aapredbook.aappublications.org/site/news#76 (Accessed on December 04, 2012).
- US Food and Drug Administration. Current Drug Shortages. http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm314739.htm (Accessed on December 04, 2012).
- American Academy of Pediatrics. Red Book Online. Antiviral recommendations for herpes simplex virus (HSV) and varicella zoster virus (vzv) infections in hospitalized pediatric patients during the intravenous acyclovir shortage. http://aapredbook.aappublications.org/site/news/acyclovir.xhtml (Accessed on December 04, 2012).
- MECHANISM OF ACTION
- Spectrum of activity
- Mechanism of resistance
- BASIC PHARMACOKINETICS
- DOSE ADJUSTMENTS
- Reduced renal function
- Acute renal failure
- Neurologic toxicity
- USE IN PREGNANCY
- USE OF ACYCLOVIR IN IMMUNOCOMPETENT PATIENTS
- IF THERE IS AN ACYCLOVIR SHORTAGE
- Overview of alternative agents
- Management of clinical conditions when IV acyclovir is unavailable
- SUMMARY AND RECOMMENDATIONS