Continuous infusion of high-dose acyclovir for serious herpesvirus infections

Abstract

Thirteen patients with herpesvirus infections who were unresponsive to at least 72 h of intermittent acyclovir administration received high-dose continuous infusion. Steady-state concentrations were maintained at between 20 and 98 ,umol/liter. Of 12 patients who had continuous infusion for >5 days, 7 (58%) resolved their infections, as determined by clinical and virologic parameters, suggesting that continuous infusion may succeed in some patients who do not respond to conventional therapy.Acyclovir is a purine nucleoside with in vitro activity against herpes simplex virus (HSV), varicella-zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (1). The drug has been shown to be of clinical benefit when administered topically, orally, or parenterally for the prophylaxis and treatment of certain herpesvirus infections (1). While acyclovir is conventionally given by intermittent oral or intravenous routes, the method of administration that best inhibits viral replication is not known. This report describes the use of high-dose acyclovir given by continuous intravenous infusion to 13 patients with serious herpesvirus infections.Patients hospitalized at the University of Minnesota Hospital were eligible for this study if they (i) had serious, systemic, life-threatening herpesvirus infections; (ii) had received at least 72 h of intermittent oral or intravenous acyclovir; and (iii) were judged by the attending physicians to have had poor responses to conventional, intermittent acyclovir administration. Clinical indicators of poor response included continued fever and weakness in CMVinfected individuals, progression of mucocutaneous lesions in HSV-infected individuals, and continued fever or lymphadenopathy in EBV-infected individuals.The acyclovir dosing regimen for continuous infusion was designed by using a two-compartment pharmacokinetic model (5), with acyclovir elimination defined as a function of creatinine clearance (CLCR). Nominal values of the pharmacokinetic parameters used for simulation of concentration in plasma and dosage regimen design were as follows: volume of distribution of the central compartment, 0.32 liter/kg of body weight, and intercompartmental rate constants of 1.3 h-1 (k12) and 0.8 h-1 (k21 (Fig. 1). To optimize therapy, the administration rate was subsequently increased in patients 2, 3, 4, 10, and 12. Acyclovir CL (Fig. 2)

Improvement of refractory acyclovir-resistant herpes simplex virus type 1 infection by continuous acyclovir administration

“…One interesting aspect of this case is that continuous ACV administration was predominantly effective, even though some HSV-1 strains obtained from this patient had mutations in the DNA pol gene. In a previous study, similar to our case, administration of ACV by continuous infusion was reported to be effective even in virologically ACV-resistant HSV cases [9]. The detailed mechanisms why ACV could overcome drug-resistance strain remain unclear, but to increase intracellular ACV concentration would be a rational explanation referred to the effectiveness of continuous ACV administration.…”

Therapeutic Drug Monitoring of Continuous-Infusion Acylovir for Disseminated Herpes Simplex Virus Infection in a Neonate Receiving Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy

“…From a safety perspective, acyclovir plasma concentrations would need to remain below 50–70 mg/L, as these concentrations have been associated with neurotoxicity in a small subset of patients . Continuous‐infusion acyclovir has been effective in treating HSV after conventional intermittent acyclovir treatment failure . However, to our knowledge, the use and pharmacokinetics of continuous‐infusion acyclovir in the setting of concurrent extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT) have never been described.…”

“…[7][8][9][10] Continuous-infusion acyclovir has been effective in treating HSV after conventional intermittent acyclovir treatment failure. [11][12][13][14][15] However, to our knowledge, the use and pharmacokinetics of continuous-infusion acyclovir in the setting of concurrent extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT) have never been described. In this case report, we describe the pharmacokinetics of continuous-infusion acyclovir in a patient receiving concurrent ECLS and CRRT.…”

Continuous infusion of acyclovir is more effective than discontinuous infusion for treatment of genital herpes in an immunocompromised patient

“…Because of the nephrotoxicity and severe metabolic disturbances associated with foscarnet administration [7], the only remaining alternative therapeutic approach was the continuous infusion of acyclovir. Indeed, effectiveness of continuous infusion of acyclovir for serious HSV infections has been previously reported in five immunocompromised patients [8,9]. Although we could not monitor the acyclovir levels, no clinical or laboratory adverse reactions occurred in our patient, who quickly improved and recovered.…”