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Aciclovir CSF concentration in children with viral encephalitis: is it adequate?

Aciclovir CSF concentration in children with viral encephalitis: is it adequate? Sir, Viral encephalitis is a medical emergency with significant mortality.1 Aciclovir, as the first-line treatment, has significantly reduced mortality in children, while neurodevelopmental impairment among survivors remains high.2–5 Previous studies have shown that inadequate antiviral exposure might lead to the persistence of virus in the CSF in infants.1 Despite wide use in paediatric clinical practice, limited data were available in children.6 Thus, our study aims to evaluate aciclovir CSF concentration in children with viral encephalitis. This study was conducted in our department of neurology between 2016 and 2017. Thirty-nine children receiving aciclovir as part of standard treatment for viral encephalitis (10 mg/kg q8h) were enrolled in this non-interventional study, which was designed in accordance with the legal requirements and the Declaration of Helsinki, and was approved by the institute Ethics Committee. The informed consents were obtained from the patients' parents or guardians. The CSF samples were obtained at steady-state condition using an opportunistic sampling approach after routine biochemical and microbiological tests performed as part of patient clinical care. The routine care time was adjusted to match the trough concentration (6–8 h post-dose).7 The concentration of aciclovir in CSF was determined by using HPLC coupled with a UV detection method using 100 μL of CSF. The method was linear over the concentration range from 0.04 to 8 mg/L. The lower limit of quantification was 0.04 mg/L. A total of 39 children were included from 2016 to 2017. The mean age and weight were 5.8 (range, 2.5 to 11.3) years and 22.4 (range, 13 to 57.5) kg, respectively. All children received standard dosing of aciclovir (10 mg/kg q8h) as part of their routine clinical care. The CSF samples were taken at a mean of 8 (range, 6 to 15) days after treatment. A total of 39 CSF samples were obtainable for analysis with a mean trough concentration of 0.24 (range, 0.11 to 0.43) mg/L. The distribution of aciclovir trough concentration is shown in Figure 1. Figure 1. View largeDownload slide Distribution of aciclovir trough concentration. Figure 1. View largeDownload slide Distribution of aciclovir trough concentration. As shown by our results, the aciclovir CSF trough concentation after receiving the standard dosing could not achieve the pharmacodynamic targets of herpes simplex virus (HSV; 1.0 mg/L) or varicella zoster virus (VZV; 0.45 mg/L) infection.6,8 The inadequate aciclovir exposure may be one of the significant causes of high mortality and poor neural outcomes among survivors of viral encephalitis. In infants with CNS HSV infection, after giving the standard dose of aciclovir, the neurodevelopment non-normalization rates at 12 months after treatment reached 71%.3 A high dosing regimen of 20 mg/kg q8h has been suggested in neonates with CNS disease and showed reduced mortality and improved neurodevelopment.2 Moreover, treatment with inadequate doses of aciclovir might also increase viral persistence and lead to the selection of resistant strains of virus.9 The prevalence of aciclovir-resistant HSV infection has reached 36% in transplant patients.10 In conclusion, to our knowledge, aciclovir CSF concentration has been systematically evaluated for the first time in children suffering from viral encephalitis. The results demonstrated underdosing in most children. The standard dosage regimen of 10 mg/kg q8h was not sufficient for children with viral encephalitis caused by HSV or VZV. Funding This work was supported by the Science and Technology Planning Project of Hebei Province (15277705D), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), the Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security, CG2016030001) and the Hundred-Talent Program (The People’s Government of Hebei Province, E2015100010). Transparency declarations None to declare. References 1 Kimberlin DW , Lakeman FD , Arvin AM et al. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease . J Infect Dis 1996 ; 174 : 1162 – 7 . Google Scholar CrossRef Search ADS PubMed 2 Kimberlin DW , Lin CY , Jacobs RF et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections . Pediatrics 2001 ; 108 : 230 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Whitley R , Arvin A , Prober C et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection . N Engl J Med 1991 ; 324 : 444 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Engman ML , Adolfsson I , Lewensohn-Fuchs I et al. Neuropsychologic outcomes in children with neonatal herpes encephalitis . Pediatr Neurol 2008 ; 38 : 398 – 401 . Google Scholar CrossRef Search ADS PubMed 5 Steiner I , Budka H , Chaudhuri A et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management . Eur J Neurol 2010 ; 17 : 999 – e57 . Google Scholar CrossRef Search ADS PubMed 6 Sampson MR , Bloom BT , Lenfestey RW et al. Population pharmacokinetics of intravenous acyclovir in preterm and term infants . Pediatr Infect Dis J 2014 ; 33 : 42 – 9 . Google Scholar CrossRef Search ADS PubMed 7 Zhao W , Jacqz-Aigrain E. Author's reply to Standing et al. Pharmacokinetic studies in neonates: the utility of an opportunistic sampling design . Clin Pharmacokinet 2015 ; 54 : 1289 – 91 . Google Scholar CrossRef Search ADS PubMed 8 Jacobson MA , Berger TG , Fikrig S et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) . Ann Intern Med 1990 ; 112 : 187 – 91 . Google Scholar CrossRef Search ADS PubMed 9 Hoppenjans WB , Bibler MR , Orme RL et al. Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome . Arch Dermatol 1990 ; 126 : 1048 – 50 . Google Scholar CrossRef Search ADS PubMed 10 Langston AA , Redei I , Caliendo AM et al. Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation . Blood 2002 ; 99 : 1085 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Aciclovir CSF concentration in children with viral encephalitis: is it adequate?

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
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10.1093/jac/dky217
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Abstract

Sir, Viral encephalitis is a medical emergency with significant mortality.1 Aciclovir, as the first-line treatment, has significantly reduced mortality in children, while neurodevelopmental impairment among survivors remains high.2–5 Previous studies have shown that inadequate antiviral exposure might lead to the persistence of virus in the CSF in infants.1 Despite wide use in paediatric clinical practice, limited data were available in children.6 Thus, our study aims to evaluate aciclovir CSF concentration in children with viral encephalitis. This study was conducted in our department of neurology between 2016 and 2017. Thirty-nine children receiving aciclovir as part of standard treatment for viral encephalitis (10 mg/kg q8h) were enrolled in this non-interventional study, which was designed in accordance with the legal requirements and the Declaration of Helsinki, and was approved by the institute Ethics Committee. The informed consents were obtained from the patients' parents or guardians. The CSF samples were obtained at steady-state condition using an opportunistic sampling approach after routine biochemical and microbiological tests performed as part of patient clinical care. The routine care time was adjusted to match the trough concentration (6–8 h post-dose).7 The concentration of aciclovir in CSF was determined by using HPLC coupled with a UV detection method using 100 μL of CSF. The method was linear over the concentration range from 0.04 to 8 mg/L. The lower limit of quantification was 0.04 mg/L. A total of 39 children were included from 2016 to 2017. The mean age and weight were 5.8 (range, 2.5 to 11.3) years and 22.4 (range, 13 to 57.5) kg, respectively. All children received standard dosing of aciclovir (10 mg/kg q8h) as part of their routine clinical care. The CSF samples were taken at a mean of 8 (range, 6 to 15) days after treatment. A total of 39 CSF samples were obtainable for analysis with a mean trough concentration of 0.24 (range, 0.11 to 0.43) mg/L. The distribution of aciclovir trough concentration is shown in Figure 1. Figure 1. View largeDownload slide Distribution of aciclovir trough concentration. Figure 1. View largeDownload slide Distribution of aciclovir trough concentration. As shown by our results, the aciclovir CSF trough concentation after receiving the standard dosing could not achieve the pharmacodynamic targets of herpes simplex virus (HSV; 1.0 mg/L) or varicella zoster virus (VZV; 0.45 mg/L) infection.6,8 The inadequate aciclovir exposure may be one of the significant causes of high mortality and poor neural outcomes among survivors of viral encephalitis. In infants with CNS HSV infection, after giving the standard dose of aciclovir, the neurodevelopment non-normalization rates at 12 months after treatment reached 71%.3 A high dosing regimen of 20 mg/kg q8h has been suggested in neonates with CNS disease and showed reduced mortality and improved neurodevelopment.2 Moreover, treatment with inadequate doses of aciclovir might also increase viral persistence and lead to the selection of resistant strains of virus.9 The prevalence of aciclovir-resistant HSV infection has reached 36% in transplant patients.10 In conclusion, to our knowledge, aciclovir CSF concentration has been systematically evaluated for the first time in children suffering from viral encephalitis. The results demonstrated underdosing in most children. The standard dosage regimen of 10 mg/kg q8h was not sufficient for children with viral encephalitis caused by HSV or VZV. Funding This work was supported by the Science and Technology Planning Project of Hebei Province (15277705D), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), the Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security, CG2016030001) and the Hundred-Talent Program (The People’s Government of Hebei Province, E2015100010). Transparency declarations None to declare. References 1 Kimberlin DW , Lakeman FD , Arvin AM et al. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease . J Infect Dis 1996 ; 174 : 1162 – 7 . Google Scholar CrossRef Search ADS PubMed 2 Kimberlin DW , Lin CY , Jacobs RF et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections . Pediatrics 2001 ; 108 : 230 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Whitley R , Arvin A , Prober C et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection . N Engl J Med 1991 ; 324 : 444 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Engman ML , Adolfsson I , Lewensohn-Fuchs I et al. Neuropsychologic outcomes in children with neonatal herpes encephalitis . Pediatr Neurol 2008 ; 38 : 398 – 401 . Google Scholar CrossRef Search ADS PubMed 5 Steiner I , Budka H , Chaudhuri A et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management . Eur J Neurol 2010 ; 17 : 999 – e57 . Google Scholar CrossRef Search ADS PubMed 6 Sampson MR , Bloom BT , Lenfestey RW et al. Population pharmacokinetics of intravenous acyclovir in preterm and term infants . Pediatr Infect Dis J 2014 ; 33 : 42 – 9 . Google Scholar CrossRef Search ADS PubMed 7 Zhao W , Jacqz-Aigrain E. Author's reply to Standing et al. Pharmacokinetic studies in neonates: the utility of an opportunistic sampling design . Clin Pharmacokinet 2015 ; 54 : 1289 – 91 . Google Scholar CrossRef Search ADS PubMed 8 Jacobson MA , Berger TG , Fikrig S et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) . Ann Intern Med 1990 ; 112 : 187 – 91 . Google Scholar CrossRef Search ADS PubMed 9 Hoppenjans WB , Bibler MR , Orme RL et al. Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome . Arch Dermatol 1990 ; 126 : 1048 – 50 . Google Scholar CrossRef Search ADS PubMed 10 Langston AA , Redei I , Caliendo AM et al. Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation . Blood 2002 ; 99 : 1085 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial Chemotherapy – Oxford University Press

Published: Jun 6, 2018

References

  • Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease
    Kimberlin
  • Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections
    Kimberlin
  • A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection
    Whitley
  • Neuropsychologic outcomes in children with neonatal herpes encephalitis
    Engman
  • Viral meningoencephalitis: a review of diagnostic methods and guidelines for management
    Steiner
  • Population pharmacokinetics of intravenous acyclovir in preterm and term infants
    Sampson
  • Author's reply to Standing et al. Pharmacokinetic studies in neonates: the utility of an opportunistic sampling design
    Zhao
  • Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS)
    Jacobson
  • Prolonged cutaneous herpes zoster in acquired immunodeficiency syndrome
    Hoppenjans
  • Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation
    Langston