Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease.



Neonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991.


Determine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs).

Study design

We obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model.


Infants <120 days of age with neonatal HSV discharged from four academic children's hospitals.

Outcome measures

We identified clinical and laboratory adverse events (AEs).

Results and conclusions

We identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2-37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.





Published Version (Please cite this version)


Publication Info

Ericson, Jessica E, Daniel K Benjamin, Felix Boakye-Agyeman, Stephen J Balevic, C Michael Cotten, Felice Adler-Shohet, Matthew Laughon, Brenda Poindexter, et al. (2022). Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease. Early human development, 170. p. 105616. 10.1016/j.earlhumdev.2022.105616 Retrieved from https://hdl.handle.net/10161/26055.

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Stephen Joseph Balevic

Associate Professor of Pediatrics

I am an Adult and Pediatric Rheumatologist and care for patients with a wide variety of autoimmune and rheumatic diseases, including: systemic lupus, rheumatoid arthritis, juvenile arthritis, vasculitis, and sarcoidosis, among others. I have a special interest in using musculoskeletal ultrasound to optimize diagnosis and treatment decisions at the bedside.

I am also a clinical researcher at the Duke Clinical Research Institute (DCRI). My research interests are in clinical trials and precision medicine through population pharmacokinetic/pharmacodynamic modeling. I obtained my PhD in Pharmaceutical Sciences from the UNC Eshelman School of Pharmacy. I serve as the principal investigator on several grants studying hydroxychloroquine and azathioprine pharmacokinetics and exposure-response in lupus, as well as principal investigator or co-investigator for several clinical trials at the DCRI. Additionally, I am an Assistant Scientific Director for the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry- the largest registry of children with rheumatic diseases in North America.


Charles Michael Cotten

Professor of Pediatrics

I am involved in 4 major areas of research:
1) Neuroprotection. Working with colleagues from Cell Therapies, we have added to Duke's experience participating in pivotal trials of hypothermia for term newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE) by completing, with Duke CTSI support,  phase I studies of autologous cord blood cells and allogeneic cord tissue derived mesenchymal stromal cells for these infants.  and developing and currently leading a multicenter, double-blind randomized clinical trial of autologous cord blood cells or placebo in term infants with moderate or severe HIE. 
2) Genomics. We at Duke have been in the NICHD Neonatal Research Network (NRN) since 2001. I led the NRN's development of an Anonymized DNA bank of samples collected from 1,000 extremely low birthweight infants, with phenotype information linked to the samples. This resource has been the basis for multiple candidate gene, and genome wide scan analysis, and has identified variants associated with severe retinopathy of prematurity and necrotizing enterocolitis. We partnered with the Vermont Oxford Network-Rady Genomics collaborative to bring 48 hour turnaround Whole Genome Sequencing to patients in the Duke Intensive Care Nursery, and are continuing work with Medical Genetics faculty to keep Duke at the forefront of testing the effectiveness of applied next-gen sequencing in the NICU. 
3) New Technologies: I  collaborated with Drs. David Millington from Duke and Vamsee Pamula (a Duke Pratt School graduate), from BAEBIES Inc, on prototype new technology devices for use in newborn screening for lysosomal storage disease as well as multiplex chips for screening for hyperbilirubinemia and related conditions, as well as working with Dr. Pamula and Dr. Michael Freemark (Peds Endocrinology) on screening panels for hypoglycemia and hypothyroidism, and with investigators from UAB on an Acute Kidney Injury panel.  I continue active collaborations with Dr. Cynthia Toth and the DARSI lab in pediatric ophthalmology, and Pratt School investigators to develop and apply use of optical coherence tomography (OCT) for retinal imaging that will assess associations between retinal neurovascular development, brain development, and neurodevelopmental outcomes. We continue with a comparative trial of the value and effectiveness of utilization of OCT compared with the current standard indirect ophthalmoscopy for ROP screening in the NICU. 
4)Microbiome in Micropreemies and health outcomes of periviable infants.  I have worked with multiple epidemiology researchers to assess practice variation within our center, and within the Neonatal Research Network centers, to identify how variation in practice can influence outcomes, with a particular focus on antibiotic use. This work demonstrated strong associations between high empirical antibiotic use in infants with sterile cultures and subsequent morbidities and mortality. This discovery has led to strong collaborations and new initiatives by early career faculty leading studies of the evolving microbiome, leading to hypothesis generation re: the microbiome and optimal growth in extremely preterm infants.


Phillip Brian Smith

Samuel L. Katz Distinguished Professor of Pediatrics

Dr. Smith completed his residency in pediatrics and a fellowship in neonatal medicine at Duke University Medical Center in 2004 and 2007, respectively. He completed an MHS in clinical research from Duke University in 2006 and an MPH in biostatistics from the University of North Carolina at Chapel Hill in 2009. His research is focused on pediatric drug safety, neonatal pharmacology, and the epidemiology of neonatal infections. Dr. Smith is or has been the protocol chair for more than 14 studies of drugs in infants and children. He is the Principal Investigator for the Environmental Influences on Child Health Outcomes (ECHO) Coordinating Center.

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