Amy Holmes

Dose & administration Acyclovir is dosed 20mg/kg/dose IV at intervals depending on gestational age. Specifically, Sampson et al (PMID: 24346595) recommend dosing intervals to be 12 hours (q12h) in infants < 30 weeks PMA; 8 hours (q8h) in infants 30 to <36 weeks PMA; and 6 hours (q6h) in infants 36-41 weeks PMA. Administer over one hour in order to prevent adverse effects. For congenital HSV infections, treatment course depends on type of infection. SEM disease is treated for 14 days. Disseminated and CNS infections require a minimum of 21 days of therapy. Asymptomatic infants born to mothers with active genital lesions may require 10 days of treatment. Oral acyclovir may be used for suppressive therapy following completion of full IV course. This dose is 300mg/m2 PO three times daily. Indications Acyclovir is most commonly used in the neonatal population as treatment for congenital herpes simplex infections. It may also be used for chronic suppression of HSV or for treatment of herpes zoster infection. Contraindications and special considerations (incl incompatibilities) The risk of nephrotoxicity is increased when acyclovir is administered in conjunction with other nephrotoxic drugs. Acyclovir’s incompatibilities include: dopamine, dobutamine, epinephrine, fat emulsions, aztreonam, caffeine, caspofungin, cefepime, meropenem, piperacillin/tazobactam, and parenteral nutrition solutions. Adverse effects The most common adverse effects are neutropenia and renal dysfunction secondary to crystalluria. Ensuring adequate hydration during therapy can prevent crystalluria and subsequent renal dysfunction. Frequent monitoring of CBCs can detect neutropenia. With a pH of 10, acyclovir can cause phlebitis and may be very damaging to tissue if extravasation occurs. One might consider using a dedicated PICC-line for acyclovir administration. Pharmacological aspects Acyclovir works by inhibiting viral DNA synthesis. Its primary route of elimination is renal. Postmenstrual age has been determined to be the variable with the most significant influence on clearance of acyclovir. References Oral acyclovir suppression and neurodevelopment after neonatal herpes. NEJM. 2011;365:1284-92. PMID 21991950. Population pharmacokinetics of intravenous acyclovir in preterm and term infants. Pediatr Infect Dis J. 2014;33:42-9. PMID 24346595. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013;131:e635-e646. PMID 23359576. The use of antiviral drugs during the neonatal period. Clin Perinatol. 2012;39:69-81. PMID 22341538. Document version history Created 2016/6/26 / Amy Holmes

Dose & administration There are different schools of thought regarding gentamicin dosing in neonates and tertiary dosing references vary in their dosing recommendations. Commonly accepted dosing regimens include both a gestational age based dosing approach as well as birth-weight based dosing approach. Doses range from 4-5mg/kg per dose administered every 24 to 48 hours with lower gestational ages requiring the higher weight based dosing and longer dosing interval than older gestational age infants. The NICE guidelines (UK) recommend 5 mg/kg every 36 hours as the starting dose. The dose and interval should be guided by measurements of blood gentamicin concentrations, typically immediately before the second dose and before later doses if the serum concentration is high. The recommended concentration is < 2 mg/L. Indications Widely used in the NICU in combination with a beta lactam or other antibiotic as empiric therapy in both early onset and late onset sepsis. Contraindications and special considerations (including incompatibilities) Caution should be used in infants with decreased renal function or history that might suggest poor renal perfusion such as asphyxiation, indomethacin exposure, PDA, etc. May interact with neuromuscular blockers. Additional monitoring of gentamicin levels may be required during ECMO and/or therapeutic hypothermia as either may affect gentamicin pharmacokinetics. Target peaks of 8-12 mcg/mL; target troughs < 1 to minimize toxicity. Due to incompatibility, gentamicin should not be administered in the same line with ampicillin, indomethacin, amphotericin B, and furosemide. Adverse effects Nephrotoxicity Ototoxicity May enhance neuromuscular blockade when administered concomitantly with neuromuscular blockers Pharmacological aspects Gentamicin, like other aminoglycosides, exhibits its action by inhibiting protein synthesis by irreversibly binding to ribosomal RNA of the microorganism. Gentamicin is active against Gram-negative bacteria including Pseudomonas aeruginosa. It may be used with other agents for synergy against Gram-positive organisms, but should not be used alone to treat these infections. Aminoglycosides are concentration dependent antibiotics. They work best when the serum concentration of the drug reaches very high concentrations. Conversely, they also possess a unique property known as post-antibiotic effect where bacterial killing continues to occur when the drug is no longer present in appreciable amounts in the bloodstream. References Neonatal infection: antibiotics for prevention and treatment. NICE guidelines [CG149]. 2012. https://www.nice.org.uk/guidance/CG149/ Effect of hypothermia and extracorporeal life support on drug disposition in neonates. Seminars in Fetal & Neonatal Medicine. 2013; 18(1): 23-27. PMID 23158109. Dose optimisation of antibiotics in children: application of pharmacokinetics/ pharmacodynamics in paediatrics. Int J Antimicrob Agents. 2014 Mar;43(3):223-30. PMID: 24389079. Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study. Clin Pharmacokinet. 2009 Jan;48(4):253-63. PMID: 19492870. Document version history Created 2016/06/22 / Amy Holmes