Pediatric Syringe Pump

In January 2014, ALiEM featured a must-read post by Bryan Hayes regarding proper dosing of vancomycin in the emergency department, including a special note related to the recommendations regarding consideration of loading doses of vancomycin ranging from 25 to 30 mg/kg in adult patients who are critically ill with a high suspicion for MRSA infection.

Recommended pediatric dosing of vancomycin

In pediatric patients with serious and/or invasive infection, the recommended dosing regimen of vancomycin is:1

15 mg/kg/dose administered every 6 hours

Challenges associated with aggressive empiric dosing of vancomycin in pediatrics

Although a number pharmacokinetic models have established that such a dosing scheme may achieve a desired area under the curve/minimum inhibitory concentration (AUC:MIC) ratio of at least 400 mcg • hr/mL,2,3 several studies in pediatric patients have demonstrated that even this aggressive regimen does not lead to desired associated serum concentrations of 15 to 20 mcg/mL for serious infections when measured at steady state.4,5

Is more aggressive empiric dosing necessary?

Results of the recently published Pediatric Assessment of Vancomycin Empiric Dosing (PAVED) study suggest that empiric dosing of vancomycin in pediatric patients may need to be more aggressive based on age and desired therapeutic concentration:6

Desired Therapeutic Concentration Age
1 to 6 years >6 years
10 to 15 mcg/mL 70 mg/kg/day divided q6h 60 mg/kg/day divided q8h
15 to 20 mcg/mL 90 mg/kg/day divided q6h 70 mg/kg/day divided q6h

Pharmacokinetic considerations in pediatrics

Pharmacokinetic parameters to be considered in pediatric patients related to vancomycin include the following:

  • Volume of distribution (Vd): Neonates and young infants tend to possess higher apparent volumes of distribution. As a result, these patients may exhibit lower plasma concentrations following the administration of hydrophilic medications such as vancomycin.7
  • Clearance: Age-dependent variations in clearance of occur in the early stages of life, with peak clearance generally occurring between 2 and 6 years of age before decreasing and ultimately reaching the adult plateau by puberty.8

Is a loading dose of vancomycin the answer in pediatrics?

Given the physiological and pharmacokinetic challenges of vancomycin in pediatric patients, can these be overcome with a loading dose of vancomycin in pediatric patients? That is, does a loading dose of 25-30 mg/kg of vancomycin hold any benefit in critically ill pediatric patients in achieving therapeutic concentrations without posing a serious risk for toxicity?

Clinical studies

Surprisingly, the evidence for loading doses of vancomycin is relatively scarce in the pediatric population.

  • STUDY 1: In a prospective, double-blind study conducted by Demirjian and colleagues,9 59 patients between the ages of 2 and 18 years of age were randomized to receive either a loading dose of vancomycin of 30 mg/kg or a standard dose of 20 mg/kg, both followed by a standard dose of 20 mg/kg administered every 8 hours.
    • At 8 hours post-infusion of the first dose, 11% of patients in the loading dose group (2/19) attained a serum concentration of 15 to 20 mcg/mL compared to none of the 27 patients in conventional dosing group (p = 0.17).
    • Yet, pharmacokinetic analyses demonstrated no measurable differences in achievement of AUC:MIC, as both groups reached levels greater than 400 mcg • hr/mL (p = 0.79).
    • In terms of adverse effects:
      • Red man syndrome occurred in 48% and 24% of patients in the loading dose and conventional dosing groups, respectively (p = 0.06).
      • In addition, serum creatinine doubled from baseline values within 7 days of initiation of vancomycin in 4 patients in the loading dose group (13%) versus 1 patient in the conventional dosing group (3%) (p = 0.14).
    • Conclusion: A loading dose did not necessarily lead to rapid achievement of therapeutic concentrations, and systemic exposure to vancomycin was sufficient, based on observed AUC:MIC, in both treatment arms.
  • STUDY 2: Bartlett and colleagues evaluated the effects of vancomycin loading doses based on subsequent trough concentrations in a single center retrospective study.10
    • 54 pediatric patients who were at least 3 months in age were included in the analysis.
    • 11 patients who received a loading dose of vancomycin had higher initial median steady state concentrations relative to those who received conventional dosing of vancomycin (10.5 mcg/mL versus 9.8 mcg/mL).
    • Loading doses of vancomycin ranged from 18 to 27 mg/kg, and none of these patients experienced nephrotoxicity.
    • Conclusion: Loading doses of vancomycin are associated with higher initial trough concentrations, and that more aggressive dosing strategies for vancomycin may be of benefit in pediatric patients.

Application to clinical practice

Clinical outcomes such as eradication of confirmed infection, length of stay, and mortality remain to be observed in this patient population. With the limited and inconsistent data associated with loading doses of vancomycin in pediatric patients, it is somewhat challenging to validate or contest its use as a standard practice in this population.

Take home point

Until we have more investigations to validate the results of the PAVED study related to more aggressive dosing of vancomycin, pediatric patients should still be prescribed a vancomycin dose of 15 mg/kg/dose every 6 hours. Loading doses of vancomycin of 25-30 mg/kg may be considered on a case-by-case basis in critically ill pediatric patients.

1.
Liu C, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-55. [PubMed]
2.
Le J, Bradley J, Murray W, et al. Improved vancomycin dosing in children using area under the curve exposure. Pediatr Infect Dis J. 2013;32(4):e155-63. [PubMed]
3.
Frymoyer A, Guglielmo B, Wilson S, Scarpace S, Benet L, Hersh A. Impact of a hospitalwide increase in empiric pediatric vancomycin dosing on initial trough concentrations. Pharmacotherapy. 2011;31(9):871-876. [PubMed]
4.
Frymoyer A, Hersh A, Benet L, Guglielmo B. Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009;28(5):398-402. [PubMed]
5.
Eiland L, English T, Eiland E. Assessment of vancomycin dosing and subsequent serum concentrations in pediatric patients. Ann Pharmacother. 2011;45(5):582-589. [PubMed]
6.
Rainkie D, Ensom M, Carr R. Pediatric Assessment of Vancomycin Empiric Dosing (PAVED): a Retrospective Review. Paediatr Drugs. 2015;17(3):245-253. [PubMed]
7.
Kearns G, Abdel-Rahman S, Alander S, Blowey D, Leeder J, Kauffman R. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167. [PubMed]
8.
Neuman G, Nulman I, Adeli K, Koren G, Colantonio D, Helldén A. Implications of serum creatinine measurements on GFR estimation and vancomycin dosing in children. J Clin Pharmacol. 2014;54(7):785-791. [PubMed]
9.
Demirjian A, Finkelstein Y, Nava-Ocampo A, et al. A randomized controlled trial of a vancomycin loading dose in children. Pediatr Infect Dis J. 2013;32(11):1217-1223. [PubMed]
10.
Bartlett A, Brown-Alm D, Landon E, et al. Vancomycin loading dose in pediatric patients receiving intermittent vancomycin dosing. Abstract 162. Presented at ID Week; October 2-6, 2013; San Francisco, CA.
Nadia Awad, PharmD, BCPS
Emergency Medicine Pharmacist
Robert Wood Johnson University Hospital
Staff Blogger at Emergency Medicine PharmD
Nadia Awad, PharmD, BCPS

@Nadia_EMPharmD

Emergency Medicine Pharmacist, RWJUH | Associate Editor, EMPharmD and ALiEMU Capsules | Striving to maintain the faith and make a difference. #FOAMed