Pharmacokinetic and Pharmacodynamic Properties of Metronidazole in Pediatric Patients With Acute Appendicitis: A Prospective Study.

Abstract

BACKGROUND:

Metronidazole is traditionally dosed every 6-8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis.

METHODS:

One hundred pediatric patients aged 4-17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole.

RESULTS:

Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%-100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours.

CONCLUSIONS:

Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population.

• Authors: Jason Child, Xinhui Chen, Rakesh D Mistry, Stig Somme, Christine MacBrayne, Peter L Anderson, Ronald N Jones, Sarah K Parker
• Journal: Journal of the Pediatric Infectious Diseases Society (J Pediatric Infect Dis Soc) Vol. 8 Issue 4 Pg. 297-302 (Sep 25 2019) ISSN: 2048-7207 [Electronic] England
• PMID: 29788329 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Metronidazole

Topics

• Acute Disease
• Adolescent
• Appendicitis (drug therapy)
• Area Under Curve
• Bacteroides fragilis (drug effects)
• Child
• Child, Preschool
• Female
• Humans
• Male
• Metronidazole (administration & dosage, blood, pharmacokinetics)
• Microbial Sensitivity Tests
• Monte Carlo Method
• Prospective Studies