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Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for

Kensuke Shoji1, John S Bradley2, Michael D Reed3

  • 1Center for Research in Pediatric and Developmental Pharmacology, University of California, San Diego, La Jolla, and Rady Children's Hospital, San Diego, California, USA National Center for Child Health and Development, Tokyo, Japan.

Antimicrobial Agents and Chemotherapy
|January 27, 2016
PubMed

Insights

New pediatric dosing guidelines for cefepime (CFP) are needed for susceptible-dose dependent (SDD) Enterobacteriaceae. Simulations suggest extended intravenous infusions of CFP are effective for treating serious infections in children.

Area of Science:

  • Pharmacology
  • Pediatric Infectious Diseases
  • Clinical Microbiology

Background:

  • The Clinical and Laboratory Standards Institute (CLSI) updated cefepime (CFP) breakpoints in 2014, reclassifying certain MICs as susceptible-dose dependent (SDD).
  • Optimal pediatric dosing regimens for CFP against SDD organisms remain undefined, posing a challenge for effective treatment.

Purpose of the Study:

  • To analyze cefepime (CFP) pharmacokinetic (PK) data from published pediatric studies.
  • To determine appropriate CFP dosage regimens for pediatric patients with infections caused by SDD organisms using population PK modeling and Monte Carlo simulations.

Main Methods:

  • Analyzed 664 CFP plasma concentrations from 91 neonates, infants, and children.
  • Utilized NONMEM for population PK parameter estimation.
  • Conducted Monte Carlo simulations to evaluate dosing regimens and predict drug exposure.

Main Results:

  • Serum creatinine (SCR) and postmenstrual age (PMA) were identified as significant covariates in the CFP PK model.
  • A dosing regimen of 50 mg/kg every 8 hours (q8h) via 0.5-hour intravenous (i.v.) infusion achieved target free-CFP concentrations (>4 and >8 μg/ml) for over 60% of the dose interval in 87.1% and 68.6% of pediatric patients (≥30 days), respectively.
  • Extending i.v. infusion duration to 3 hours increased the probability of achieving free-CFP levels >8 μg/ml for >60% of the dose interval to 92.3%.

Conclusions:

  • Standard CFP dosing (50 mg/kg q8h-q12h) may be inadequate for older children with serious Gram-negative infections and MICs of 8 μg/ml.
  • Prolonged i.v. infusions of cefepime (CFP) show promise for optimizing therapeutic drug concentrations in pediatric patients with SDD organisms.

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