Pharmacokinetics of prophylactic cefazolin in parturients undergoing cesarean delivery

Abstract

The objectives of this work were (i) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (ii) to assess cefazolin transplacental transmission; (iii) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (iv) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g of cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 liters. [corrected] The values for pre- and postdelivery clearance were 7.18 and 4.12 liters/h, respectively. Computer simulations revealed that the probability of maintaining free cefazolin concentrations in plasma above 8 mg/liter during scheduled caesarean surgery was <50% in the cord blood when cefazolin was administered in doses of <2 g or when it was administered <1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates >5 h after birth. Cefazolin clearance increases during pregnancy, and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates than in adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates.

FIG 1

Pharmacokinetic model for cefazolin disposition in pregnant women and their neonates. C_M, C_UC, and C_N denote concentration in the blood of mothers, umbilical cord, and neonates, respectively. CL_preg and CL_postpreg denote clearance during and after pregnancy, respectively. V is the maternal volume of distribution. K_eq is the mother-to-cord equilibration rate constant, and K_N0 is the neonatal elimination rate constant.

FIG 2

Cefazolin observed versus population (open circles) and individual (closed squares) predicted total concentrations in maternal (A), cord (B), and neonatal (C) blood. The identity line is shown.

FIG 3

Conditional weighted residuals versus population predicted cefazolin total concentrations in maternal (A), cord (B), and neonatal (C) blood. The zero line is shown.

FIG 4

Conditional weighted residuals versus time (in hours) in maternal (A), cord (B), and neonatal (C) blood. The zero line is shown.

FIG 5

Visual predictive check of the final pharmacokinetic model for total cefazolin plasma concentrations in maternal blood. The dashed lines represent the 5th, 50th, and 95th percentiles of observed concentrations. The shaded areas represent the 95% confidence interval (95% CI) for the 5th, 50th, and 95th percentiles of simulated concentrations. The circles represent the binned observed concentrations.

FIG 6

Visual predictive check of the final pharmacokinetic model showing comparison between the median (dashed line) and 90% prediction interval (shaded area) obtained from 1,000 simulations and the observed data (circles) for cefazolin total concentrations in cord (A) and neonatal (B) blood.

FIG 7

Response surface plot of the joint probability of maintaining free cefazolin plasma concentration of ≥8 μg/ml during surgery in maternal and cord blood as a function of dose and delay till surgery.

FIG 8

Box plot of the marginal probability of maintaining free cefazolin plasma concentration of ≥8 μg/ml during surgery in maternal (black) or cord (gray) blood following administration of 1 g (A), 1.5 g (B), or 2 g (C) as a function of delay between drug administration and surgery.