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Comparative
Pharmacokinetics of Ceftiofur in Neonatal Foals and Adult Horses Introduction and Objectives Bacterial infections are the leading cause of death in foals during the first month of life. Ceftiofur, a 3rd-generation cephalosporin, shows excellent in vitro activity against many Gram-positive and Gram-negative bacteria, including E. coli, Actinobacillus spp, and other important pathogens of neonatal foals. This antimicrobial has recently been approved for treating Streptococcal respiratory tract infections in horses at a 24-hour dosage interval and at doses (2.2 to 4.4 mg/kg IM) substantially lower than those recommended for use of other 3rd-generation cephalosporins. The pharmacokinetics of ceftiofur administered IM to foals and adult horses have been reported, but no data is available concerning the pharmacokinetics of ceftiofur after IV use, the preferred administration route for critically ill foals. The objectives of this study were: 1. To determine the pharmacokinetics of ceftiofur after IV administration IV administration to foals and adult horses, and to use this data as a basis for age-specific dosage recommendations. 2. To derive information regarding functional maturity of the excretory pathways for ceftiofur in foals. Materials and Methods Single bolus doses of ceftiofur sodium (NaxcelÒ, Upjohn) were administered IV (5 mg/kg) to 6 normal foals on 5 occasions at 1, 3, 7, 14 and 28 days of age and to mares on one occasion when their foals were 28 days old. Blood samples were collected into heparinized evacuated tubes before, and at intervals for 24 hours after administration of each dose. Ceftiofur concentrations in plasma samples were measured using a microbiologic (Providencia alcalifaciens) assay with a lower limit of detection of 0.15 mg/ml. Plasma concentration-time profiles were analyzed using a 2-compartment open pharmacokinetic model and values for the major pharmacokinetic constants and exponents (A, B, a and b) were obtained using a curve-fitting computer program (AUTOAN) based on nonlinear iterative least squares regression analysis. Values for the major pharmacokinetic terms (distribution half-life [t1/2a], elimination half-life [t1/2b], mean residence time [MRT], body clearance [ClB], volume of distribution [V'd(area)], volume of distribution at steady rate [V'd(ss)], and area under the curve [AUC]) were calculated using standard equations, as were the predicted mean, minimum, and maximum plasma concentrations of ceftiofur at steady-state using IV doses of 2.2 mg/kg and 5.0 mg/kg at 12 hour intervals. Results Ceftiofur was widely distributed in the body, as evidenced by volumes of distribution which exceeded 1000 ml/kg for adult horses and for foals at all ages (Table 1). Ceftiofur was cleared more slowly by foals than by adult horses and there was a progressive decline in values for t1/2b and MRT between 1 day and 7 days of age, with a further decline in values between 28-day-old foals and adult horses (Table 1). Mean values for t1/2a were 3.5, 3.1, 2.4, 2.3, 2.5 and 1.6 hours for foals aged 1, 3, 7, 14 and 28 days, and adult horses, respectively. Corresponding values for MRT were 4.6, 4.2, 3.3, 3.2, 3.3 and 1.9 hours, respectively. Values for clearance increased from 4.8 ml/min/kg in 1-day-old foals to 9.6 ml/min/kg in adult horses (Table 1). Dosage calculations were determined based on the mean data for each age group and a dose of 2.2 mg/kg IV revealed that predicted maximum plasma concentrations of ceftiofur at steady-state would be below 2.5 mg/ml for all age groups. Maximum plasma concentrations at steady-state exceeding 3 mg/ml would be predicted for all age groups using a dosage regimen of 5 mg/kg IV administered at 12 hour intervals, although this dosage regimen would result in minimum concentrations below 0.1 mg/ml in adult horses. Discussion and Conclusions The mechanisms involved in the metabolism and elimination of ceftiofur are functional at birth and undergo rapid maturation during the first week of life. Further development appears to be negligible through 1 month of age, but substantial additional maturation of excretory mechanisms occurs before horses reach adulthood. Dosage calculations revealed that, whereas ceftiofur sodium administered IV to foals at a dose of 5 mg/kg at 12 hour intervals will likely maintain appropriate peak (> 3.0 mg/ml) and trough (> 0. 15 mg/ml) plasma concentrations for treating infections caused by susceptible Gram-negative and Gram-positive bacteria, this dosage regimen is unlikely to be optimal for treating Gram-negative infections in adult horses. This conclusion likely also applies when the lower dose (2.2 mg/kg administered at 24 hour intervals) recommended for treating infections caused by highly susceptible P-hemolytic Streptococcus spp. is used to treat infections with less susceptible Gram-negative bacteria in horses of any age. Plasma concentrations of ceftiofur administered IV in this study were approximately half those observed in a published study in which ceftiofur was administered to foals by the recommended IM route. These results suggest that the IM route of administration for ceftiofur may be more appropriate than the IV route. We speculate that rapid IV administration may overwhelm the ability of enzyme systems to convert ceftiofur to the more highly protein bound desfuroylceftiofur metabolite and may result in rapid renal elimination of a substantial fraction of the less highly protein bound parent drug. Table 1. Pharmacokinetics of Ceftiofur (5 mg/kg IV) in Foals and Adult Horses
*Denotes harmonic mean
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