Comparative
Pharmacokinetics of Ceftiofur in Neonatal Foals and Adult Horses
W.
David Wilson and Judy E. Mihalyi
University
of California School of Veterinary Medicine, Department
of Medicine and Epidemiology, Davis,
CA 95616
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
Kinetic
Parameter
(Units)
|
Age
of Horse
|
1
Day
(mean
± sd)
|
3
Days
(mean
± sd)
|
7
Days
(mean
± sd)
|
14
Days
(mean
± sd)
|
28
Days (mean ± sd)
|
Adult
(mean
± sd)
|
t
1/2a* (h)
|
0.122
|
0.052
|
0.029
|
0.040
|
0.031
|
0.056
|
t1/2b* (h)
|
3.5
|
3.03
|
2.43
|
2.26
|
2.46
|
1.57
|
MRT
(h)
|
4.64±0.34
|
4.16±0.61
|
3.34±0.28
|
3.17±0.23
|
3.33±0.41
|
1.94±0.30
|
ClB
(ml/min· kg)
|
4.82±0.64
|
6.27±1.74
|
5.65±0.84
|
5.17±0.77
|
5.12±1.49
|
9.56±2.73
|
V'd
(area) (ml/kg)
|
1467±194.0
|
1737±698.0
|
1197±219.3
|
1027±203.8
|
1101±349.8
|
1361±489.7
|
V'd(ss)
(ml/kg)
|
1351±149.1
|
1574±545.0
|
1139±223.2
|
988±186.1
|
1027±324.3
|
1118±364.4
|
AUC
(mg· h/ml)
|
17.62±2.78
|
14.07±3.34
|
15.10±2.82
|
15.98±3.26
|
17.43±4.89
|
9.33±2.66
|
*Denotes
harmonic mean