Albarellos, G. A., Montoya, L., Lorenzini, P. M., Passini, S. M., Lupi, M. P.,
Landoni, M. F. Pharmacokinetics of cefuroxime after intravenous,
intramuscular, and subcutaneous administration to dogs. J. vet. Pharmacol.
Therap. 39, 4044.
S. M. PASSINI*
M. P. LUPI* &
M. F. LANDONI
*Catedra de Farmacologa, Facultad de
Ciencias Veterinarias, Universidad de
Buenos Aires, Buenos Aires, Argentina;
INTRODUCTION
Cefuroxime is a second-generation cephalosporin with a
broader spectrum of activity. It is active against many grampositive (e.g., staphylococci and streptococci), gram-negative
(Enterobacteriaceae), and some anaerobes bacteria (Prescott,
2013). Although there is no information on cefuroxime susceptibility of bacteria isolated from animals, reports from
human medicine indicate that cefuroxime minimum inhibitory
concentration (MIC) could be as low as 0.015 lg/mL (MIC90
for S. pyogenes) (Dohar et al., 2004). However, it is usually
higher for other bacteria (MIC90 for staphylococci: 1 lg/mL
and MIC90 for E. coli: 4 lg/mL) (von Eiff et al., 2005; Lerma
et al., 2008). Susceptibility break point for human isolates is
0.5 lg/mL for Streptococcus pneumoniae and 8 lg/mL for Enterobacteriaceae (CLSI, 2014).
Efficacy of cephalosporins is related to the time that plasma
concentrations exceed the MIC, and a T > MIC of 4060% of
the dosing interval is the best efficacy predictor for assuring
40
Dosage forms
Pharmacokinetic analysis
Experimental design
A three-period, three-treatment crossover design was used. As
a result, each animal received cefuroxime i.v., i.m., and s.c. in
a randomized sequence.
For i.v. administration, cefuroxime was given via bolus (over
a 2 min period) through a catheter placed in the left cephalic
vein. For the i.m. route, the dose was administered in the dorsal lumbar muscles, and for the s.c. administration, the dose
was injected under the lateral ribcage skin. A 2-week washout
period elapsed between each phase.
Blood sampling
Samples (2.5 mL) were collected through a catheter placed in
the right cephalic vein prior antibiotic administration and at 5,
10, 20, 30, 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h.
Samples were taken with heparinized syringes, placed into
tubes, mixed, and kept on ice until plasma separation. Plasma
42 G. A. Albarellos et al.
Statistical analysis
Pharmacokinetic parameters are expressed as mean standard deviation. Main estimated pharmacokinetic parameters
were statistically compared for the different administration
routes, applying an ANOVA test (AUC(0t), AUC(0), t, MRT) or
a t test (ka, t(a), MAT, Tmax, Cmax, F) (GraphPad Prism,
GraphPad Software, version 5.00, 2007, San Diego, CA, USA).
Results were considered significant when P < 0.05.
IV
IM
SC
where AUCEV and AUCiv are the areas under the concentration
time curves for the extravascular routes (i.m. or s.c.) and the
i.v. administration, respectively.
100
10
MIC = 4 g/mL
MIC = 1 g/mL
0.1
PK/PD integration
Time above the minimum inhibitory concentration (T > MIC)
for the three studied administration routes was estimated by
visual approximation from the plasma concentration vs. time
curve. The MIC value applied was based on human reports
(staphylococci MIC90 = 1 lg/mL; E. Coli MIC90 = 4 lg/mL)
(von Eiff et al., 2005; Lerma et al., 2008).
RESULTS
No adverse effects were recorded by physical examination in
any of the dogs during or after cefuroxime administration.
The applied blood sample withdrawal schedules after i.v.,
i.m., and s.c. cefuroxime administration allowed a proper
description of the plasma concentrations vs. time curves as
shown in Fig. 1. Estimated pharmacokinetic parameters are
shown in Table 1.
Cefuroxime plasma concentrations after intravascular and
extravascular administrations were best fitted to a bicompartmental (i.v.) and a monocompartmental (with first-order input)
model (i.m. and s.c.).
After i.v. administration, cefuroxime showed a rapid distribution, reflected by the rate constant of the process (k1
10.73 8.25 h1) and its short half-life (T(d) 0.10
0.06 h). However, the extent of distribution was moderate,
with a volume of distribution (V(d(ss))) of 0.49 0.03 L/kg.
After i.v. administration, cefuroxime was rapidly eliminated
from the body as reflected by the high body clearance (ClB)
(0.34 0.04 L/hkg), short elimination half-life (T)
(1.12 0.19 h), and short mean residence time (MRT)
(1.49 0.21 h). Cefuroxime blood concentrations remained
above the LLOQ for 4 h in only three dogs.
Cefuroxime absorption was much slower after s.c. than after
i.m. administration, and this was evident (P < 0.05) when
parameters associated with this process (ka, T(a), Tmax, and
Cmax) were compared. However, extent of absorption was the
same for both extravascular routes, with a bioavailability of
Time (h)
79.70 14.43% and 77.22 21.41% for the i.m. and s.c.
administration, respectively.
Cefuroxime elimination after i.m. and s.c. administration
was rather similar, with identical body clearance (0.34
0.04 L/hkg) and similar elimination half-life (1.13 0.13 h,
i.m.; 1.04 0.23 h, s.c.). However, significant differences
were found when MRT values were compared. As body clearances were identical for the three routes, observed MRT differences should be consequence of an absorption delay after
extravascular administrations.
Cefuroxime blood concentration was above 0.40 lg/mL
(LLOQ) for 6 h after i.m. (5/6 dogs) and s.c. (6/6 dogs) administration.
Cefuroxime plasma concentrations above the MIC are shown
in Fig. 1. After i.m. and s.c. administration, T > MIC for more
susceptible bacteria (MIC 1 lg/mL) was 5.56 h, while for
less susceptible micro-organisms (MIC 4 lg/mL), this time
was 3.54 h.
DISCUSSION
Cefuroxime could be a good option to treat susceptible bacteria
causing infections in dogs. However, the lack of pharmacokinetic information makes impossible the design of a rational
administration schedule.
The results obtained on this study would be useful to optimize cefuroxime parenteral use in dogs.
Observed cefuroxime pharmacokinetic profile after i.v.
administration was the expected for a beta-lactam and similar
to that reported for dogs, goats, calves, and buffalo calves
(Soback et al., 1989; Chaudhary et al., 1999; Abo El-Sooud
Pharmacokinetic
Parameter
C1 (lg/mL)
C2 (lg/mL)
Cp(0) (lg/mL)
k1 (h1)
k2 (h1)
AUC(0t)
(lgh/mL)
AUC(0)
(lgh/mL)
K12 (h1)
K21 (h1)
K12/k21
T(d) (h)
Varea (L/kg)
V(d(ss)) (L/kg)
ka (h1)
T(a) (h)
MAT (h)
Tmax (h)
Cmax (lg/mL)
ClB (L/hkg)
T (h)
MRT (h)
F (%)
Intravenous
administration
(mean SD)
Intramuscular
administration
(mean SD)
Subcutaneous
administration
(mean SD)
45.93 8.50
43.69 8.33
47.56 8.17*
45.52 9.01*
8.43
0.13
0.31
0.43
22.99
0.34
1.13
1.79
79.70
1.47
0.50
0.72
0.99
15.37
0.34
1.04
2.21
77.22
38.15
34.94
73.09
10.73
0.63
52.29
22.87
4.26
23.62
8.25
0.11
6.69
60.13 6.91
4.95
5.16
0.81
0.10
0.53
0.49
0.34
1.12
1.49
5.45
2.68
0.54
0.06
0.04
0.03
0.04
0.19
0.21
6.39
0.09
0.37
0.20
7.87
0.04
0.13
0.24
14.43
0.38
0.14
0.32
0.10
3.07
0.04
0.23
0.23
21.41
ClB corrected by F.
et al., 2000; Zhao et al., 2012b) characterized by a fast distribution into the extracellular fluid and a relatively rapid renal
excretion.
The distribution process was rapid but, moderate in its
extension (high rate constant, short half-life, and moderate volume of distribution). These pharmacokinetic parameters
resulted rather similar to those reported for buffalo calves
(Chaudhary et al., 1999), goats (Abo El-Sooud et al., 2000),
and dogs (Zhao et al., 2012b). Also, pharmacokinetic parameters evaluating elimination process (high clearance, short halflife, and MRT) were very similar in the other studied species.
Zhao et al. (2012b) studied cefuroxime disposition in dogs at
2015 John Wiley & Sons Ltd
three intravenous doses (20, 40, and 80 mg/kg) demonstrating a linear pharmacokinetic. They report values of ClB of
0.31 L/hkg, t of 1.50 h, and MRT of 1.86 h, for the 20 mg/kg
dosage. These values are slightly different than those found in
the present study. Cefuroxime elimination lasted longer in the
study of Zhao et al. (2012b); this difference is modest and
could be explained by the more sensitive analytical method
(triple-quadrupole tandem mass spectrometer) used by these
authors.
Cefuroxime ClB (0.34 L/hkg) was higher than glomerular
filtration rate in dogs (0.24 L/hkg) (Baggot, 2001), indicating
that other mechanisms (e.g., renal tubular secretion) are
implicated in cefuroxime elimination as reported for humans
and other species (Foord, 1976; Soback et al., 1989; Tsuji,
2006).
Moderated pain was observed after i.m. administration,
although no reaction at the injection site (intramuscular or
subcutaneous) was clinically observed in any of the dogs.
After i.m. administration, cefuroxime absorption was faster
and Cmax higher than after s.c. administration. Moreover, after
s.c. administration, cefuroxime remained in the plasma longer
than after i.m. administration. These findings could be
explained through the flip-flop phenomenon, where terminal
T is reflecting the ka rather than the k. This pharmacokinetic
phenomenon would have clinical implications as it would prolong dosage intervals.
The most common cause for retardation of drugs absorption,
mainly after s.c. administration, is a local tissue reaction (irritation and inflammation) (Py
or
al
a et al., 1994). In fact, for
sodium cefuroxime a mild irritation, after subcutaneous administration to dogs, has been reported (Glaxo Laboratories,
1986).
Cefuroxime bioavailability after both extravascular administration routes was equally high (i.m., 79.70% and s.c.,
77.22%) without significant differences between them. The relatively longer permanence of cefuroxime in plasma when
administered extravascularly (especially subcutaneously) could
bring a bit more desirable plasma concentration profile in dogs
than after intravenous administration.
For beta-lactams, a T > MIC 50% of the dose interval has
been established as optimal for bactericidal action. At the dose
used in this study, a dose interval of 11 h (i.v., i.m.) or 12 h
(s.c.) would be effective for treating bacteria with a MIC value
of 1 lg/mL. However, for less susceptible bacteria (e.g.,
MIC 4 lg/mL), the dose interval should be shorter (8 h)
(i.m., s.c.).
More pharmacokinetic and pharmacodynamic studies are
necessary to support the present results. Furthermore, clinical
controlled trials are mandatory to establish proper cefuroxime
dosing schedules in dogs.
ACKNOWLEDGMENTS
The authors wish to thank to the personnel of Caniles, FCV,
and UBA for the technical assistance with the dogs employed
44 G. A. Albarellos et al.
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