Objective—To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.
Animals—6 healthy Beagles.
Procedures—In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling.
Results—When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t1/2) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t1/2 was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t1/2 of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%).
Conclusions and Clinical Relevance—Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.
Antibiotic recommendations for treating skin infections have been published many times in the past 30 years. Prior to 2000, the recommendations focused on the use of β-lactam antibiotics, such as cephalosporins, amoxicillin-clavulanate, or β-lactamase stable penicillins. These agents are still recommended, and used, for wild-type methicillin-susceptible strains of Staphylococcus spp. However, since the mid-2000s there has been an increase in methicillin-resistant Staphylococcus spp (MRSP). The increase among S pseudintermedius in animals coincided with the increase in methicillin-resistant S aureus that was observed in people near the same time. This increase led veterinarians to reevaluate their approach to treating skin infections, particularly in dogs. Prior antibiotic exposure and hospitalization are identified as risk factors for MRSP. Topical treatments are more often used to treat these infections. Culture and susceptibility testing is performed more often, especially in refractory cases, to identify MRSP. If resistant strains are identified, veterinarians may have to rely on antibiotics that were previously used uncommonly for skin infections, such as chloramphenicol, aminoglycosides, tetracyclines, and human-label antibiotics such as rifampin and linezolid. These drugs carry risks and uncertainties that must be considered before they are routinely prescribed. This article will discuss these concerns and provide veterinarians guidance on the treatment of these skin infections.
OBJECTIVE To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet.
ANIMALS 6 healthy dogs.
PROCEDURES Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography.
RESULTS IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension.
CONCLUSIONS AND CLINICAL RELEVANCE Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.
Objective—To estimate pharmacokinetic variables
and measure tissue fluid concentrations of meropenem
after IV and SC administration in dogs.
Animals—6 healthy adult dogs.
Procedure—Dogs were administered a single dose
of meropenem (20 mg/kg) IV and SC in a crossover
design. To characterize the distribution of meropenem
in dogs and to evaluate a unique tissue fluid collection
method, an in vivo ultrafiltration device was used to
collect interstitial fluid. Plasma, tissue fluid, and urine
samples were analyzed by use of high-performance
liquid chromatography. Protein binding was determined
by use of an ultrafiltration device.
Results—Plasma data were analyzed by compartmental
and noncompartmental pharmacokinetic
methods. Mean ± SD values for half-life, volume of
distribution, and clearance after IV administration for
plasma samples were 0.67 ± 0.07 hours, 0.372 ±
0.053 L/kg, and 6.53 ± 1.51 mL/min/kg, respectively,
and half-life for tissue fluid samples was 1.15 ± 0.57
hours. Half-life after SC administration was 0.98 ±
0.21 and 1.31 ± 0.54 hours for plasma and tissue fluid,
respectively. Protein binding was 11.87%, and
bioavailability after SC administration was 84%.
Conclusions and Clinical Relevance—Analysis of
our data revealed that tissue fluid and plasma
(unbound fraction) concentrations were similar.
Because of the kinetic similarity of meropenem in the
extravascular and vascular spaces, tissue fluid concentrations
can be predicted from plasma concentrations.
We concluded that a dosage of 8 mg/kg, SC,
every 12 hours would achieve adequate tissue fluid
and urine concentrations for susceptible bacteria with
a minimum inhibitory concentration of 0.12 µg/mL.
(Am J Vet Res 2002;63:1622–1628)
Objective—To compare plasma (total and unbound)
and interstitial fluid (ISF) concentrations of doxycycline
and meropenem in dogs following constant rate
IV infusion of each drug.
Animals—6 adult Beagles.
Procedure—Dogs were given a loading dose of
doxycycline and meropenem followed by a constant
rate IV infusion of each drug to maintain an 8-hour
steady state concentration. Interstitial fluid was collected
with an ultrafiltration device. Plasma and ISF
were analyzed by high performance liquid chromatography.
Protein binding and lipophilicity were determined.
Plasma data were analyzed by use of compartmental
Results—Compared with meropenem, doxycycline
had higher protein binding (11.87% [previously published
value] vs 91.75 ± 0.63%) and lipophilicity (partition
coefficients, 0.02 ± 0.01 vs 0.68 ± 0.05). A significant
difference was found between ISF and plasma
total doxycycline concentrations. No significant difference
was found between ISF and plasma unbound
doxycycline concentrations. Concentrations of
meropenem in ISF and plasma (total and unbound)
were similar. Plasma half-life, volume of distribution,
and clearance were 4.56 ± 0.57 hours, 0.65 ± 0.82
L/kg, and 1.66 ± 2.21 mL/min/kg, respectively, for doxycycline
and 0.73 ± 0.07 hours, 0.34 ± 0.06 L/kg, and
5.65 ± 2.76 mL/min/kg, respectively, for meropenem.
The ISF half-life of doxycycline and meropenem was
4.94 ± 0.67 and 2.31 ± 0.36 hours, respectively.
Conclusions and Clinical Relevance—The extent of
protein binding determines distribution of doxycycline
and meropenem into ISF. As a result of high protein
binding, ISF doxycycline concentrations are lower
than plasma total doxycycline concentrations.
Concentrations of meropenem in ISF can be predicted
from plasma total meropenem concentrations.
(Am J Vet Res 2003;64:1040–1046)
Objective—To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds.
Animals—6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg.
Procedures—A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device.
Results—Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration.
Conclusions and Clinical Relevance—Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.
Objective—To compare pharmacokinetics of
enrofloxacin administered IV and in various oral preparations
Animals—5 mature Katahdin ewes weighing 42 to 50
Procedure—Ewes received 4 single-dose treatments
of enrofloxacin in a nonrandomized crossover design
followed by a multiple-dose oral regimen. Single-dose
treatments consisted of an IV bolus of enrofloxacin
(5 mg/kg), an oral drench (10 mg/kg) made from
crushed enrofloxacin tablets, oral administration in
feed (10 mg/kg; mixture of crushed enrofloxacin
tablets and grain), and another type of oral administration
in feed (10 mg/kg; mixture of enrofloxacin solution
and grain). The multiple-dose regimen consisted of
feeding a mixture of enrofloxacin solution and grain (10
mg/kg, q 24 h, for 7 days). Plasma concentrations of
enrofloxacin and ciprofloxacin were measured by use
of high-performance liquid chromatography.
Results—Harmonic mean half-life for oral administration
was 14.80, 10.80, and 13.07 hours, respectively,
for the oral drench, crushed tablets in grain, and
enrofloxacin solution in grain. Oral bioavailability for the
oral drench, crushed tablets in grain, and enrofloxacin
in grain was 47.89, 98.07, and 94.60%, respectively,
and median maximum concentration (Cmax) was 1.61,
2.69, and 2.26 µg/ml, respectively. Median Cmax of the
multiple-dose regimen was 2.99 µg/ml.
Conclusions and Clinical Relevance—Enrofloxacin
administered orally to sheep has a prolonged half-life
and high oral bioavailability. Oral administration at 10
mg/kg, q 24 h, was sufficient to achieve a plasma concentration
of 8 to 10 times the minimum inhibitory
concentration (MIC) of any microorganism with an
MIC ≤ 0.29 µg/ml. (Am J Vet Res 2002;
Objective—To determine the pharmacokinetics of butorphanol in cats following IM and buccal transmucosal (BTM) administration, to determine the relative bioavailability of butorphanol following BTM administration, and to extrapolate a plasma concentration associated with antinociception on the basis of existing data from pharmacologic studies of butorphanol in cats.
Animals—6 healthy adult cats.
Procedures—Following IM or BTM butorphanol tartrate (0.4 mg/kg) administration to cats in a 2-way crossover trial, plasma samples were obtained from blood collected via a central venous catheter during a 9-hour period. Plasma butorphanol concentrations were determined by high-performance liquid chromatography.
Results—Data from 1 cat contained outliers and were excluded from pharmacokinetic analysis. Mean ± SD terminal half-life of butorphanol for the remaining 5 cats was 6.3 ± 2.8 hours and 5.2 ± 1.7 hours for IM and BTM administration, respectively. Peak plasma butorphanol concentrations were 132.0 and 34.4 ng/mL for IM and BTM administration, respectively. Time to maximal plasma concentration was 0.35 and 1.1 hours for IM and BTM administration, respectively. Extent of butorphanol absorption was 37.16% following BTM application. On the basis of data from extant pharmacologic studies of butorphanol in cats, mean ± SD duration of antinociception was 155 ± 130 minutes. The estimated plasma concentration corresponding to this time point was 45 ng/mL.
Conclusions and Clinical Relevance—In cats, IM butorphanol administration at 0.4 mg/kg maintained a plasma concentration of > 45 ng/mL for 2.7 ± 2.2 hours, whereas BTM administration at the same dose was not effective at maintaining plasma concentrations at > 45 ng/mL.
To determine the pharmacokinetics of levofloxacin following oral administration of a generic levofloxacin tablet and IV administration to dogs and whether the achieved plasma levofloxacin concentration would be sufficient to treat susceptible bacterial infections.
6 healthy adult Beagles.
Levofloxacin was administered orally as a generic 250-mg tablet (mean dose, 23.7 mg/kg) or IV as a solution (15 mg/kg) to each dog in a crossover study design, with treatments separated by a minimum 2-day washout period. Blood samples were collected at various points for measurement of plasma levofloxacin concentration via high-pressure liquid chromatography. Pharmacokinetic analysis was performed with compartmental modeling.
After oral administration of the levofloxacin tablet, mean (coefficient of variation) peak plasma concentration was 15.5 μg/mL (23.8%), mean elimination half-life was 5.84 hours (20.0%), and mean bioavailability was 104% (29.0%). After IV administration, mean elimination half-life (coefficient of variation) was 6.23 hours (14.7%), systemic clearance was 145.0 mL/kg/h (22.2%), and volume of distribution was 1.19 L/kg (17.1%).
CONCLUSIONS AND CLINICAL RELEVANCE
In these dogs, levofloxacin was well absorbed when administered orally, and a dose of approximately 25 mg/kg was sufficient to reach pharmacokinetic-pharmacodynamic targets for treating infections with susceptible Enterobacteriaceae (ie, ≤ 0.5 μg/mL) or Pseudomonas aeruginosa (ie, ≤ 1 μg/mL) according to clinical breakpoints established by the Clinical and Laboratory Standards Institute.
Objective—To determine plasma concentrations of
enrofloxacin and the active metabolite ciprofloxacin
after PO, SC, and IV administration of enrofloxacin to
Animals—6 adult female alpacas.
Procedure—A crossover design was used for administration
of 3 single-dose treatments of enrofloxacin
to alpacas, which was followed by an observational
14-day multiple-dose regimen. Single-dose treatments
consisted of IV and SC administration of
injectable enrofloxacin (5 mg/kg) and PO administration
of enrofloxacin tablets (10 mg/kg) dissolved in
grain to form a slurry. Plasma enrofloxacin concentrations
were measured by use of high-performance liquid
chromatography. The multiple-dose regimen consisted
of feeding a mixture of crushed and moistened
enrofloxacin tablets mixed with grain. Behavior,
appetite, and fecal quality were monitored throughout
the 14-day treatment regimen and for 71 additional
days following treatment.
Results—Mean half-life following IV, SC, and PO
administration was 11.2, 8.7, and 16.1 hours, respectively.
For SC and PO administration, mean total systemic
availability was 90.18% and 29.31%, respectively;
mean maximum plasma concentration was
3.79 and 1.81 µg/mL, respectively; and area under the
curve (AUC) was 50.05 and 33.97 (µg × h)/mL,
respectively. The SC or PO administration of a single
dose of enrofloxacin yielded a ratio for AUC to minimum
inhibitory concentration > 100 for many grampositive
and gram-negative bacterial pathogens common
Conclusions and Clinical Relevance—The administration
of enrofloxacin (5 mg/kg, SC, or 10 mg/kg, PO)
may be appropriate for antimicrobial treatment of
alpacas. (Am J Vet Res 2005;66:767–771)