OBJECTIVE To determine whether target values for pharmacokinetic-pharmacodynamic (PK-PD) indices against selected canine pathogens were achievable for pradofloxacin in various canine fluids and leukocytes.
ANIMALS 8 healthy adult hounds (experiments 1 and 2) and 6 healthy adult dogs (experiment 3).
PROCEDURES In 3 experiments, pradofloxacin (3, 6, or 12 mg/kg) and enrofloxacin (5 or 10 mg/kg) were orally administered once a day for 5 days, and blood, interstitial fluid (ISF), and other fluid samples were collected at various points. Sample drug concentrations were measured, and noncompartmental pharmacokinetic analysis was performed; then, PK-PD indices (ratios between maximum observed concentration [Cmax] and minimum inhibitory or mutant prevention concentrations) were determined for 7 bacterial species.
RESULTS PK-PD values for pradofloxacin at 3 mg/kg were approximately 5 times as high in leukocyte versus plasma and were lowest in CSF, synovial fluid, and aqueous humor. No significant differences were noted between serum and ISF. Value ratios for serum versus other body fluids were numerically higher for pradofloxacin (vs enrofloxacin) for all fluid types except CSF and aqueous humor. Target PK-PD values were exceeded for pradofloxacin against all 7 bacterial species in leukocytes and against all species except Bacteroides spp in serum and ISF. Enrofloxacin achieved the target Cmax-to-minimum inhibitory concentration ratio against Pasteurella multocida in serum, ISF, and leukocytes and for Staphylococcus pseudintermedius in serum and leukocytes. A Cmax-to-mutant prevention concentration ratio ≥ 1 against Eschericha coli was achieved for pradofloxacin at 6 mg/kg.
CONCLUSIONS AND CLINICAL RELEVANCE These findings supported once-daily oral administration of pradofloxacin to dogs at the currently recommended dose (7.5 mg/kg).
Objective—To establish a dosing regimen for potassium
bromide and evaluate use of bromide to treat
spontaneous seizures in cats.
Design—Prospective and retrospective studies.
Animals—7 healthy adult male cats and records of
17 cats with seizures.
Procedure—Seven healthy cats were administered
potassium bromide (15 mg/kg [6.8 mg/lb], PO, q 12 h)
until steady-state concentrations were reached.
Serum samples for pharmacokinetic analysis were
obtained weekly until bromide concentrations were
not detectable. Clinical data were obtained from
records of 17 treated cats.
Results—In the prospective study, maximum serum
bromide concentration was 1.1 ± 0.2 mg/mL at 8
weeks. Mean disappearance half-life was 1.6 ± 0.2
weeks. Steady state was achieved at a mean of 5.3 ±
1.1 weeks. No adverse effects were detected and
bromide was well tolerated. In the retrospective
study, administration of bromide (n = 4) or bromide
and phenobarbital (3) was associated with eradication
of seizures in 7 of 15 cats (serum bromide concentration
range, 1.0 to 1.6 mg/mL); however, bromide
administration was associated with adverse effects in
8 of 16 cats. Coughing developed in 6 of these cats,
leading to euthanasia in 1 cat and discontinuation of
bromide administration in 2 cats.
Conclusions and Clinical Relevance—Therapeutic
concentrations of bromide are attained within 2
weeks in cats that receive 30 mg/kg/d (13.6 mg/lb/d)
orally. Although somewhat effective in seizure control,
the incidence of adverse effects may not warrant
routine use of bromide for control of seizures in cats.
(J Am Vet Med Assoc 2002;221:1131–1135)
Objective—To determine the effects of cephalexin
and enrofloxacin on results of 4 commercially available
urine glucose tests in dogs.
Animals—6 healthy adult female dogs.
Procedure—In a crossover design, cephalexin (22 and
44 mg/kg [10 and 20 mg/lb], PO, q 8 h) or enrofloxacin (5
and 10 mg/kg [2.3 and 4.5 mg/lb], PO, q 12 h) was administered
to dogs for 1 day. Urine samples were tested for
glucose at 0, 6, and 24 hours after drug administration.
In vitro, dextrose was added to pooled glucose-negative
canine urine samples containing either no antimicrobial
or known concentrations of either antimicrobial; urine
samples were then tested for glucose.
Results—In vivo, false-positive results were obtained
by use of a tablet test in the presence of both antimicrobials
and by use of a strip test in the presence of
cephalexin. In vitro, false-positive results were
obtained with the tablet test at the highest urine concentration
of cephalexin (2,400 μg/mL) and with a
strip test at the highest concentration of enrofloxacin
(600 μg/mL). Enrofloxacin in urine samples containing
dextrose caused the urine glucose tests to underestimate
urine glucose concentration.
Conclusions and Clinical Relevance—Cephalexin
and enrofloxacin at dosages used in clinical practice
may result in false-positive or false-negative urine glucose
results, and care should be taken when using
urine as a basis for identifying or monitoring diabetic
animals. (J Am Vet Med Assoc 2004;224:1455–1458)
Objective—To determine pharmacokinetics of buprenorphine in dogs after IV administration.
Animals—6 healthy adult dogs.
Procedures—6 dogs received buprenorphine at 0.015 mg/kg, IV. Blood samples were collected at time 0 prior to drug administration and at 2, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180, 240, 360, 540, 720, 1,080, and 1,440 minutes after drug administration. Serum buprenorphine concentrations were determined by use of double-antibody radioimmunoassay. Data were subjected to noncompartmental analysis with area under the time-concentration curve to infinity (AUC) and area under the first moment curve calculated to infinity by use of a log-linear trapezoidal model. Other kinetic variables included terminal rate constant (kel) and elimination half-life (t1/2), plasma clearance (Cl), volume of distribution at steady state (Vdss), and mean residence time (MRT). Time to maximal concentration (Tmax) and maximal serum concentration (Cmax) were measured.
Results—Median (range) values for Tmax and MRT were 2 minutes (2 to 5 minutes) and 264 minutes (199 to 600 minutes), respectively. Harmonic mean and pseudo SD for t1/2 were 270 ± 130 minutes; mean ± SD values for remaining pharmacokinetic variables were as follows: Cmax, 14 ± 2.6 ng/mL; AUC, 3,082 ± 1,047 ng•min/mL; Vdss, 1.59 ± 0.285 L/kg; Cl, 5.4 ± 1.9 mL/min/kg; and, kel, 0.0026 ± 0.0,012.
Conclusions and Clinical Relevance—Pharmacokinetic variables of buprenorphine reported here differed from those previously reported for dogs. Wide variations in individual t1/2 values suggested that dosing intervals be based on assessment of pain status rather than prescribed dosing intervals.
OBJECTIVE To evaluate a fluorescence resonance energy transfer quantitative PCR (FRET-qPCR) assay for detection of gyrA mutations conferring fluoroquinolone resistance in canine urinary Escherichia coli isolates and canine urine specimens.
SAMPLE 264 canine urinary E coli isolates and 283 clinical canine urine specimens.
PROCEDURES The E coli isolates were used to validate the FRET-qPCR assay. Urine specimens were evaluated by bacterial culture and identification, isolate enrofloxacin susceptibility testing, and FRET-qPCR assay. Sensitivity and specificity of the FRET-qPCR assay for detection of gyrA mutations in urine specimens and in E coli isolated from urine specimens were computed, with results of enrofloxacin susceptibility testing used as the reference standard.
RESULTS The validated FRET-qPCR assay discriminated between enrofloxacin-resistant and enrofloxacin-susceptible E coli isolates with an area under the receiver operating characteristic curve of 0.92. The assay accurately identified 25 of 40 urine specimens as containing enrofloxacin-resistant isolates (sensitivity, 62.5%) and 226 of 243 urine specimens as containing enrofloxacin-susceptible isolates (specificity, 93.0%). When the same assay was performed on E coli isolates recovered from these specimens, sensitivity (77.8%) and specificity (94.8%) increased. Moderate agreement was achieved between results of the FRET-qPCR assay and enrofloxacin susceptibility testing for E coli isolates recovered from urine specimens.
CONCLUSIONS AND CLINICAL RELEVANCE The FRET-qPCR assay was able to rapidly distinguish between enrofloxacin-resistant and enrofloxacin-susceptible E coli in canine clinical urine specimens through detection of gyrA mutations. Therefore, the assay may be useful in clinical settings to screen such specimens for enrofloxacin-resistant E coli to avoid inappropriate use of enrofloxacin and contributing to antimicrobial resistance.
Objective—To determine whether therapeutic concentrations of levetiracetam can be achieved in cats and to establish reasonable IV and oral dosing intervals that would not be associated with adverse effects in cats.
Animals—10 healthy purpose-bred cats.
Procedures—In a randomized crossover study, levetiracetam (20 mg/kg) was administered orally and IV to each cat. Blood samples were collected 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. Plasma levetiracetam concentrations were determined via high-performance liquid chromatography.
Results—Mean ± SD peak concentration was 25.54 ± 7.97 μg/mL. The mean y-intercept for IV administration was 37.52 ± 6.79 μg/mL. Half-life (harmonic mean ± pseudo-SD) was 2.95 ± 0.95 hours and 2.86 ± 0.65 hours for oral and IV administration, respectively. Mean volume of distribution at steady state was 0.52 ± 0.09 L/kg, and mean clearance was 2.0 ± 0.60 mL/kg/min. Mean oral bioavailability was 102 ± 39%. Plasma drug concentrations were maintained in the therapeutic range reported for humans (5 to 45 μg/mL) for at least 9 hours after administration in 7 of 10 cats. Only mild, transient hypersalivation was evident in some cats after oral administration.
Conclusions and Clinical Relevance—Levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain concentrations within the therapeutic range for humans. Levetiracetam administration has favorable pharmacokinetics for clinical use, was apparently tolerated well, and may be a reasonable alternative antiepileptic drug in cats.
Objective—To determine the effect of treatment approach on outcome and the appropriateness of initial empirical antimicrobial treatment in dogs with pyothorax.
Design—Retrospective case series.
Animals—46 dogs with pyothorax confirmed by either (n = 15) or both (31) of the following: intracellular bacteria in pleural fluid or tissue (41) and bacteria recovered via culture of pleural fluid (36).
Procedures—Medical records of dogs treated for pyothorax from 1983 through 2001 were reviewed. Data on signalment, history, clinical signs, and treatment and results of diagnostic imaging and cytologic and microbiological evaluations were obtained. Follow-up was performed via reexamination (n = 15) and contact with referring veterinarians (26) and owners (24).
Results—46 dogs were treated with at least 1 antimicrobial and thoracocentesis (n = 7; noninvasive group), a thoracostomy tube (26; invasive group) with or without pleural lavage and heparin, or a thoracotomy (13; surgical group) and thoracostomy tube with or without pleural lavage and heparin. Pyothorax recurred in 7 dogs, and 5 of the 7 died or were euthanatized. In the respective groups, the short-term survival rate was 29%, 77%, and 92% and the long-term survival rate was 29%, 71%, and 70%. Pleural lavage and heparin treatment increased the likelihood of short- and long-term survival. Results of antimicrobial susceptibility testing suggested empirical antimicrobial selection was associated with a 35% risk of inefficacy.
Conclusions and Clinical Relevance—In the dogs with pyothorax in this study, favorable treatment effects were achieved with surgery (for short-term survival) and pleural lavage and heparin treatment (for short- and long-term survival). Findings failed to support the hypothesis that invasive (surgical) versus noninvasive treatment of pyothorax in dogs leads to a better long-term outcome.
Objective—To document blood nitric oxide concentrations
in the portal vein and systemic circulation in a rat
model of acute portal hypertension and compare values
with a control group and a sham surgical group.
Procedure—Following induction of anesthesia,
catheters were placed surgically in the carotid artery,
jugular, and portal veins of group 2 and 3 rats and in
the carotid artery and jugular vein of group 1 rats.
Baseline heart and respiratory rates, rectal temperature,
and vascular pressure measurements were
obtained, and blood was drawn from all catheters for
baseline nitric oxide (NO) concentrations. Acute portal
hypertension was induced in the group 3 rats by tying
a partially occluding suture around the portal vein and
a 22-gauge catheter. The catheter was then removed,
resulting in a repeatable degree of portal vein impingement.
After catheter placement, all variables were
remeasured at 15-minute intervals for 3 hours.
Results—Blood nitric oxide concentrations were greater
in all vessels tested in group 3 than in group 2 rats.
Conclusions and Clinical Relevance—Acute portal
hypertension in this experimental model results in
increased concentrations of NO in the systemic and
portal circulation. On the basis of information in the
rat, it is possible that increased NO concentrations
may develop in dogs following surgical treatment of
congenital portosystemic shunts if acute life-threatening
portal hypertension develops. Increased NO
concentrations may contribute to the shock syndrome
that develops in these dogs. (Am J Vet Res
Objective—To determine concentrations of marbofloxacin
in alveolar macrophages (AMs) and epithelial
lining fluid (ELF) and compare those concentrations
with plasma concentrations in healthy dogs.
Animals—12 adult mixed-breed and purebred
Procedure—10 dogs received orally administered marbofloxacin
at a dosage of 2.75 mg/kg every 24 hours for
5 days. Two dogs served as nontreated controls.
Fiberoptic bronchoscopy and bronchoalveolar lavage
procedures were performed while dogs were anesthetized
with propofol, approximately 6 hours after the
fifth dose. The concentrations of marbofloxacin in plasma
and bronchoalveolar fluid (cell and supernatant fractions)
were determined by use of high-performance liquid
chromatography with detection of fluorescence.
Results—Mean ± SD plasma marbofloxacin concentrations
2 and 6 hours after the fifth dose were 2.36 ±
0.52 µg/mL and 1.81 ± 0.21 µg/mL, respectively.
Mean ± SD marbofloxacin concentration 6 hours after
the fifth dose in AMs (37.43 ± 24.61 µg/mL) was significantly
greater than that in plasma (1.81 ± 0.21
µg/mL) and ELF (0.82 ± 0.34 µg/mL), resulting in a
mean AM concentration-to-plasma concentration
ratio of 20.4, a mean AM:ELF ratio of 60.8, and a
mean ELF-to-plasma ratio of 0.46. Marbofloxacin was
not detected in any samples from control dogs.
Conclusions and Clinical Relevance—Marbofloxacin
concentrations in AMs were greater than the mean
inhibitory concentrations of major bacterial pathogens
in dogs. Results indicated that marbofloxacin accumulates
in AMs at concentrations exceeding those
reached in plasma and ELF. The accumulation of marbofloxacin
in AMs may facilitate treatment for susceptible
intracellular pathogens or infections associated
with pulmonary macrophage infiltration. (Am J Vet Res