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in Journal of the American Veterinary Medical Association

Abstract

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).

Full access
in American Journal of Veterinary Research

Abstract

Objective

To document presence of endotoxin in portal and systemic blood in a model of canine multiple portosystemic shunts (PSS), and compare values in clinically normal dogs, before and after vena caval banding.

Animals

6 control dogs and 10 dogs with dimethylnitrosamine-induced multiple PSS that were subjected to vena caval banding.

Procedure

Dimethylnitrosamine was administered orally (2 mg/kg of body weight, twice weekly) to the 10 dogs in the diseased group until multiple PSS developed. Surgery was then performed on all 16 dogs (both groups), and shunts were confirmed in the diseased dogs. Blood was collected from the portal vein, hepatic vein, and caudal vena cava for baseline endotoxin determination and aerobic and anaerobic blood culturing. Baseline pressure measurements were taken from the portal venous catheter; then vena caval banding was performed. Blood for endotoxin determinations was taken from all vessels 20, 40, 60, 120, 240, and 360 minutes after banding; portal pressure measurements were taken at the same time as sample acquisition. Blood for culturing was taken from the portal and hepatic venous catheters at 120, 240, and 360 minutes after banding.

Results

Dogs in the diseased group had significantly greater overall presence of endotoxin in the portal vein (P ≤ 0.0002), hepatic vein (P ≤ 0.0001), and caudal vena cava (P ≤ 0.0004) than did control dogs. With respect to time, endotoxin presence was greater in the diseased group before banding (P ≤ 0.0002), and at 20 (P ≤ 0.0008), 40 (P ≤ 0.002), 60 (P ≤ 0.006), and 120 (P ≤ 0.01) minutes after banding.

Conclusions

Endotoxemia is more frequently present in catheterized dogs with dimethylnitrosamine-induced hepatic disease and multiple PSS, compared with clinically normal dogs. Additionally, portal pressure changes induced by vena caval banding did not affect endotoxemia.

Clinical Relevance

Endotoxemia may exist in dogs with hepatic disease and multiple PSS, and should be kept in mind when formulating treatment (particularly antimicrobial selection) for dogs with suspected endotoxemia. (Am J Vet Res 1997;58:83–88)

Free access
in American Journal of Veterinary Research

Abstract

Objective

To determine existence of portal and systemic bacteremia in dogs with induced severe hepatic disease, compared with clinically normal dogs, before and after vena caval banding.

Animals

6 control dogs and 10 dogs with induced severe hepatic disease and multiple portosystemic shunts (PSS).

Procedure

Dogs of the diseased group were given dimethylnitrosamine (2 mg/kg of body weight, PO) twice weekly until multiple PSS developed. Surgery was performed on dogs of both groups, and blood for baseline aerobic and anaerobic bacterial culture was collected from catheters placed in the portal and hepatic veins and caudal vena cava. All dogs underwent vena caval banding, and blood for aerobic and anaerobic bacterial culture was collected from the portal and hepatic venous catheters at 120, 240, and 360 minutes after banding.

Results

Compared with control dogs (16% gram-positive and 84% gram-negative bacteria), diseased dogs had significantly higher percentage of gram-positive bacteria (42% of positive culture results, P ≤ 0.01) and significantly lower percentage of gram-negative bacteria (58% of positive culture results, P ≤ 0.01) isolated. Pseudomonas aeruginosa was isolated most frequently from dogs of both groups; more than 1 organism was isolated from 5 dogs of each group. Antimicrobial susceptibility included that to aminoglycosides (particularly amikacin), fluorinated quinolones, and imipenem.

Conclusions

Portal and systemic, predominantly gram-negative, bacteremia is present in catheterized, clinically normal dogs and dogs with dimethylnitrosamine-induced hepatic disease and multiple PSS. (Am J Vet Res 1999;60:181-185)

Free access
in American Journal of Veterinary Research

Abstract

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.

Full access
in American Journal of Veterinary Research

Abstract

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.

Full access
in American Journal of Veterinary Research

Abstract

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)

Full access
in Journal of the American Veterinary Medical Association

Abstract

Objective

To characterize the effects of serum separation tubes (SST) on serum drug concentrations.

Sample Population

Clinically normal dogs (clorazepate, n = 7) or dogs with epilepsy (phenobarbital, n = 7) were studied in experiment 1, and samples submitted for therapeutic drug monitoring (n = 87) were studied in ex-periment 2.

Procedure

In experiment 1, blood containing either drug was placed in 2 types of 4-ml SST (SST-A and SST-B) and in nonserum separation tubes (non-SST [control]). Samples were processed, then stored at 20 to 22 C (both drugs) or 10 C (phenobarbital only). Aliquots were collected for 96 hours. The rate constant of disappearance and the percentage decrease of each drug over time were determined for each tube. For experiment 2, paired samples were collected in non-SST and SST and submitted by mail for therapeutic drug monitoring. The SST samples were either decanted from SST prior to shipment (group 1; n = 30) or mailed in SST with serum in contact with the silica gel (group 2; n = 57). Drug concentrations and drug elimination half-life were compared between groups. For both experiments, drugs were detected in samples, using polarized immunofluorescence.

Results

For experiment 1, the rate constant of drug disappearance for both drugs was greater in the 4-ml SST-A (P <0.0001). This SST also caused the greatest percentage decrease (20% for phenobarbital and 35% for benzodiazepines) at 96 hours. Refrigeration reduced the mean decrease in phenobarbital at 96 hours to 11%. For experiment 2, phenobarbital concentration was lower for both SST, compared with non-SST (P < 0.0005). Phenobarbital had decreased a mean 6.4 ± 0.5% in group-1 and a mean 30.5 ± 11.1% in group-2 (P < 0.0005) samples.

Conclusion

The SST should be avoided when collecting serum for monitoring of either phenobarbital or benzodiazepines.

Clinical Relevance

The SST can falsely decrease serum drug concentrations and should be avoided when collecting blood for therapeutic drug monitoring. (Am J Vet Res 1996;57:1299-1303)

Free access
in American Journal of Veterinary Research

Summary

Twenty-five animals (21 dogs and 4 cats) in which hepatobiliary scintigraphy (hbs) was performed between 1982 and 1989 were included in a retrospective study to determine the utility of hbs for diagnosis of extrahepatic biliary obstruction. Final diagnoses, which were based on liver biopsy results and surgical findings in all animals, were hepatocellular disease alone (n = 17), hepatocellular disease and extrahepatic biliary obstruction (n = 7), and normal liver (n = 1). Hepatobiliary scintigraphy was performed by use of 99mTc-diisopropyl iminodiacetic acid in all cases. All 7 cases of extrahepatic biliary obstruction were confirmed at surgery. In animals with biliary obstruction, hbs failed to demonstrate radiolabel within either the gallbladder or intestine at any time. Using nonvisualization of the intestine by 180 minutes as the scintigraphic criterion for diagnosis of biliary obstruction, sensitivity was 83% and specificity was 94% in this series. Hepatobiliary scintigraphy was concluded to be an accurate indicator of extrahepatic biliary obstruction in this group of animals. High serum bilirubin concentration at the time hbs was performed did not appear to reduce the diagnostic usefulness of the scintigraphic findings.

Free access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To evaluate the effect of an indwelling nasogastric tube on gastric emptying of liquids in horses.

Animals—9 healthy adult horses.

Procedure—A randomized block crossover design was used. For treatment group horses, a nasogastric tube was placed and 18 hours later, acetaminophen was administered; the nasogastric tube remained in place until the experiment was complete. For control group horses, a nasogastric tube was passed into the stomach, acetaminophen was administered, and the nasogastric tube was removed immediately. Serial blood samples were collected 15 minutes before and after administration of acetaminophen. Serum concentration of acetaminophen was determined by use of fluorescence polarization immunoassay. The variables, time to maximum acetaminophen concentration (Tmax) and the appearance constant for acetaminophen (Kapp), were determined. The values for Kapp and Tmax in horses with and without prolonged nasogastric tube placement were compared.

Results—No significant difference was found in Kapp between horses with and without prolonged nasogastric tube placement; the median difference in Kapp was 0.01 min–1 (range, –0.48 to 0.80 min–1). No significant difference was found in Tmax between horses with and without prolonged nasogastric tube placement; the median difference in Tmax was 5 minutes (range, –30 to 50 minutes). Reanalysis of data following the removal of possible outlier values from 1 horse resulted in a significant difference in Tmax between horses with and without prolonged nasogastric tube placement.

Conclusions and Clinical Relevance—Although no clinically important impact of 18 hours of nasogastric intubation was found on gastric emptying in healthy horses, considerable variability in Kapp and Tmax was found among horses. (Am J Vet Res 2005;66:642–645)

Full access
in American Journal of Veterinary Research