Azithromycin concentration in severely inflamed canine external ear canals - a case series.

OBJECTIVE: To determine azithromycin concentration in severely inflamed canine external ear canals. MATERIAL AND METHODS: Five dogs of various breeds and ages with severe and chronic otitis externa underwent ear canal reconstruction surgery. A single oral dose of azithromycin at 10 mg/kg was administered 12 to 24 hours prior to surgery. Tissue samples were collected from the excised external ear canals and azithromycin concentration was determined using a liquid chromatography-tandem mass spectrometry method. RESULTS: Azithromycin concentrations ranging from 11.4 to 107.0 µg/g (mean 59.2 ± 44.6 µg/g, median 50.9 µg/g) were detected in the chronically infected external ear canal tissue 12 to 24 hours after administration. CLINICAL SIGNIFICANCE: Little information exists on antibiotic concentrations in pathological tissues of dogs. Macrolides are known to concentrate in skin tissue. In light of the present results, investigation of clinical efficacy of azithromycin in chronic canine otitis externa is warranted.

Evaluation of the pharmacokinetics of imipenem following regional limb perfusion using the saphenous and the cephalic veins in standing horses.

This prospective experimental study goal was to determine the pharmacokinetics of imipenem after intravenous regional limb perfusion (IV-RLP) in standing horses. Nine horses participated in the study; that was approved by the University Animal Care and Use Committee. One thoracic limb or one pelvic limb of each horse was randomly selected. After the veins were catheterized, an Esmarch bandage tourniquet was applied and the catheter was injected with a solution containing 500mg of imipenem. Synovial fluid samples were collected from the fetlock joint and blood samples were collected from the jugular vein. All samples were analyzed for imipenem concentration using liquid chromatography mass spectrometry. Cmax of imipenem in the fetlock joint using the cephalic and the saphenous vein was 87 and 60µg/mL, respectively. The results indicate that by performing IV-RLP using the cephalic/saphenous, one can achieve imipenem concentrations in the fetlock joint that are well above the MIC of most susceptible pathogens including resistant bacteria such as Methicillin Resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Thus, with selective; judicious use, RLP with imipenem can markedly increase treatment efficacy of severe distal limb infections in horses.

Evaluation of regional limb perfusion with chloramphenicol using the saphenous or cephalic vein in standing horses.

Regional limb perfusion (RLP) significantly decreases morbidity and mortality associated with distal limb injuries in horses. There is an urgent need for finding additional effective antimicrobial drugs for use in RLP. In this study, we tested the pharmacokinetics (PK) of chloramphenicol in RLP. Eight horses participated in the study, which was approved by the University Animal Care and Use Committee. The cephalic and the saphenous veins were used to perfuse the limbs. Synovial samples were collected from the metacarpo/metatarsophalangeal (MCP/MTP) joint. The Friedman Test was applied for assessing change in PK concentration over time, for all time points. The Wilcoxon Signed Ranks Test was used to test the difference between PK concentration in joint & serum as well as concentration in joint vs. MIC. The comparison of measurements between measurements taken on hind vs. front legs was carried out using the Mann-Whitney Test. A P-value of 5% or less was considered statistically significant. After RLP, the concentration of chloramphenicol in the synovial fluid of the MCP/MTP joint using either the cephalic or the saphenous vein was initially far above the minimal inhibitory concentration (MIC) of most susceptible pathogens and remained above the MIC for approximately 6 h. The results indicate that performing RLP using the cephalic and saphenous veins enables reaching concentrations of chloramphenicol in the MCP/MTP joint that are well above the MIC of most susceptible pathogens. The chloramphenicol concentrations achieved in the synovial fluid of the MCP/MTP joint in the current study were between 1.5 (MTP) and 7 (MCP) times the MIC of MRSA in horses. These results are encouraging since MRSA infections are becoming far more common, causing considerable morbidity. To the best of our knowledge, this is the first study to evaluate the pharmacokinetics of chloramphenicol following RLP in the horse and the results are positive.

Intravenous infusion of electrolyte solution changes pharmacokinetics of drugs: pharmacokinetics of ampicillin.

The pharmacokinetics of ampicillin in dogs was determined after intravenous (i.v.) bolus and constant rate infusion. Ampicillin was administered to six beagle dogs as an i.v. bolus at 20 mg/kg and as a constant rate i.v. infusion (CRI) at 20 mg/kg during 8 h (0.042 mL/min/kg) in Ringer's lactate (Hartmann's) solution. The concentrations were determined by an LC/MS/MS method. After i.v. bolus, ampicillin total body clearance, apparent volume of distribution at steady-state, mean residence time (MRT), and half-life were 4.53 ± 0.70 mL/min/kg, 0.275 ± 0.044 L/kg, 61 ± 13 min, and 111 (85-169) min, respectively. The corresponding parameters calculated after CRI were 13.5 ± 1.06 mL/min/kg, 0.993 ± 0.415 L/kg, 73 ± 27 min, and 49 (31-69) min. Ampicillin concentration decreased by 30% in the Ringer's lactate infusion solution mostly during the first hour after preparation of the solution. Constant rate infusion of Ringer's lactate solution during 8 h caused significant changes in ampicillin pharmacokinetics. The results suggested that special attention should be given to drug pharmacokinetics when co-administered intravenously with electrolyte solutions.

Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration.

Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat moderate to moderately severe pain in humans. The present study investigated tramadol administration in horses by intravenous, intramuscular, oral as immediate-release and oral as sustained-release dosage-form routes. Seven horses were used in a four-way crossover study design in which racemic tramadol was administered at 2 mg/kg by each route of administration. Altogether, 23 blood samples were collected between 0 and 2880 min. The concentration of tramadol and its M1 metabolite were determined in the obtained plasma samples by use of an LC/MS/MS method and were used for pharmacokinetic calculations. Tramadol clearance, apparent volume of distribution at steady-state, mean residence time (MRT) and half-life after intravenous administration were 26+/-3 mL/min/kg, 2.17+/-0.52 L/kg, 83+/-10 min, and 82+/-10 min, respectively. The MRT and half-life after intramuscular administration were 155+/-23 and 92+/-14 min. The mean absorption time was 72+/-22 min and the bioavailability 111+/-39%. Tramadol was poorly absorbed after oral administration and only 3% of the administered dose was found in systemic circulation. The fate of the tramadol M1 metabolite was also investigated. M1 appeared to be a minor metabolite in horses, which could hardly be detected in plasma samples. The poor bioavailability after oral administration and the short half-life of tramadol may restrict its usefulness in clinical applications.

Genetic polymorphism of CYP2D6 and CYP2C19 metabolism determined by phenotyping Israeli ethnic groups.

Genetic polymorphism of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 was determined by phenotyping four ethnic groups of the Israeli population. The groups consisted of Ethiopian subjects, Yemenite subjects, and Russian subjects representing first-generation new immigrants and an Israeli Arab group. Dextromethorphan was used as the probe for CYP2D6 activity and mephenytoin was used for CYP2C19 activity. The two drugs were administered simultaneously and urine samples were collected over a period of 8 hours. The CYP2D6 phenotype was determined from the ratio of dextromethorphan conversion to dextrorphan and the CYP2C19 phenotype from the ratio of S-mephenytoin and R-mephenytoin. The used liquid chromatographic method was able to completely separate dextrorphan and dextromethorphan. Fluorescence detection allowed dextromethorphan quantification at 1 ng/mL. Mephenytoin enantiomers were completely separated in high-performance liquid chromatography and the respective fractions were collected and analyzed using a gas chromatography/mass spectrometry system with selective ion monitoring. The prevalence of poor metabolizer phenotype of dextromethorphan (CYP2D6) in the Yemenite (0%) and Ethiopian groups (0%) was significantly different from the prevalence in the Russian (17%) and Israeli Arab (9%) groups. A significant difference was also found in the distribution of the metabolic ratio of the extensive metabolizer phenotype between the Ethiopian group and the Russian and Yemenite groups. No significant difference was found in the prevalence of poor mephenytoin metabolizer phenotype (CYP2C19) between the Yemenite (8%), Ethiopian (6%), Russian (9%), and Israeli Arab (8%) groups. No difference was observed in the distribution of metabolic ratio within the extensive metabolizer phenotype subgroups of the four ethnic groups.