Pharmacokinetics of chlortetracycline in maternal plasma and in fetal tissues following oral administration to pregnant ewes.

The purpose of this study was to determine if concentrations of chlortetracycline could be detected in fetal plasma or tissues after administering an oral dose of chlortetracycline (CTC; 500 mg/head/day) reported to be effective in controlling Campylobacter spp. abortions. Five pregnant ewes were administered 250 mg/head twice a day (total dose 500 mg/hd/d) for 7 days. On the beginning of day 7, intravenous catheters were surgically implanted or inserted into the fetus and dam. Plasma samples were collected from the ewe and fetus at various time points before and up to 36 hr after the last dose of CTC. All ewes were then sacrificed, and tissues were harvested from the fetus for drug analysis. Concentrations of CTC in maternal plasma were consistent with our previous study and below the minimum inhibitory concentration of Campylobacter abortion isolates. Concentrations of CTC were below the limit of detection in three of five fetal plasma samples and all of the placenta, amniotic fluid, and fetal stomach contents. Low concentrations were detectable in fetal kidney and liver, suggesting that CTC reaches the fetus, although at a variable and low ratio when compared to maternal concentrations.

Pharmacokinetics of single-dose oral ponazuril in weanling goats.

Ponazuril (toltrazuril sulfone) is a triazine antiprotozoal agent that targets apicomplexan organisms. Ponazuril may have clinical application in the treatment of clinical coccidiosis due to Eimeria species in goats, along with other protozoal infections. To evaluate the absorption, distribution and elimination characteristics of ponazuril in goats, a sensitive, validated high-pressure liquid chromatography and mass spectroscopy method for ponazuril in caprine plasma was developed. After a single oral dose of ponazuril at 10 mg/kg, plasma samples from seven weanling goats were collected and assayed. Plasma concentrations of ponazuril in the goats peaked at 36 ± 13 h post drug administration at a concentration of 9 ± 2 µg/mL. Concentrations declined to an average of 4.2 ± 0.8 µg/mL after 168 h with an average elimination half-life of 129 ± 72 h post drug administration. This study shows that ponazuril is relatively well absorbed after a single oral dose in goats. Efficacy trials are underway to determine clinical efficacy of ponazuril in the treatment of clinical coccidiosis in goats at 10 mg/kg dosage.

Scoping review to identify potential non-antimicrobial interventions to mitigate antimicrobial resistance in commensal enteric bacteria in North American cattle production systems.

A scoping review was conducted to identify modifiable non-antimicrobial factors to reduce the occurrence of antimicrobial resistance in cattle populations. Searches were developed to retrieve peer-reviewed published studies in animal, human and in vitro microbial populations. Citations were retained when modifiable non-antimicrobial factors or interventions potentially associated with antimicrobial resistance were described. Studies described resistance in five bacterial genera, species or types, and 40 antimicrobials. Modifiable non-antimicrobial factors or interventions ranged widely in type, and the depth of evidence in animal populations was shallow. Specific associations between a factor or intervention with antimicrobial resistance in a population (e.g. associations between organic systems and tetracycline susceptibility in E. coli from cattle) were reported in a maximum of three studies. The identified non-antimicrobial factors or interventions were classified into 16 themes. Most reported associations between the non-antimicrobial modifiable factors or interventions and antimicrobial resistance were not statistically significant (P > 0·05 and a confidence interval including 1), but when significant, the results were not consistent in direction (increase or decrease in antimicrobial resistance) or magnitude. Research is needed to better understand the impacts of promising modifiable factors or interventions on the occurrence of antimicrobial resistance before any recommendations can be offered or adopted.

Pharmacokinetics of tulathromycin in nonpregnant adult ewes.

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of tulathromycin after a single subcutaneous administration in the cervical region in sheep using the cattle labeled dose of 2.5 mg/kg. Six adult healthy ewes were administered tulathromycin on day 0. Blood samples were collected just prior to dosing and at selected time points for 360 h. Plasma samples were analyzed to determine tulathromycin concentrations, and noncompartmental analysis was performed for pharmacokinetic parameters. The mean maximum plasma concentration was 3598 ng/mL, the mean time to maximum concentration was 1.6 h, and the apparent elimination half-life ranged from 68.1 to 233.1 h (mean 118 h). When comparing our results to goats and cattle, it appears sheep are more similar to cattle in regard to the concentrations observed and pharmacokinetic parameters. In summary, the pharmacokinetics of tulathromycin in sheep appear to be similar enough to those in goats and cattle to recommend similar dosing (2.5 mg/kg SC), assuming that the target pathogens have similar inhibitory concentrations.

Pharmacokinetics of oral chlortetracycline in nonpregnant adult ewes.

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of feed-grade chlortetracycline (CTC) in sheep after oral administration of 80 or 500 mg/head daily, divided into two equal doses given at 12-h intervals for 8 days. These are the approved, and commonly used but unapproved, feed additive doses, respectively, in the United States for the prevention of ovine infectious abortion. Blood samples were collected just prior to dosing at 0, 12, 24, 72, 96, and 192 h, as well as 4, 8, 12, 24, and 36 h after the last dose, and noncompartmental pharmacokinetic analysis was performed to estimate elimination half-life and area under the plasma concentration-time curve (AUC). Mean observed maximum CTC concentrations (Cmax ) were 20.0 ng/mL (80 mg dose) and 101 ng/mL (500 mg dose). Mean apparent elimination half-life was 18 h (80 mg dose) and 20 h (500 mg dose). Although published data do not exist to estimate plasma CTC concentrations necessary for the prevention of ovine infectious abortion, concentrations reached in our study suggest that either the FDA-approved and FDA-unapproved dosages are not high enough or that the pharmacodynamic parameter relating preventive dose to pathogen minimum inhibitory concentrations is yet to be determined.

Pharmacokinetics and pharmacodynamics of xylazine administered by the intravenous or intra-osseous route in adult horses.

In certain situations, an alternate route for parenteral drug administration in horses may be useful. The intra-osseous (IO) route may provide a safe alternative to the intravenous (i.v.) route for administration of sedatives to horses when the i.v. route is inaccessible or undesirable. Six adult horses were administered xylazine i.v. or IO in a block-randomized crossover design. For the i.v. trial, both jugular veins were catheterized, and one was used for xylazine administration, while the other was used for blood collection. For the IO trial, one jugular vein was catheterized for blood collection and an intra-osseous device was placed in the tuber coxae using a powered driver for xylazine administration. Heart rate, respiratory rate, and head position were measured, and concentration of sedation was assessed at various times up to 90 min. Xylazine concentrations were measured using high-performance liquid chromatography and noncompartmental analysis was performed. General linear mixed modeling and Wilcoxon signed-rank tests were used for statistical analysis, with P ≤ 0.05. There were no significant differences in heart rate, respiratory rate, head position, concentration of sedation, Cmax , Tmax , half-life, or AUC between the i.v. and the IO routes of drug administration. No complications were observed following placement of the intra-osseous device. Intra-osseous xylazine administration provides a useful option in emergent and other settings in which i.v. access is difficult or contraindicated.

Caprine abscess model of tulathromycin concentrations in interstitial fluid from tissue chambers inoculated with Corynebacterium pseudotuberculosis following subcutaneous or intrachamber administration.

Corynebacterium pseudotuberculosis causes chronic, suppurative, abscessing conditions in livestock and humans. We used an in vivo model to evaluate antimicrobial efficacy for focal abscesses caused by C. pseudotuberculosis. Tissue chambers were surgically implanted in the subcutaneous tissues of the right and left paralumbar fossa of 12 goats to serve as a model for isolated, focal abscesses. For each goat, one tissue chamber was inoculated with C. pseudotuberculosis, while the contralateral chamber served as an uninoculated control. Six goats were administered a single dose of tulathromycin at 2.5 mg/kg of body weight subcutaneously, while the other six received the same dose by injection directly into the inoculated chambers. Our objective was to compare the effects and tulathromycin concentrations in interstitial fluid (IF) samples collected from C. pseudotuberculosis-infected and control chambers following subcutaneous or intrachamber injection of tulathromycin. In addition, the effects of tulathromycin on the quantity of C. pseudotuberculosis reisolated from inoculated chambers were assessed over time. Tulathromycin IF concentrations from C. pseudotuberculosis-infected and control tissue chambers were similar to those in plasma following subcutaneous administration. Following intrachamber administration, tulathromycin IF concentrations in infected chambers were continuously above the MIC for the C. pseudotuberculosis isolate for 15 days. There were no significant differences for plasma area under the curve and elimination half-lives between subcutaneous and intrachamber administration. Six of the 12 infected chambers had no growth of C. pseudotuberculosis 15 days postadministration. Results of this study indicate that tulathromycin may be beneficial in the treatment of focal infections such as those caused by C. pseudotuberculosis.

Frequency of resistance in obligate anaerobic bacteria isolated from dogs, cats, and horses to antimicrobial agents.

Clinical specimens from dogs, cats, and horses were examined for the presence of obligate anaerobic bacteria. Of 4,018 specimens cultured, 368 yielded 606 isolates of obligate anaerobic bacteria (248 from dogs, 50 from cats, and 308 from horses). There were 100 specimens from 94 animals from which only anaerobes were isolated (25 dogs, 8 cats, and 61 horses). The most common sites tested were abdominal fluid (dogs and cats) and intestinal contents (horses). The most common microorganism isolated from dogs, cats, and horses was Clostridium perfringens (75, 13, and101 isolates, respectively). The MICs of amoxicillin with clavulanate, ampicillin, chloramphenicol, metronidazole, and penicillin were determined using a gradient endpoint method for anaerobes. Isolates collected at necropsy were not tested for antimicrobial susceptibility unless so requested by the clinician. There were 1/145 isolates tested that were resistant to amoxicillin-clavulanate (resistance breakpoint ≥ 16/8 µg/ml), 7/77 isolates tested were resistant to ampicillin (resistance breakpoint ≥ 2 µg/ml), 4/242 isolates tested were resistant to chloramphenicol (resistance breakpoint ≥ 32 µg/ml), 12/158 isolates tested were resistant to clindamycin (resistance breakpoint ≥ 8 µg/ml), 10/247 isolates tested were resistant to metronidazole (resistance breakpoint ≥ 32 µg/ml), and 54/243 isolates tested were resistant to penicillin (resistance breakpoint ≥ 2 µg/ml). These data suggest that anaerobes are generally susceptible to antimicrobial drugs in vitro.

The effect of intramuscular injection of dinoprost or gonadotropin-releasing hormone in dairy cows on beef quality.

Intramuscular injections of drugs and vaccines cause tissue damage and subsequent effects on tenderness and consumer acceptability of beef. In the 2007 National Market Cow and Bull Beef Quality Audit, 100% of plants reported fabricating subprimal cuts such as rib eyes and tenderloins from cow and bull carcasses. Dairy beef quality should therefore be a consideration when injections are given to dairy animals. The discussion about injection site reactions and tenderness has focused on vaccines and antimicrobial drugs with little concern for the effects of reproductive hormones. The objective of this study was to quantify antemortem the effects of semimembranosis/semitendinosis muscle injection of dinoprost and GnRH in lactating dairy cows by estimating the weight of tissue damaged and comparing that with a drug known to cause extensive tissue damage, flunixin meglumine. Tissue damage was estimated from previously reported equations for grams of muscle tissue damage based on area under the curve of serum concentrations of the muscle enzyme creatine kinase over time. Dinoprost and flunixin injection both caused a significantly increased estimate of muscle tissue damaged compared with needle only (P = 0.0351 and 0.0355, respectively). Dinoprost and flunixin caused a marginally significant increased muscle tissue damage compared with GnRH (P = 0.1394 and 0.1475, respectively). No statistically significant difference was found between the estimated weight of muscle tissue damaged by flunixin compared with dinoprost (P = 1.0000), or by saline compared with GnRH (P = 0.7736) or needle only (P = 0.4902). The assumption that reproductive hormones are less damaging than vaccines and antimicrobial drugs should be examined more closely, including postmortem evaluation of injection site lesions and effects on tenderness.

Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals.

Gallium is a trivalent semi-metal with anti-microbial effects because of its incorporation into crucial iron-dependent reproductive enzyme systems. Gallium maltolate (GaM) provides significant gallium bioavailability to people and mice following oral administration and to neonatal foals following intragastric administration. To study the prophylactic and therapeutic effects of GaM against Rhodococcus equi pneumonia in foals, we developed a methylcellulose formulation of GaM (GaM-MCF) for oral administration to neonatal foals. Normal neonatal foals were studied. Six foals received 20 mg/kg and another six foals received 40 mg/kg of GaM-MCF orally. Serial serum samples were collected and serum gallium concentrations were determined using inductively coupled plasma mass spectroscopy. Gallium was rapidly absorbed (T(max) of 4 h), and a mean C(max) of 0.90 or 1.8 microg/mL was achieved in foals receiving 20 or 40 mg/kg respectively. Marked variability existed in C(max) among foals: only half of the foals receiving 20 mg/kg attained serum concentrations of >0.7 microg/mL, a level suggested to be therapeutic against R. equi by previous studies. Mean elimination half-life was 32.8 or 32.4 h for foals receiving 20 or 40 mg/kg respectively. The results of this study suggest that at least 30 mg/kg orally every 24 h should be considered in future pharmacodynamic and efficacy studies.

Relationship between level of antibiotic use and resistance among Escherichia coli isolates from integrated multi-site cohorts of humans and swine.

The objective of this longitudinal ecological study was to examine the relationship between the prevalence of antibiotic-resistant (AR) commensal Escherichia coli isolates from both monthly human wastewater and composite swine fecal samples and the concurrent aggregated monthly antibiotic use recorded within each host species in multi-site vertically integrated swine and human populations. In addition, human vocation (swine worker versus non-swine worker), swine production group, and season were examined as potential confounding variables. Human and swine E. coli isolates (n=2469 human and 2310 swine, respectively) were tested for antimicrobial susceptibility using a commercial broth microdilution system. In the human population, among swine workers the relative odds of tetracycline resistance were increased significantly for tetracycline (class) drug use at the third quartile and above of mean monthly dosage (MMD) (OR=1.8) as compared to the referent category (non-use). The relative odds of ciprofloxacin resistance were significantly increased for ciprofloxacin use in non-swine workers (OR=5.5) as compared to the referent (non-use). The relative odds of tetracycline resistance were increased significantly for chlortetracycline use in medicated feed for the upper tertile of MMD category (OR=2.9) as compared to the referent category (no use) across all swine production groups. While high variability among seasonal samples over the 3-year period was observed, no common seasonal trends relating to antibiotic use and prevalence of resistance over the 3-year period were apparent. The overall effects of concurrent human and swine antibiotic use on AR E. coli levels were inconsistent and modest in this study.

Skills and competencies required by veterinary pharmacologists: a blueprint for graduate education in veterinary pharmacology in North America.

This report describes the results of two efforts to gather data on the needs of veterinary pharmacology, whether academic or industrial, to better define the skills and competencies that graduate programs in veterinary pharmacology should endeavor to provide. Data collected from an on-line survey of the animal health industry were used to develop a workshop at the biennial meeting of the American Academy of Veterinary Pharmacology and Therapeutics. Lists of skills were developed and categorized, and differences among the skills identified by industry vs. academy were outlined. This report offers a blueprint for graduate education in veterinary pharmacology in terms of the types and details of skills and competencies to better prepare future veterinary pharmacologists.

The effects of danofloxacin and tilmicosin on neutrophil function and lung consolidation in beef heifer calves with induced Pasteurella (Mannheimia) haemolytica pneumonia.

Pneumonia caused by Pasteurella (Mannheimia) haemolytica was induced in weaned beef heifer calves, approximately 6 months of age. Calves were treated at 20 h after challenge with therapeutic doses of danofloxacin or tilmicosin. Peripheral blood neutrophils were collected at 3, 24 and 48 h after treatment. The ex vivo effects on neutrophil function, neutrophil apoptosis, and hematological parameters were examined, as was the effect on percentage lung consolidation. Neutrophil function assays included random migration under agarose, cytochrome C reduction, iodination, Staphylococcus aureus ingestion, chemotaxis, and antibody-dependent and antibody-independent cell-mediated cytotoxicity. Apoptosis was determined using a cell death detection kit. Killing was performed at 72 h after treatment. Statistical comparisons were made among the three groups of challenged-treated animals: saline, danofloxacin, and tilmicosin. Comparisons were also made between nonchallenged nontreated animals (NCH) and challenged saline-treated animals. There were no significant differences for any of the neutrophil function assays or neutrophil apoptosis among the challenged-treated groups. This suggests that danofloxacin and tilmicosin have no clinically significant effects on neutrophil function or apoptosis. There were also no significant differences in percentage lung consolidation among the challenged-treated groups. Significant differences were found between the NCH calves and the challenged saline-treated calves in several neutrophil assays, which were attributed to effects of P. haemolytica infection.

Label and extra label drug use in small ruminants.

The small ruminant practitioner has a small arsenal of approved drugs in the United States, so the practitioner must be familiar with the laws and regulations related to extra label use. Drugs can be used extra label in food animals only under specific circumstances and can be used only for therapeutic purposes. Drugs that are illegal in small ruminants include chloramphenicol; clenbuterol; diethylstilbestrol; dimetridazole, ipranidazole, and other nitroimidazoles such as metronidazole; dipyrone; fluoroquinolones; glycopeptides; nitrofurans; furazolidone; and extra label use of medication in feed. It is also illegal to use any drug that results in residues above established tolerances or safe levels.

Antimicrobial issues in bovine lameness.

This article reviews some of the issues surrounding antimicrobial use in treating diseases that cause lameness in cattle. The discussion includes sections on selection of an antimicrobial, regimen design, and medication of multiple animals. Pathogen susceptibility testing is covered, along with empiric selection of antimicrobials. Other issues covered include regional perfusion and topical application of antimicrobials, antimicrobials in footbaths and in feed, and withdrawal time estimates.

Feedlot therapeutics.

This article discusses therapeutic approaches to conditions commonly encountered in feedlots. Challenges discussed include bovine respiratory complex, tracheal edema, atypical interstitial pneumonia, footrot, toe abscesses, mycoplasma arthritis, cardiovascular disease, lactic acidosis, bloat, coccidiosis, central nervous system diseases, abscesses and cellulitis, pregnancy management and abortion, and ocular disease.

Sry-negative XX sex reversal in the German shorthaired pointer dog.

Present hypotheses indicate that a testis differentiation cascade in mammals is induced by Sry, a gene encoding a DNA binding protein of the high mobility group (HMG) class. In XX sex reversal, individuals lacking a Y chromosome develop testicular tissue. Sry translocation from the Y to the X chromosome has been found in some, but not all, of these individuals. XX sex reversal in the German shorthaired pointer dog may be a model of Sry-negative XX sex reversal in humans. The purposes of this study were to report the familial occurrence of sex reversal and determine whether the conserved Sry HMG box, the region of the Sry protein essential for testis induction, is present in genomic DNA of affected dogs. Canine Sry HMG box sequences were used as primers in polymerase chain reactions. A 104 bp Sry HMG box product was generated from normal males, but not from females or XX sex reversed dogs. Parallel control reactions using hypoxanthine phosphoribosyl transferase primers generated a 177 bp product from all dogs. The pedigree of affected dogs and the absence of Sry HMG box sequences in their genomic DNA suggest that this disorder is due to a mutant autosomal gene in the testis differentiation cascade.