The pharmacokinetics of transdermal flunixin in lactating dairy goats.

Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.

Invited review: Abomasal emptying in calves and its potential influence on gastrointestinal disease.

Creating the ideal nutrition program for calves is a demanding task that has undergone tremendous change in recent years. Products and technologies including novel milk replacers and automated calf feeding systems have been developed to facilitate the ability of dairy producers to feed for higher growth rates before weaning. The creation of new feeding programs and milk replacers has to be looked at carefully, not only from a nutrition point of view but also from the perspective of a potential effect on physiologic digestion and calf health. Abomasal emptying is a critical factor that may link nutrition and disease. The purpose of this article is to review both intrinsic and extrinsic factors that are responsible for abomasal emptying. Predominant extrinsic factors controlling abomasal emptying include meal volume, energy density, and osmolality along with the content and source of protein. This article also reviews experimental methods used to measure abomasal emptying in the calf including those that would be appropriate for use under field conditions. Among these methods, the use of ultrasonography and different absorption tests (d-xylose, acetaminophen) as tools to measure abomasal emptying are discussed. The relationship between abomasal emptying and disease is explored, particularly as it relates to abomasal bloat. Abomasal bloat is a complex syndrome that seems to be increasing in frequency and whose etiology likely at least partially involves slowing of abomasal emptying. Suggestions for minimizing the effect of feeding programs on abomasal emptying are explored as well as needs for future research.

Short communication: Pharmacokinetics of intramammary hetacillin in dairy cattle milked 3 times per day.

Mastitis remains a critical disease in the dairy industry and the use of intramammary antibiotics plays a critical role in mastitis treatment. Hetacillin is currently approved as an intramammary antibiotic that is used to treat mastitis in dairy cows. It is approved for once a day administration and can be used for a total of 3 d. An increasing number of dairy farms are milking 3 times per day (instead of the traditional 2 times per day) and very little pharmacokinetic data exists on the use of intramammary drugs in a 3×system. The primary purpose of this study was to determine if once a day intramammary infusion of hetacillin is sufficient to maintain therapeutic drug concentrations in cattle milked 3 times per day. Eight Holstein cattle milked 3 times per day were used in this study. After collecting a baseline milk sample, each cow received intramammary infusions of hetacillin in the left front and right rear quarters once a day for 3 d. Milk samples from each of the treated quarters were collected at each milking and frozen until analysis. Milk samples were analyzed for ampicillin concentrations using an ultra-performance liquid chromatography method. All treated quarters had antibiotic concentrations well above the minimum inhibitory concentration (MIC) for gram-positive mastitis pathogens at 8 and 16 h postinfusion. Milk concentrations had fallen well below the MIC by the 24-h period (before the next infusion). All 8 cows in this study consistently had individual quarter milk ampicillin concentrations below the FDA tolerance of 0.01 µg/mL (10 ppb) within 48 h of the last infusion. Based on this study, milk ampicillin concentrations exceed the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) for at least 65% of the dosing interval, which is sufficient for once-daily dosing with most cases of gram-positive mastitis. Therefore, intramammary hetacillin should be an effective treatment for the vast majority of gram-positive mastitis pathogens when used according to label (once per day) in cows milked 3 times per day.

Short communication: Characterization of the serologic response induced by vaccination of late-gestation cows with a Salmonella Dublin vaccine.

Diarrhea due to Salmonella infection is an important cause of neonatal calf diarrhea. The acquisition of passive immunity in the calf by vaccinating the dam has shown some success in previous studies; however, no data exists on the use of currently licensed vaccines in the United States. Therefore, the purpose of this study was to determine whether vaccinating cows in late gestation with a commercially available Salmonella Dublin vaccine would stimulate Salmonella-specific antibodies in the colostrum of cows at calving and whether these antibodies would be transferred to the calf. Thirty Holstein cows were vaccinated 3 wk before the end of lactation with a Salmonella enterica serovar Dublin vaccine, with a second dose given at dry-off. An additional 30 cows received only saline. Calves had a blood sample collected immediately after birth and were then fed fresh colostrum from their dam within 2 h of calving. A postcolostrum blood sample was collected 24 to 48 h later. Salmonella Dublin antibodies in colostrum as well as serum from the cows and calves were measured using an ELISA technique. Results of this study showed that vaccinated cattle had elevated Salmonella Dublin antibody titers at the time of calving (40.3 ± 9.1) as compared with control cows (-9.4 ± 1.1). Calves that received colostrum from vaccinated cattle also had a significant increase in Salmonella Dublin antibodies (88.5 ± 8.9) as compared with calves born to unvaccinated cows (-3.2 ± 1.2). This study demonstrated that the use of a commercially available Salmonella Dublin vaccine can stimulate antibodies that are passed on to the calf via colostral transfer. Further studies need to be done to determine whether these antibodies will offer protection against Salmonella challenge.

Milk residues following multiple doses of meloxicam and gabapentin in lactating dairy cattle.

OBJECTIVE: To determine the influence of stage of lactation on the pharmacokinetics in milk when multiple doses of meloxicam were administered alone or in combination with gabapentin to postpartum (PP) and mid-lactation (ML) cows. ANIMALS: 8 postpartum and 8 mid-lactation dairy cows. METHODS: Cows were randomly divided into 2 groups (n = 8) which included 4 PP cows and 4 ML cows. Group I received only 6 oral daily doses of meloxicam (1.0 mg/kg for 6 doses). Group II received 6 oral daily doses of co-administered meloxicam (1.0 mg/kg) and gabapentin (20 mg/kg) for 6 doses. Meloxicam and gabapentin were quantified in plasma and milk samples by ultra-high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic analysis of milk and plasma was performed using a non-compartmental approach. RESULTS: Regardless of lactation status, dairy cattle administered multiple doses of meloxicam and/or gabapentin showed low drug residue concentrations and little accumulation in milk. The terminal plasma half-life of meloxicam was significantly increased (P < .02) in PP cows (12.9 hr) compared to ML cows (9.4 hr). The apparent terminal half-life in milk for meloxicam and gabapentin was not affected by stage of lactation. Co-administration of gabapentin did not alter plasma or milk concentrations of meloxicam. CLINICAL RELEVANCE: The results of this study suggest that milk from cows treated with multiple doses of meloxicam alone or in combination with gabapentin will have low drug concentrations and falls below our reported limit of detection for meloxicam or gabapentin 120 and 60 hours respectively, following the final dose regardless of their stage of lactation.

Development and evaluation of a bovine lung-on-chip (bLOC) to study bovine respiratory diseases.

Purpose: Current air-liquid interface (ALI) models of bovine proximal airways have their limitations. They do not simulate blood flow necessary to mimic systemic drug administration, and repeated sampling requires multiple, independent cultures. A bovine lung-on-chip (bLOC) would overcome these limitations, providing a convenient and cost-effective model for pharmacokinetic or pathogenicity studies. Methods: Bovine pulmonary arterial endothelial cells seeded into the endothelial channel of an Emulate Lung-Chip were interfaced with bovine bronchial epithelial cells in the epithelial channel. Cells were cultured at ALI for up to 21 days. Differentiation was assessed by mucin quantification, phase-contrast light microscopy and immunofluorescence of cell-specific markers in fixed cultures. Barrier integrity was determined by FITC-labelled dextran 3-5 kDa permeability. To evaluate the model, endothelial-epithelial transport of the antibiotic drug, danofloxacin, was followed using liquid chromatography-mass spectrometry, with the aim of replicating data previously determined in vivo. Results: bLOC cultures secreted quantifiable mucins, whilst cilia formation was evident in the epithelial channel. Barrier integrity of the model was demonstrated by resistance to FITC-Dextran 3-5 kDa permeation. Bronchial epithelial and endothelial cell-specific markers were observed. Close to plasma, representative PK data for danofloxacin was observed in the endothelial channel; however, danofloxacin in the epithelial channel was mostly below the limit of quantification. Conclusion: A co-culture model of the bovine proximal airway was successfully generated, with potential to replace in vivo experimentation. With further optimisation and characterisation, the bLOC may be suitable to perform drug pharmacokinetic studies for bovine respiratory disease (BRD), and other applications.

Efficacy and production benefits following use of eprinomectin extended-release injection in pastured dairy heifers.

A study was conducted in grazing dairy heifers to assess anthelmintic efficacy and production responses in dairy heifers treated with a single injection of eprinomectin in an extended-release formulation over a 123 day-period. The study was conducted on a pasture-based dairy in the Southeastern United States (North Carolina) over the summer months. Sixty crossbred dairy heifers were weighed and randomly allocated into 2 groups. One group (n = 30) was given 5% eprinomectin subcutaneously in the cervical region while the other group (n = 30) was given an equivalent volume of saline. Calves were weighed every 30 days throughout the trial for calculation of average daily gain and differences in overall weight gain. In addition, fecal samples were collected at days 0, 30, 60, 90 and 123 for worm egg count and coproculture. Both groups of cattle had similar worm egg concentrations at the start of the study. However, the control group had increasing concentrations of fecal worm eggs throughout the summer months while the heifers that received eprinomectin had minimal fecal worm eggs. The primary parasite species identified in this study were Haemonchus placei, Cooperia species and Ostertagia. The heifers that received eprinomectin gained 105 + 2.8 kg during the 123-day study period, representing an average daily gain of 0.85 kg/day compared to 78.3 + 4.1 kg (0.64 kg/day) for the control group. This represented a 33 % increase in average daily gain associated with deworming. The results of this study indicate that a single dose of extended-release eprinomectin was sufficient to control parasites through a 123-day summer grazing season and that administration of the anthelmintic had a significant impact on weight gain.

Elimination kinetics of tilmicosin following intramammary administration in lactating dairy cattle.

OBJECTIVE: To determine elimination kinetics of tilmicosin in milk following intramammary administration in lactating dairy cattle. DESIGN: Prospective pharmacokinetic study. ANIMALS: 6 lactating dairy cows. PROCEDURES: Following collection of baseline milk samples, 1,200 mg (4 mL) of tilmicosin was infused into the left front and right rear mammary glands of each cow. Approximately 12 hours later, an additional 1,200 mg of tilmicosin was infused into the left front and right rear glands after milking. Milk samples were then collected from each gland at milking time for 40 days. Concentration of tilmicosin was determined by means of ultraperformance liquid chromatography-mass spectrometry, and a milk withdrawal interval for tilmicosin was calculated on the basis of the tolerance limit method. RESULTS: Although there was considerable variation between glands, concentration of tilmicosin was high in milk from treated glands and had a long half-life in treated and untreated glands. Tilmicosin was detected in all treated glands for the entire 40-day study period and was detected in untreated glands for approximately 30 to 35 days. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that tilmicosin should not be administered by the intramammary route in lactating dairy cows. Milk from all glands of any cows accidentally treated should be discarded for a minimum of 82 days following intramammary administration.

Treatment of calf diarrhea: oral fluid therapy.

Diarrhea remains the leading cause of mortality in beef and dairy calves. Calves that have diarrhea frequently develop dehydration, strong ion acidosis, and electrolyte abnormalities, and are in a state of negative energy balance. Oral electrolyte therapy is a simple and economical method of addressing all of these potential complications. This article gives an overview of oral electrolyte therapy of calves, including indications, guidelines for administration, and how to choose an electrolyte product.

Pathophysiology of diarrhea in calves.

Infectious diarrhea in calves is most commonly associated with enterotoxigenic Escherichia coli, Cryptosporidium parvum, rotavirus, coronavirus, or some combination of these pathogens. Each of these agents leads to diarrhea through either secretion or malabsorption/maldigestion, though the specific mechanisms and pathways may differ. Specific pharmacologic control and treatment are dependent on gaining a greater understanding of the pathophysiology of these organisms.

Exploratory cohort study to determine if dry cow vaccination with a Salmonella Newport bacterin can protect dairy calves against oral Salmonella challenge.

BACKGROUND: Salmonellosis is a major cause of morbidity and mortality in neonatal calves, often occurring before preventative vaccines can be administered. HYPOTHESIS/OBJECTIVE: To evaluate the protective effect on calves of colostrum from cows vaccinated with a commercially available Salmonella Newport bacterin against a Salmonella Typhimurium challenge. ANIMALS: Twenty Holstein bull calves from a university dairy farm. METHODS: Nonrandomized placebo-controlled trial in which colostrum was harvested from 30 cows that received 2 doses of either Salmonella bacterin or saline before calving. Colostrum collected from each group was pooled and fed to 2 groups of 10 calves at birth. At approximately 2 weeks of age, calves were challenged with Salmonella Typhimurium. Clinical, hematologic, microbiological, and postmortem findings were compared between the 2 groups. RESULTS: No differences in mortality, clinical findings, hematology results, blood and fecal cultures, or necropsy findings between the 2 groups were observed. Vaccinated cows had higher colostral titers, and calves fed this colostrum had higher serum titers (mean difference, 0.429; mean [SE], 0.852 [0.02] for vaccinated versus 0.423 [0.02] for control calves). CONCLUSIONS AND CLINICAL IMPORTANCE: Transfer of colostral immunoglobulins from Salmonella enterica serotype Newport bacterin to neonatal calves was not sufficient to decrease mortality, clinical signs, sepsis, intestinal damage, or fecal shedding when exposed to a highly pathogenic Salmonella isolate. A large-scale randomized controlled clinical trial is needed to evaluate the efficacy of this bacterin when administered in the dry period for prevention of salmonellosis in neonatal calves.

Impact of bovine respiratory disease on the pharmacokinetics of danofloxacin and tulathromycin in different ages of calves.

Pneumonia is one of the most economically important respiratory diseases of calves and knowledge of the impact of clinical disease on pharmacokinetics (PK) in young calves is limited. This study was undertaken to investigate the efficacy and PK of two antibiotics, tulathromycin and danofloxacin, in two age groups of calves experimentally infected with Pasteurella multocida. Both danofloxacin, a fluoroquinolone antibiotic, and tulathromycin, a macrolide antibiotic is approved for the treatment of bovine respiratory disease (BRD). To evaluate potential influences of age and disease on drug distribution and elimination in calves, plasma, interstitial fluid (ISF), and pulmonary epithelial lining fluid (PELF) were analyzed for drug concentrations. Concentrations for both drugs in the PELF were estimated by a urea dilution assay of the collected bronchoalveolar lavage fluids. Age was determined to be a significant covariate for calves administered danofloxacin and tulathromycin for plasma PK parameters. For calves administered danofloxacin, the area under the curve (AUC) in the plasma was lower in 6-month old calves (18.9 ± 12.6 hr* µg/mL) vs. 3-week old calves (32.0 ± 8.2 hr* µg/mL). Clearance (CL/F) of danofloxacin was higher in 6-month old calves. In contrast, tulathromycin plasma concentrations were higher in 6 month old calves and CL/F was higher in 3-week old calves. Age did not significantly influence the ISF concentrations of danofloxacin or tulathromycin in calves with respiratory disease, unlike previous studies which reported higher ISF concentrations of danofloxacin and tulathromycin in 6-month old calves when compared to younger calves. PELF concentrations were higher than plasma and ISF for both danofloxacin and tulathromycin, but did not differ between age groups. Potential reasons for age-related differences on plasma concentration-time profiles and the impact of disease on the partitioning of the drug from the blood to the lungs and ISF as a function of age are explored.

Pharmacokinetics of melamine in pigs following intravenous administration.

Melamine-contaminated pet food was recently added as a supplement to livestock feed. There is little or no information concerning the pharmacokinetics of melamine in livestock, and the aim of this study was to obtain pharmacokinetic parameters for this contaminant in pigs. Melamine was administered intravenously to five weanling pigs at a dose of 6.13 mg/kg and plasma samples were collected over 24 h, extracted for melamine, and then analyzed by HPLC-UV. The data was shown to best fit a one-compartment model with melamine's half-life of 4.04 (+/- 0.37) h, clearance of 0.11 (+/- 0.01) L/h/kg, and volume of distribution of 0.61 (+/- 0.04) L/kg. These data are comparable to the only mammalian study in rats and suggests that melamine is readily cleared by the kidney and there is unlikely to be significant tissue binding. Further tissue residue studies are required to assess the depletion kinetics of this contaminant in the pig which will determine whether residue levels in the kidney should be of public health concern if pigs were exposed to a similar dose.

Effect of age on the pharmacokinetics and distribution of tulathromycin in interstitial and pulmonary epithelial lining fluid in healthy calves.

OBJECTIVE To compare the plasma pharmacokinetics of tulathromycin between 3-week-old (preweaned) and 6-month-old (weaned) calves and to characterize the distribution of tulathromcyin into pulmonary epithelial lining fluid (PELF) and interstitial fluid (ISF) of preweaned and weaned calves following SC administration of a single dose (2.5 mg/kg). ANIMALS 8 healthy 3-week-old and 8 healthy 6-month-old Holstein steers. PROCEDURES A jugular catheter and SC ultrafiltration probe were aseptically placed in the neck of each calf before tulathromycin administration. Blood, ISF, and bronchoalveolar lavage fluid samples were collected at predetermined times before and after tulathromycin administration for quantification of drug concentration. A urea dilution method was used to estimate tulathromycin concentration in PELF from that in bronchoalveolar lavage fluid. Tulathromycin-plasma protein binding was determined by in vitro methods. Plasma pharmacokinetics were determined by a 2-compartment model. Pharmacokinetic parameters and drug concentrations were compared between preweaned and weaned calves. RESULTS Clearance and volume of distribution per fraction of tulathromycin absorbed were significantly greater for weaned calves than preweaned calves. Tulathromycin-plasma protein binding was significantly greater for weaned calves than preweaned calves. Maximum PELF tulathromycin concentration was significantly greater than the maximum plasma and maximum ISF tulathromycin concentrations in both groups. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age affected multiple pharmacokinetic parameters of tulathromycin, likely owing to physiologic changes as calves mature from preruminants to ruminants. Knowledge of those changes may be useful in the development of studies to evaluate potential dose adjustments during treatment of calves with respiratory tract disease.

Effect of age on plasma protein binding of several veterinary drugs in dairy calves 2.

The intent of this study was to determine what influence, if any, increasing age has on the binding of drugs to plasma proteins in cattle. Plasma from three different cohorts of calves were used. The first group (n = 20) had plasma samples taken at 1, 7 and 21 days of age. These were compared to results from a second group of calves at 8 weeks and third group sampled at 6 months of age. The plasma protein binding of danofloxacin, florfenicol, flunixin meglumine and tulathromycin was determined in vitro via microcentrifugation using three different drug concentrations spiked into the individual plasma samples derived from each calf. Albumin concentrations were lowest at 1 day of age as compared to plasma samples taken from 2 month old and 6 month old calves. There were significant decreases in alpha1-acid glycoprotein in calves until 21 days of age. However, statistically significant age-effects on plasma protein binding were not observed for any of the drugs evaluated in this study. Findings from these calves suggest that age is not an important factor in the binding of these drugs to plasma proteins.

Cerebral Disorders of Calves.

Neurologic diseases of the cerebrum are relatively common in cattle. In calves, the primary cerebral disorders are polioencephalomalacia, meningitis, and sodium toxicity. Because diagnostic testing is not always readily available, the practitioner must often decide on a course of treatment based on knowledge of the likely disease, as well as his or her own clinical experience. This is particularly true with neurologic diseases in which the prognosis is often poor and euthanasia may be the most humane outcome. This article reviews the most common diseases affecting the cerebrum of calves with a focus on pathophysiology, diagnosis, and treatment.

Efficacy of vaccination and antimicrobial treatment to eliminate chronic intramammary Staphylococcus aureus infections in dairy cattle.

OBJECTIVE: To determine whether a combination of vaccination and extended intramammary antimicrobial treatment would eliminate chronic intramammary Staphylococcus aureus infections in lactating dairy cows. DESIGN: Randomized controlled clinical trial. ANIMALS: 50 dairy cows with chronic mastitis caused by S aureus. PROCEDURE: Cows were identified and paired within herd on the basis of days in milk, lactation number, milk production, and numbers of quarters infected. Treated cows (n=20) received 3 doses of a polyvalent S aureus bacterin on days 1, 15, and 21 of the study along with intramammary administration of pirlimycin in all 4 quarters once daily for 5 treatments (days 16 to 20). Control cows (n=23) received no treatment. Follow-up samples for bacteriologic culture were collected for at least 3 months after treatment to determine treatment success rates. RESULTS: Significantly more S aureus infections were eliminated from treated cows (8/20 [40%]), compared with control cows (2/23 [9%]). The proportion of infected quarters that yielded negative results throughout the follow-up period was also significantly higher in treated cows (13/28 [46%]) than in control cows (2/41 [5%]). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that a combination of vaccination and antimicrobial treatment can be successful in eliminating some cases of chronic intramammary S aureus infections in dairy cattle. However, it is important to consider extended treatment protocols carefully because many cows are likely to remain infected with S aureus despite treatment and vaccination.

Serum IgG and total protein concentrations in dairy calves fed two colostrum replacement products.

OBJECTIVE: To evaluate effects of 2 commercially available colostrum replacement products on serum IgG and total protein concentrations in dairy calves. DESIGN: Prospective clinical trial. ANIMALS: 84 Holstein bull calves from a single dairy. PROCEDURES: Calves were randomly assigned to be given 4 quarts of colostrum (group 1; n = 21), 2 packages of a colostrum replacement product (product A; group 2; 21), 1 package of a different colostrum replacement product (product B; group 3; 21), or 2 packages of product B (group 4; 21). Treatments were given within 3 hours after birth, and blood samples were collected 24 hours later and submitted for determination of serum total protein and IgG concentrations. RESULTS: Group 1 calves had significantly higher serum total protein and IgG concentrations than did calves in the other 3 groups. However, the percentage of calves with adequate passive transfer (ie, serum IgG concentration > 1,000 mg/dL) was not significantly different among groups 1 (90%), 3 (81%), and 4 (95%). In contrast, only 10% of calves in group 2 had adequate passive transfer. It was predicted that calves fed product B that had serum total protein concentrations > 5.2 g/dL would have serum IgG concentrations > 1,000 mg/dL at least 90% of the time. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that product B could be considered as an alternative to colostrum in dairy calves, but product A failed to routinely provide adequate serum IgG concentrations when fed according to label directions.

Health concerns and management of select veterinary drug residues.

The aim of this manuscript is to review the potential adverse health effects in humans if exposed to residues of selected veterinary drugs used in food-producing animals. Our other objectives are to briefly inform the reader of why many of these drugs are or were approved for use in livestock production and how drug residues can be mitigated for these drugs. The selected drugs include several antimicrobials, beta agonists, and phenylbutazone. The antimicrobials continue to be of regulatory concern not only because of their acute adverse effects but also because their use as growth promoters have been linked to antimicrobial resistance. Furthermore, nitroimidazoles and arsenicals are no longer approved for use in food animals in most jurisdictions. In recent years, the risk assessment and risk management of beta agonists, have been the focus of national and international agencies and this manuscript attempts to review the pharmacology of these drugs and regulatory challenges. Several of the drugs selected for this review can cause noncancer effects (e.g., penicillins) and others are potential carcinogens (e.g., nitroimidazoles). This review also focuses on how regulatory and independent organizations manage the risk of these veterinary drugs based on data from human health risk assessments.