Clinical pharmacology of mecillinam in calves

The minimal inhibitory concentrations (MIC) of mecillinam, a novel beta-amidinopenicillanic acid derivative with unusual activity against Gram-negative bacteria, were compared with the MIC of cephazolin, cephalothin, amoxycillin, oxytetracycline, chloramphenicol, dihydrostreptomycin, neomycin, kanamycin, gentamicin and sulfadoxin/trimethoprim (TMP) against pathogenic Gram-negative bacteria recovered from neonatal calves. The MIC values of mecillinam ranged between 0.05 microgram/ml and 12.5 micrograms/ml, and the MIC90 values were 1.56 micrograms/ml and 3.12 micrograms/ml. The activity of mecillinam against salmonella, Escherichia coli and Pasteurella multocida was similar to or slightly greater than the activities of the first-generation cephalosporins, gentamicin and sulfa/TMP. Mecillinam concentrations less than or equal to 3.12 micrograms/ml inhibited the growth of the majority of isolates which were resistant (MIC90 greater than 100 micrograms/ml) to the other antibiotics studied. The minimum bactericidal concentration (MBC) values of mecillinam were two- to three-fold higher than the MIC values. The two-compartment open model was appropriate for the analysis of serum mecillinam concentrations measured after intravenous administration. The distribution half-life (t1/2 alpha) was 11.7 min, the elimination half-life (t1/2 beta) was 53.3 min, and the apparent volume of distribution (Vd (area)) and the distribution volume at steady state (Vd (ss)) were 0.568 and 0.896 l/kg, respectively. The drug was quickly absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered. They were obtained 30 min after treatment and the i.m. t1/2 was approximately 65 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology of apramycin in calves

The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, were compared with the MIC of dihydrostreptomycin and neomycin for 323 Salmonella, 178 Escherichia coli and twenty-six Pasteurella multocida isolates recovered from newborn calves. Apramycin exhibited better in vitro anti-bacterial activity than dihydrostreptomycin and neomycin; isolates of Salmonella group B and E. coli resistant to the latter were sensitive to apramycin. The two-compartment open model was appropriate for the analysis of serum apramycin concentrations measured after intravenous (i.v.) administration. The distribution half-life (t 1/2 alpha) of the drug was 28 min, the elimination half-life (t 1/2 beta) was 4.4 h, and the apparent volume of distribution (V1) and the distribution volume at steady state (Vdss) were 0.34 and 0.71 l/kg, respectively. The drug was quickly and completely absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered, they were obtained 1-2 h after treatment and the i.m. t 1/2 beta was 5 h. There was no evidence of drug accumulation in the serum after three daily i.m. injections at 20 mg/kg. More than 95% of the i.v. and i.m. doses were recovered in the urine within 96 h post-treatment but the cumulative percentage of drug recovery in the urine after oral treatment was 11%. The durations of free drug concentrations in the tissues after i.v. and i.m. injection were estimated from the serum drug level data, percent of serum protein binding, Vdss, t 1/2 beta, and the MIC. Computations showed that apramycin should be administered i.m. at 20 mg/kg every 24 h in order to maintain in tissues potentially effective drug concentrations sufficient to inhibit 50% of the Salmonella, E. coli, and P. multocida isolates, and at 12-h intervals to inhibit 90% of the isolates.     

Pharmacokinetics of single-dose administration of moxalactam in unweaned calves

Twenty-nine healthy 17- to 29-day-old unweaned Israeli-Friesian male calves were each given a single IV or IM injection of 10 or 20 mg of moxalactam disodium/kg of body weight. Serum concentrations were measured serially during a 12-hour period. Serum concentration vs time profiles were analyzed by use of linear least-squares regression analysis and the statistical moment theory. The elimination half-lives after IV administration were 143.7 +/- 30.2 minutes and 155.5 +/- 10.5 minutes (harmonic mean +/- SD) at dosages of 10 and 20 mg of moxalactam/kg of body weight, respectively. Corresponding mean residence time values were 153.1 +/- 26.8 minutes and 169.9 +/- 19.3 minutes (arithmetic mean +/- SD). Mean residence time values after IM administration were 200.4 +/- 17.5 minutes and 198.4 +/- 19.9 minutes at dosages of 10 and 20 mg/kg, respectively. The volumes of distribution at steady state were 0.285 +/- 0.073 L/kg and 0.313 +/- 0.020 L/kg and total body clearance values were 1.96 +/- 0.69 ml/min/kg and 1.86 +/- 0.18 ml/min/kg after administration of dosages of 10 and 20 mg/kg, respectively. Moxalactam was rapidly absorbed from the IM injection site and peak serum concentrations occurred at 1 hour. The estimated bioavailability ranged from 69.8 to 79.1%. The amount of serum protein binding was 53.4, 55.0, and 61.5% when a concentration of moxalactam was at 50, 10, and 2 micrograms/ml, respectively. The minimal inhibitory concentrations of moxalactam ranged from 0.01 to 0.2 micrograms/ml against Salmonella and Escherichia coli strains and from 0.005 to 6.25 micrograms/ml against Pasteurella multocida strains.     

Clinical pharmacology of polymyxin B, colistin and colistimethate in young dairy calves

The in vitro sensitivity of 592 Gram-negative bacteria isolated from cattle against polymyxin B was determined by the agar plate dilution method. The minimal inhibitory concentration of polymyxin B for all but ten of the isolates was ≤ 2.0 μg/ml and 75% of the isolates were inhibited at 1.0 μg of polymyxin B/ml or less. Intramuscular injections of polymyxin B, colistin and colistimethate (CMS) were given to veal calves once daily for 3 days. Mean peak serum drug concentrations were observed within 0.5–1 h after treatment and were between 2.7 and 4.7 μg/ml when polymyxin B and colistin were administered at a dose rate of 2.5 mg/kg/day, and between 5.3 and 7.5 μg/ml at dose rate of 5.0 mg/kg/day. When CMS was given at 5.0 mg/kg/day mean peak drug concentration was 14.1 μg/ml. The elimination half-life ( t _1/2) of polymyxin B and colistin was 4–5 h but was approximately 2 h for CMS. Kidney function tests, using the double isotope single-injection method, were performed before and after the course of antibiotic treatment. No changes were detected in the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF) and blood urea levels were not raised following treatment. Several calves treated with the higher doses of polymyxin B and colistin exhibited transient ataxia and apathy 2–4 h after treatment but clinical signs suggesting interference with neurological function were not observed after an equivalent dose of CMS was administered.     

Pharmacokinetics of ceftazidime given alone and combination with probenecid to unweaned calves

Ceftazidime pharmacokinetic values were studied in unweaned calves given the antibiotic alone or in combination with probenecid. Ceftazidime was administered IV to 9 calves at a dosage of 10 mg/kg of body weight and IM (10 mg/kg) to 8 calves, to 7 calves (10 mg/kg plus probenecid [40 mg/kg]), and to 9 calves (10 mg/kg plus probenecid [80 mg/kg]). Serum concentration-vs-time data were analyzed, using noncompartmental methods based on statistical moment theory. The data for IV ceftazidime administration also were fitted by use of a linear, open 2-compartment model. The mean (+/- SD) terminal half-life was 138.7 +/- 23.6 minutes and 126.3 +/- 10.5 minutes after IV and IM administrations, respectively. The mean residence time was 167.3 +/- 21.1 minutes and 201.4 +/- 16.8 minutes after IV and IM administrations, respectively. Coadministeration of probenecid did not affect the terminal half-life or mean residence time values. The total body clearance was 1.75 +/- 0.26 ml/min/kg, and the volume of distribution at steady state was 0.294 +/- 0.064 L/kg. The estimated mean absorption time was 34.1 minutes. There were no significant differences between the mean residence time calculated by statistical moment theory or by compartmental analysis, indicating central compartment output of ceftazidime. The 90% minimal inhibitory concentration values of ceftazidime determined for Escherichia coli, Salmonella spp, Pasteurella multocida, and P haemolytica isolates ranged from less than 0.01 to 0.1 micrograms/ml.     

Clinical pharmacology of antimicrobial drugs for the treatment of septic neonatal calves.

For a given infection, each antibiotic will have a probability of producing a beneficial outcome. Decisions that increase the antibacterial activity of the therapeutic regimen against the bacterial infection will increase the probability of a beneficial outcome. Unfortunately, such decisions may increase the cost of therapy or the risks of toxicity. Finally, neonatal calves presented for therapy are not of uniform value. It is logical to employ different antimicrobial drugs and ancillary therapies when the value of the individual calf is considered. A constructive balance between efficacy, cost, and toxicity establishes the value of a therapeutic approach for the client.     

Concurrent experimentally induced infection with Eimeria bovis and coronavirus in unweaned dairy calves.

Over a period of 3 summers, 21 colostrum-fed Holstein bull calves, 1 to 3 days old, were assigned to 7 replicates, each consisting of 3 calves. Within each replicate of 3 calves, 2 were selected at random, to be given 100,000 to 146,000 sporulated coccidia oocysts (principally Eimeria bovis) orally 60 hours after arrival at the college research farm. On the thirteenth day after coccidia inoculation, 1 of the 2 calves that had been given coccidia and the third calf that had not been inoculated, were given coronavirus by intranasal and oral routes. Calves were observed daily, and consistency of feces was scored visually. Nasal swab specimens for indirect immunofluorescent antibody testing for coronavirus and fecal samples for oocyst determination were obtained approximately every third day. Of 7 calves that were given only coronavirus, 3 developed diarrhea of short duration. Of 7 calves that were given only coccidia oocysts, 6 developed diarrhea. All 7 calves inoculated initially with coccidia and subsequently with coronavirus developed diarrhea. For 5 of 7 replicates, calves that were given coccidia and coronavirus developed diarrhea first. When overall severity, measured by fecal score and by blood in the feces, was compared, calves inoculated with coccidia followed by coronavirus were more severely affected (P less than 0.05) than were calves that were given only coronavirus. Calves that were given only coccidia oocysts appeared more severely affected than calves that were given only coronavirus, but differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigating the relationship between abomasal hairballs and perforating abomasal ulcers in unweaned beef calves.

This study investigated the relationship between abomasal hairballs (trichobezoars) and perforating abomasal ulcers in unweaned beef calves <4 mo of age. The calves enrolled in the study represented routine necropsy submissions to veterinary practitioners in western Canada and to the Western College of Veterinary Medicine. Regardless of the cause of death, each calf was examined for evidence of abomasal ulcers and hairballs. Thirty-two practitioners and the Western College of Veterinary Medicine provided 166 cases for the study; 56 died of perforating ulcers (ulcer calves), and 110 died of causes unrelated to abomasum (non-ulcer calves). The calves ranged in age from 1-90 d; 154 (92.8%) were <61 d of age. Overall, ulcer calves were 2.74 (P = 0.003) times more likely to die with an abomasal hairball than were the nonulcer calves. However, stratifying the calves into 2 age groups, young (<31 d) and old (>30 d), yielded conflicting results. While the young ulcer calves were 3.81 (P = 0.003) times more likely to have a hairball than were the young nonulcer calves, there was no statistically significant relationship (OR = 0.76, P = 0.65) between ulcer and hairballs in the older calves. The authors concluded that the relationship between hairballs and ulcers in the young calves was probably spurious, created by a Berkson's bias. It is unlikely that abomasal hairballs have a significant role in the development of fatal perforating ulcers in beef calves.     

Tissue disposition and depletion of penicillin G after oral administration with milk in unweaned dairy calves

OBJECTIVE: To determine tissue depletion of penicillin G in calves after oral ingestion with milk replacer and estimate a withdrawal period. DESIGN: Longitudinal controlled trial. ANIMALS: 26 Holstein calves. PROCEDURE: Once daily, 24 calves were fed milk replacer containing procaine penicillin G (0.68 mg/kg [0.31 mg/lb] of body weight); 2 calves served as controls. After 1 feeding, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after feeding. After 14 days, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after the final feeding. Concentrations of penicillin G were determined in tissues, blood, and urine by use of high-performance liquid chromatography. RESULTS: Penicillin G was not detected in muscle samples of treated calves. The highest concentrations of penicillin G in plasma, kidney, and liver were 13 ng/ml, 92 ng/g, and 142 ng/g, respectively. Thirteen carcasses had violative drug residues; 12 had violative residues in the liver only, and 1 had violative residues in the liver and kidney. A 21-hour withdrawal period was estimated. CONCLUSIONS AND CLINICAL RELEVANCE: Liver had the highest concentration of penicillin G and was most likely to have violative residues. Feeding calves milk containing penicillin G has the potential to cause violative drug residues in tissues. It is recommended to observe an appropriate withdrawal time prior to slaughter if calves are fed milk from cows treated with penicillin G.     

Pharmacokinetics of single doses of cefoxitin given by the intravenous and intramuscular routes to unweaned calves

Cefoxitin pharmacokinetics and bioavailability were studied in unweaned calves. The antibiotic was administered to nine calves intravenously (i.v.), to seven calves intramuscularly (i.m.) at 20 mg/kg and to eight calves i.m. at 20 mg/kg together with probenecid at 40 mg/kg. Serum concentration versus time data were analysed using statistical moment theory (SMT). The i.v. data were also fitted by a linear, open two-compartment model. The elimination half-life (t1/2) was 66.9 +/- 6.9 min (mean +/- SD) after i.v. and 81.0 +/- 10.9 min after i.m. administration. The t1/2 increased to 125.5 +/- 15.6 min by the co-administration of probenecid. The total body clearance (ClT) was 4.88 +/- 1.71 ml/min/kg and the volume of distribution (Vss) 0.3187 +/- 0.0950 l/kg. The mean residence time (MRT) was 68.2 +/- 12.3 min after i.v. and 118.6 +/- 16.8 min after i.m. injection and increased to 211.5 +/- 16.8 min by the co-administration of probenecid. The mean absorption time (MAT) was 50.6 min and the estimated bioavailability (F) of cefoxitin after i.m. administration was 73.8%. The cefoxitin protein binding ranged from 55.0 to 42.0% at concentrations from 2 to 50 micrograms/ml. The MIC90 values for cefoxitin were 6.25 micrograms/ml for E. coli and Salmonella group B isolates, 3.13 micrograms/ml for Salmonella group C and D and Pasteurella multocida. There were no statistically significant differences between the pharmacokinetic parameters calculated by SMT or compartmental analysis. SMT provided an additional independent parameter, the MRT, for characterization of drug disposition kinetics.     

Pharmacokinetics of single doses of cefoperazone given by the intravenous and intramuscular routes to unweaned calves

Cefoperazone pharmacokinetics were studied in unweaned calves. The antibiotic was administered to 10 calves intravenously, to eight calves intramuscularly at 20 mg kg-1 and to 10 calves intramuscularly at 20 mg kg-1 together with probenecid at 40 mg kg-1. Serum concentration versus time data were analysed by non-compartmental methods based on the statistical moment theory. The intravenous data were also fitted by a linear, open two-compartment model. The terminal halflife of cefoperazone was 127.9 +/- 28.2 min (mean +/- SD) after intravenous and 136.9 +/- 19.6 min after intramuscular administration. The t1/2 was increased to 257.3 +/- 127.3 min by the co-administration of probenecid. The total body clearance was 8.16 +/- 1.60 ml min-1 kg-1 and the volume of distribution at steady state was 0.713 +/- 0.167 litre kg-1. The mean residence time values were 87.2 +/- 10.6 min after intravenous and 140.3 +/- 20.6 min after intramuscular injection and were increased to 264.5 +/- 99.8 min by the co-administration of probenecid. The estimated mean absorption time was 53.1 min and the estimated bioavailability after intramuscular administration was 76.3 per cent. The minimal inhibitory concentration (MIC90) values of cefoperazone ranged from 0.5 to 2 micrograms ml-1 for Escherichia coli, salmonella groups C, D and E and Pasteurella multocida isolates. Salmonella group B strains appeared to be highly resistant to cefoperazone with MIC90 greater than 32 micrograms ml-1. There were no significant differences between the pharmacokinetic variables calculated by statistical moment theory or compartmental analysis indicating central compartment output of cefoperazone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influences on the assessment of resource- and animal-based welfare indicators in unweaned dairy calves for usage by farmers

Consumers, industrial stakeholders, and the legislature demand a stronger focus on animal welfare of all livestock at the farm level by using suitable indicators in self-assessments. In order to deduce farms’ animal welfare status reliably, factors that influence indicators’ results need to be identified. Hence, this study aimed to apply possible animal welfare indicators for unweaned dairy calves on conventional dairy farms with early cow–calf separation and evaluate influencing factors such as age and sex of calves or climatic conditions on the applied indicators’ results. An animal welfare assessment using 7 resource-based and 14 animal-based indicators was conducted at 42 typical Western German dairy farms (844 calves) in 2018 and 2019 by two observers. The effect of influencing factors was calculated by binary and ordinal logistic regressions and expressed as odds ratios. Although every unweaned calf was assessed during the farm visits, most farms had relatively few unweaned calves (average number of calves ± standard deviation = 20.1 ± 6.7 calves), with six farms having not more than 10 calves. The small sample sizes question the usage of those indicators to compare between farms and to set thresholds at the farm level. Only one assessed indicator (cleanliness core body) was not statistically affected by the evaluated influencing factors. Calf age was identified as the most decisive factor, as it affected 16 of 21 evaluated indicators, and calf age distribution on-farm varied greatly. Climatic conditions (ambient temperature and rainfall) influenced resource-based indicators such as access to concentrate and water or the cleanliness of feeding implements and bedding as well as animal-based cleanliness indicators and the occurrence of health-related impairments such as coughing and diarrhea. The authors found differences between calves on farms assessed by the different observers not only in resource-based hygiene indicators but also in animal-based indicators such as hyperthermia or hypothermia, highlighting the need for further evaluation of quality criteria in dairy calf welfare assessments. Nevertheless, animal welfare assessments by farmers themselves could be useful tools to sensitize farmers to animal welfare and thereby improve calves’ welfare.     

Comparative clinical pharmacology of amikacin and kanamycin in dairy calves.

The in vitro susceptibility of Escherichia coli, Salmonella sp, Pasteurella multocida, and Pseudomonas aeruginosa strains isolated from young calves and their environment to kanamycin and its semisynthetic derivative--amikacin, was compared by the tube dilution method. The minimal inhibitory concentration of amikacin was two- to fourfold lower than the minimal inhibitory concentration of kanamycin for the Salmonella group B, Ps aeruginosa and P multocida strains examined, whereas the E coli and Salmonella group D strains were eqaully susceptible to the 2 antibiotics. The concentrations of amikacin and kanamycin in the serum of calves after single intramuscular injections at 10, 25, and 50 mg/kg were determined, and differences between the 2 antibiotics were not observed. Intramuscular dosage schedules were calculated, based on the sensitivity of the different bacterial strains and the duration of effective serum drug concentrations.     

Characteristics of acetaminophen absorption in healthy unweaned calves as an indirect measurement of the oroduodenal transit rate of liquid meals

Abomasal emptying plays an important role in the incidence of digestive problems in calves. Our aim was to evaluate the acetaminophen absorption test (APAT) for characterization of the oroduodenal transit (ODT) of liquid meals in unweaned calves. Six healthy, unweaned Simmental x Red Holstein crossbred calves were involved in the project. The study was performed in three blocks at 3, 6 and 9 weeks of the calves' age. Within blocks, APAT was performed twice at an interval of at least 24 h. Once per each block, liquid transit was carried out with non-coagulating electrolyte solution (NES). The second test within a block was performed either while atropine sulphate was administered (block I), or by feeding a coagulating milk replacer (block II), or by administration of NES by ruminal tube (block III). Data were compared within and among blocks. Significant differences of several APAT traits were present for the different types of feeding, the different types of meals, the administration of atropine sulphate and the different ages of the calves. The emptying index T(max)/C(max) was suggested to be a valuable kinetic parameter for the characterization of ODT in these calves. We conclude that APAT represents a valid technique for characterization of ODT of liquid meals in healthy unweaned calves and may be a valuable tool for the evaluation of the reticular groove mechanism, the abomasal emptying and the absorption capacity of the duodenum.     

Effect of topical vapocoolant spray on perioperative pain response of unweaned calves to ear tagging and ear notching

Objective

To evaluate the efficacy of a vapocoolant spray to provide local anaesthesia for calves during ear tagging and ear notching.