Serum chloramphenicol concentrations in preruminant calves: a comparison of two formulations dosed orally

Serum concentrations of chloramphenicol were determined after oral doses (55 mg/kg body weight) were administered to 7–9 day old Holstein-Friesian calves. Chloramphenicol in an oral solution produced greater serum concentrations than did an equivalent dose of chloramphenicol in capsules ( P <0.005). A second dose of each formulation administered 12 h after the first dose elevated serum chloramphenicol concentrations significantly ( P <0.001). The average serum chloramphenicol concentration exceeded 5 μg/ml of serum 1 h after administration of the solution compared with 4 h for the capsules. Average serum chloramphenicol concentration was greater than 5 μg/ml for at least 12 h after the dose was administered for both formulations. Of the eight calves receiving repeat doses of chloramphenicol, seven (87.5%) developed diarrhea in 76 ± 8.6 h. Six of the eight calves (75%) died during or shortly after the period of chloramphenicol administration.     

Experimental chloramphenicol intoxication in neonatal calves: intravenous administration

Chloramphenicol was administered intravenously for eight to 17 days to five newborn calves at a daily dosage of 100 mg kg-1. Haemodynamic, haematological, blood chemistry, serum enzyme, urinalysis and clinical responses were evaluated. High levels of serum chloramphenicol were observed throughout the study although a marked increase in elimination rate was seen with increasing age. The most severe adverse effects were severe hypotension following rapid intravenous administration and severe gastrointestinal dysfunction with diarrhoea accompanying prolonged high dosage. There appeared to have been a haematological effect in one calf, but it was of minor significance compared with the other effects.     

Pharmacokinetics of chloramphenicol in calves during the first weeks of life

The pharmacokinetics of chloramphenicol, either administered as the monosuccinate ester or as a veterinary formulation, were studied in calves from the first day of life to the age of 10–12 weeks and compared with the results obtained in adult cattle. (1) After intravenous injection of 0.15 mmol/kg chloramphenicol monosuccinate, the plasma elimination half life of intact ester fell from a value of 33 min on the first day of life to 15 min at the age of 10–12 weeks (value in cows = 14 min). Free chloramphenicol reached maximal plasma concentrations after 2–3 h on the first day of life, but in less than 15 min in cows. The elimination half-life fell from about 15 h on day 1 to 4.8 h at the age of 10–12 weeks (4.2 h in cows). The bioavailability of the ester was more than 90% on Day 1, but declined to 50–60% from Day 7 on account of rapid renal excretion: 21–28% of the total dose was excreted as intact ester in a 2 h period following injection in calves aged 10–12 weeks. (2) The veterinary formulation of chloramphenicol proved toxic when administered intravenously at a dose of 0.15 mmol/kg, and even a dose of 0.093 mmol/kg was less well tolerated than 0.15 mmol/kg of the monosuccinate ester. (3) The pharmacokinetics of chloramphenicol fitted an open two-compartment model, the half-life of the elimination phase corresponded well to the values determined in the experiments with the monosuccinate ester. (4) The intramuscular injection of 0.15 mmol/kg of the ester or 0.093 mmol/kg of chloramphenicol provided ‘therapeutic’ plasma concentrations (≥ 5 μg/ml) within 15–30 min and for about 24 h in calves aged 7 days. (5) Chloramphenicol crossed the placenta when given to cows shortly before a Caesarian section, but equilibrium was not reached within 50–100 min. (6) The binding of chloramphenicol to serum proteins was dependent both on total protein and drug concentrations. It rose from less than 30% on day 1 to about 40% in adult cattle. (7) Recommendations for a dosage regime for chloramphenicol in calves are made on the basis of the pharmacokinetic data.     

Clinical pharmacology of cefixime in unweaned calves

Cefixime is a unique third-generation oral cephalosporin. Its in vitro activity and pharmacokinetic properties have been studied to assess its potential for use in the therapy of newborn calf infections due to gram-negative bacteria. The minimum inhibitory concentrations of cefixime for 90% (MIC₅₀) of field isolates of Escherichia coli. Salmonella and Pasteurella were 0.10–0.40 μg/mL. The serum disposition kinetics of cefixime following intravenous and oral administration was evaluated. The elimination half-life of cefixime after intravenous and oral administration was 3.5–4.0 h, the steady-state volume of distribution was 0.34 L/kg and approximately 90% of the drug was bound to serum proteins. Oral absorption was comparatively slow and bioavailability values for single 5 mg/kg doses were 20.2% after the administration of 200 mg of cefixime in capsules, 28.3% after dosing an aqueous solution of cefixime and 35.7% after fasted calves received the solution of cefixime. Mean serum drug concentrations 12 h after the cefixime solution was administered orally (5 mg/kg) were 1.05 μg/mL for the milk-fed calves and 1.76 μg/mL for the fasted calves. Computations showed that mean free drug concentrations equal to the MIC₅₀ of the drug for gram-negative pathogens associated with newborn calf infections can be maintained in tissues by multiple treatments at 5 mg/kg every 12 h or 10 mg/kg every 24 h.     

Comparative pharmacokinetics of gentamicin, neomycin and oxytetracycline in newborn calves

The pharmacokinetics of three antibiotics--gentamicin, neomycin and oxytetracycline were determined in newborn calves. The kinetic determinations, using two-compartment open models, were made at increasing ages from 1 day to 42 days and compared with those made from older calves (250+ days). Although all three antibiotics are eliminated unchanged primarily by glomerular filtration, there were marked differences in the development of elimination processes for individual drugs. The pharmacokinetics of neomycin were not influenced by age. Although the elimination half-life of gentamicin appeared to decrease with age, the changes were not significant and were due to an increased elimination rate in only one calf. There was no change with age in the remaining three calves. Oxytetracycline elimination was significantly reduced in newborn calves. This was exemplified by a decrease in the half-life of elimination t1/2 (beta) from 672.5 +/- 99.4 in the newborn to 385.6 +/- 76.8 at 6 weeks of age, and 377.3 +/- 40.8 min in the 250-day-old calf. These changes were consistent in all four calves. The rate of elimination remained low for the first 4 weeks of life. The volume of distribution Vd, area was not changed after the first week of life. Based on pharmacokinetic changes, an adjustment of dosage is indicated for oxytetracycline in the newborn calf as compared to the older calf or adult.     

Salmonellosis in veal calves. Some therapeutic aspects

The present investigation was undertaken to improve regimens dosage of amoxycillin, chloramphenicol or trimethoprim-sulphadiazine in Salmonella dublin infected veal calves. The pharmacokinetics of these drugs were studied after i.v., oral, and i.m. administration (bioavailability, local irritation at the injection site, volume of distribution, and elimination half life). The most important conclusion was that amoxycillin, chloramphenicol, and trimethoprim were suitable for oral administration to veal calves, although the bioavailability of chloramphenicol and trimethoprim was significantly less when concurrently administered with a milk replacer. In vitro, the antibacterial activities of these drugs were compared. Addition of trimethoprim to sulphadiazine lowered its MIC for S. dublin, but sulphadiazine reduced the killing rate compared to that of trimethoprim alone. In the efficacy studies the activities of several serum enzymes and the plasma concentrations of Fe, Zn, and Cu were measured, but it appeared, that these biochemical parameters were no better than the clinical parameters body temperature and body weight. Using optimal dosage regimens based on MIC values and blood levels, treatment with either of the three drugs was of equal efficacy.     

Chloramphenicol, lincomycin and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis

The effects of pneumonia on the pharmacokinetics of chloramphenicol, lincomycin, and oxytetracycline were evaluated in two-month-old calves. Pneumonia was induced by injection of Pasteurella haemolytica cultures directly through the thoracic wall into each lung. Six days prior to induction of pneumonia, the antibiotics were administered in a single i.v. dose. The antibiotics were administered again 48 (i.v.), 60 and 72 h (i.m.) following injection of P. haemolytica. The pharmacokinetics of chloramphenicol (25 mg/kg) and lincomycin (10 mg/kg) were not significantly different in calves with pneumonia. The hybrid rate constant beta for oxytetracycline was increased in calves with pneumonia from 0.0034 +/- 0.0003/min to 0.0048 +/- 0.0007/min between 2 h and 8 h. Thus the elimination half-life in serum was shortened from 212.4 +/- 20.3 min to 149.3 +/- 19.5 min. In addition, there was an apparent but not statistically significant decrease in K12 with pneumonia. These findings accentuate the need for observance of 12-h dose intervals with oxytetracycline.     

Effects of experimentally induced Pasteurella haemolytica pneumonia on the pharmacokinetics of erythromycin in the calf

Pneumonic pasteurellosis was produced experimentally in 3- to 4-month-old Holstein bull calves by bilateral intrapulmonary administration of 5 X 10(7) to 10(9) colony-forming units of Pasteurella haemolytica. Of 8 calves, 4 developed minor pulmonary changes, 1 died of an apparent bacteremia within 24 hours, and 3 developed extensive pneumonic changes. At 1 week before (1 dose) and at 48, 60, and 72 hours (3 doses) after Pasteurella administration, the calves were given erythromycin at a dosage of 15 mg/kg, and the pharmacokinetic values were determined. There were statistically (P less than or equal to 0.05) significant increases in the distribution and elimination rates associated with pneumonia. The elimination half life decreased from 132.7 +/- 9.6 minutes in prepneumonic calves to 111.1 +/- 13.8 minutes and 99.7 +/- 2.6 minutes in calves with minor and with moderate pneumonic changes, respectively. There also was a decrease in apparent volume of distribution with pneumonia. Erythromycin tissue concentrations were determined 2 hours after the last dose was given to the calves with pneumonia. Tissue concentrations in the pneumonic lung areas were as high or higher than those in nonaffected lung tissues in the same animals. Because of the increased rate of elimination from serum in pneumonic calves, it may be advisable to use shorter dosage intervals in calves with severe respiratory tract disease.     

Body fluid concentrations and pharmacokinetics of chloramphenicol given to mares intravenously or by repeated gavage

Serum concentrations and the pharmacokinetics of chloramphenicol were determined in 6 healthy mares after a single IV administration (50 mg/kg of body weight) or after the 1st and 5th sequential intragastric (IG) administration (50 mg/kg/6 hours) of chloramphenicol. Synovial fluid, peritoneal fluid, CSF, and urinary concentrations of chloramphenicol after the IG administrations also were determined. Mean (+/- SEM) overall elimination rate constant (K) values for the IV, 1st IG, and 5th IG dosages were 0.42 +/- 0.064/hr, 0.42 +/- 0.049/hr, and 0.29 +/- 0.074/hr, respectively, and were not significantly different from one another (P greater than 0.05). Bioavailability was 40 +/- 8.6% after the 1st IG administration and was 21 +/- 5.2% after the 5th IG administration. Values for the area under the curve (AUC) for the 1st and 5th IG dosages were significantly different from the AUC value for the IV dosage, and the AUC value for the 5th IG dosage was significantly different from that for the 1st IG dosage. Chloramphenicol was administered to 2 mares in 6 consecutive doses; the first and last doses were given IV and the others were given IG. Mean K values after the 2 IV doses were 0.38 +/- 0.112/hr and 0.56 +/- 0.078/hr, which were not significantly different from each other or from the mean value for the IV dosage given to all 6 mares. Absorption of chloramphenicol decreased with repeated IG administrations, resulting in lower concentrations of chloramphenicol with subsequent administrations. Five consecutive IG doses of chloramphenicol were administered to 4 of the mares in a separate experiment and did not alter intestinal xylose absorption.     

Effect of enhancing curd formation during the first colostrum feed on absorption of gamma glutamyl transferase by newborn calves

OBJECTIVE: To examine the effects of curd formation within the abomasum, on the absorption of gamma glutamyl transferase (GGT) from colostrum in newborn calves. DESIGN: An in vivo physiological study with controls, and in vitro examination of calf abomasal fluid. PROCEDURES: Newborn calves were taken from cows without allowing them to suckle. They were fed either 1.5 kg colostrum or 1.5 kg colostrum plus rennet, with intervals between calving and colostrum feeding ranging from 0.4 to 12.7 h. Absorption of proteins from the whey component of colostrum was assessed from the rise in activity of serum GGT. In in vitro studies, colostrum was incubated with bovine amniotic fluid, newborn calf abomasal fluid or newborn calf forestomach contents, with or without rennet, to test the curd inhibiting effects of components in the abomasal fluid of newborn calves. RESULTS: In vivo: addition of rennet to the colostrum feed reduced the proportion of calves with serum GGT activity below 500 U/L by 60%. In vitro: 43% of newborn calves lacked curd forming activity in their abomasal fluid, and that deficiency was corrected by adding rennet to the incubation medium. CONCLUSIONS: Some calves are born with low amounts of curd forming enzyme activity in the abomasum. This may compromise their ability to absorb large whey proteins from the first feed of colostrum. Adding rennet to the first colostrum feed may improve passive immunity in those calves.     

Protein energy malnutrition and fat mobilization in neonatal calves

Fat stores and organ weights were assessed in calves at birth (n=5) and after seven days of milk (n=5) or electrolyte (n=5) feeding.

Compared to newborn calves, milk-fed calves had a significant (p < 0.05) redistribution of fat from perirenal area to bone marrow. The thymus also involuted during milk feeding.

In electrolyte-fed calves there was a significant loss of perirenal and bone marrow fat. The visible omental, mesenteric and subcutaneous fat stores were depleted. Epicardial fat stores were not visibly affected.

There was a high correlation between bone marrow crude fat and bone marrow dry matter (R=0.92). This suggests that dry matter estimations can be used to assess bone marrow fat stores. Perirenal fat may be intermediate in type between brown and white adipose tissue because it is mobilized in response to fasting, and formalin fixed perirenal fat did not contain detectable levels of thermogenin.

     

Pestivirus in cattle: experimentally induced persistent infection in calves

Twenty-two heifers were infected intranasally with non-cytopathic bovine viral diarrhoea virus (BVDV) between days 74 and 82 of pregnancy. All animals had developed serum antibodies against BVDV 5 weeks later. No clinical effects were seen in the heifers, and they all delivered a live calf. The newborn calves were generally small, appeared unthrifty as typical 'poor doers', and some developed secondary infections with diarrhoea and signs of respiratory disease. Eighteen of the 22 calves were born without antibodies against BVDV and were persistently infected (PI) with the virus. One was weak at birth and died the following day. Four calves were born with serum antibodies against BVDV and with no detectable virus. Three of these showed signs and/or pathological changes indicating disease in the central nervous system. Otherwise, there were no obvious clinical differences between these calves and the PI calves, nor were there any apparent significant differences in blood parameters between these groups. In general, the calves showed low gamma-globulin values and thrombocytopaenia, but moderately increased fibrinogen values and relatively normal lymphocyte numbers.     

Toxicologic evaluation of a microencapsulated formulation of methyl parathion applied dermally to cattle

Acute toxicity studies in newborn calves and 2- to 3-year-old cattle were conducted with methyl parathion (O,O-dimethyl O-(p-nitrophenyl) phosphorothioate) in the form of a 22% microencapsulated slurry used in a manually operated sprayer. Twelve calves and 9 cattle were tested. The minimal toxic dosages were 4 L of a 0.5% concentration for calves and 10 L of a 0.25% concentration for mature cattle. At all toxic dosages, cholinesterase activities were decreased--that of the calves to 0 and that of the cattle to 50% of base line or less. Weight losses 2 weeks after single exposures to the treated cattle ranged from 6.5% to 11.5% of total body weight. Absorption of the formulation in its entirety or its metabolic products resulted in a possible interference with feed utilization.     

Salmonellosis in veal calves. Some therapeutic aspects

Summary

The present investigation was undertaken to improve regimens dosage of amoxycillin, chloramphenicol or trimethoprim‐sulphadiazine in Salmonella dublin infected veal calves. The pharmacokinetics of these drugs were studied after i.v., oral, and i. m. administration (bioavailability, local irritation at the injection site, volume of distribution, and elimination half life). The most important conclusion was that amoxycillin, chloramphenicol, and trimethoprim were suitable for oral administration to veal calves, although the bioavailability of chloramphenicol and trimethoprim was significantly less when concurrently administered with a milk replacer. In vitro, the antibacterial activities of these drugs were compared. Addition of trimethoprim to sulphadiazine lowered its MIC for S. dublin, but sulphadiazine reduced the killing rate compared to that of trimethoprim alone. In the efficacy studies the activities of several serum enzymes and the plasma concentrations of Fe, Zn, and Cu were measured, but it appeared, that these biochemical parameters were no better than the clinical parameters body temperature and body weight. Using optimal dosage regimens based on MIC values and blood levels, treatment with either of the three drugs was of equal efficacy.     

Thermal insulation of young calves exposed to cold.

Tissue, external and whole animal insulation values were determined for 12 newborn male Holstein calves continuously housed for two weeks in hutches within environmental chambers in which temperature was maintained at a constant 17 degrees C (three calves) or cycled on a daily basis either between -20 degrees and -8 degrees C (three calves) or between -30 degrees and -18 degrees C (six calves). Three of the six calves at the coldest temperature were outfitted with an insulated coat. The insulated coat provided calves a 52% increase in total insulation. Tissue insulation of cold-housed calves increased 37.2% over the first two weeks of life. It was concluded that the capacity for vasoconstriction improved with age. External insulation did not change significantly except during the first week in cold-housed calves without insulated coats. External insulation values were five to eight times those of tissue insulation values for all treatment groups. This indicated that insulation of structures external to the skin (hair, bedding, ground, etc.) provided most of the insulation for calves.     

Total estrogen concentrations in the blood plasma of calves during the first six days of life

From 47 mature calves ten blood samples were taken during the first six days of life for determination of total estrogen concentrations. Immediately postnatal concentration of total estrogens in blood plasma was high (1093.2 +/- 452.5 pg/ml blood plasma). Total estrogen values increased towards the sixth hour of life (1789.0 +/- 892.2 pg/ml blood plasma), which is thought to be caused by reabsorption of estrogens released from intracorporeal reservoirs. Towards the 48th hour of life total estrogen values decreased. This decrease indicates a progressive depletion of the reservoirs and also metabolisation and elimination of estrogens by the organism. The fact that total estrogens were nearly unchanged from the 4th day of life onwards reveals the approximative completed elimination of estrogens. At no time significant differences of total estrogen concentrations in blood plasma were found between female and male newborn calves.     

Age-dependent pharmacokinetics of phenylbutazone in calves

The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).     

Plasma levels of chloramphenicol after oral administration in calves during the first weeks of life

Three experiments were carried out to investigate the mechanisms whereby adequate plasma levels of chloramphenicol may be obtained following oral administration in young calves but not in older animals. In the first experiment, plasma levels of chloramphenicol following an oral dose of 50 mg/kg were followed in six calves, given weekly doses for the first 11 weeks of life. A plasma chloramphenicol level of 5 μg/ml, taken as the minimum therapeutic level, was attained only for a few hours in the 1 week old calves. Thereafter plasma levels decreased very rapidly until the fourth week, and rather more slowly between the fourth and eleventh weeks. At 11 weeks the plasma chloramphenicol level fell to around 0.3 μg/ml, which was the lower limit of sensitivity for the assay technique used. In the second experiment, the same single dose was administered to calves in the twelfth or eighteenth weeks of life which had not previously been exposed to the antibiotic. Plasma levels of 1 μg/ml were barely reached. This suggests that the non-absorbtion of chloramphenicol is unlikely to be related to repeated administration of the antibiotic. In the third experiment, the same single dose was administered orally to two cows. Chloramphenicol could not be detected in the plasma following such administration, and some side-effects were observed in the 48 h following dosing. It is suggested that rumen function may interfere with the absorbtion of chloramphenicol following oral administration to ruminants, even in relatively young animals.     

Serum concentrations of tumor necrosis factor-alpha in neonatal calves with presumed septicemia

This study was performed to determine the concentrations of tumor necrosis factor (TNF) in the serum of neonatal calves with presumed sepsis and determine the correlation between serum concentrations of TNF and the severity and outcome of disease. Thirty-five sick calves < 30 days old that suffered from enteritis, respiratory disease, or both were considered suitable for inclusion in this study by satisfying clinical and laboratory criteria suggestive of septicemia. At admission, blood samples were collected from all calves to determine the prevalence of high concentrations of TNF. The clinical course and outcome of disease then were recorded. Of the 35 calves with presumed sepsis, 10 had high serum TNF concentrations. Scleral injection, weak or absent suckling reflex, sternal or lateral recumbency, unresponsive or comatose state, and death rate of calves with high serum TNF concentration were greater than those values for calves without high serum TNF concentration. Calves with high serum TNF concentration had significantly lower mean IgG (P < .001), globulin (P < .0001), and calcium (P < .0001) concentrations; greater serum creatinine concentrations (P < .0001); and > or = 2+ toxic changes in neutrophils than did calves without high serum TNF concentrations. Mean values for packed cell volume, band neutrophil count, and venous Pco2 were significantly (P < .007) higher in the group of calves with high serum TNF concentration. Results of this study indicate that serum TNF concentration is correlated with clinical criteria of sepsis in neonatal calves. A close association was apparent between disease severity and serum TNF concentrations in this group of calves with presumed septicemia.