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.     

The failure of the oesophageal groove reflex,when fluids are given with an oesophageal feeder to newborn and young calves

The fate of colostrum and other fluids given with an oesophageal feeder was studied in newborn calves and in young calves up to 3 weeks by means of radiological techniques. Any fluid given with an oesophageal feeder was found in the forestomachs, since it apparently did not induce an oesophageal groove reflex. Also when suckling was induced during feeding with the oesophageal feeder, the oesophageal groove reflex did not occur. The outflow of colostrum and other fluids from the forestomachs to the abomasum and small intestine occurred for the most part within 3 hours. Only the emptying of the ventral ruminal sac was sometimes delayed for 24 or 48 hours.

The results obtained in calves up to 3 weeks old did not differ from those obtained in newborn calves.

It was concluded that although colostrum given by oesophageal feeder entered the forestomachs, the rapid flow to the abomasum and small intestine created the conditions for a sufficient absorption of immunoglobulins. Application of colostrum with an oesophageal feeder in newborn calves promises to be a timesaving and effective method for creating an optimum passive immunity of the calves.     

Chloramphenicol and the neonatal calf

Pharmacokinetic values and possible toxic effects of chloramphenicol on bone marrow and hematologic and serum chemical values were determined in newborn calves given the drug (IV) once a week or in repeated doses, 12 hours between doses. The rates of elimination for chloramphenicol and antipyrine also were compared. Chloramphenicol also was administered to older calves by IM and subcutaneous routes, with an apparent bioavailability of 50% to 60%. The elimination half-lives for both chloramphenicol and antipyrine were markedly increased in the newborn calf for at least the first 3 to 4 weeks of life. Despite the high and prolonged serum chloramphenicol concentrations in these calves, there was little or no indication of toxic effects. Bone marrow aspirates did not reveal any signs of intoxication such as cytoplasmic or nuclear vacuolation. Marrow cellularity was not recognizably different from the control group.     

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.     

The non-absorption of chloramphenicol after oral administration in adult ruminants: a tentative explanation from in vitro studies

The biotransformation of chloramphenicol in the ruminant forestomachs was studied by incubating the antibiotic with ovine rumen contents in vitro. Differential centrifugation of rumen contents showed that rapid reduction of the aromatic nitro group of chloramphenicol to an arylamine occurred in those fractions containing ciliates, and this activity was not inhibited by penicillin or streptomycin. It is concluded that in adult ruminants, chloramphenicol is metabolised by rumen microfauna more rapidly than it is absorbed, when administered orally.     

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.     

Age-related alterations in trimethoprim-sulfadiazine disposition following oral or parenteral administration in calves.

Age-related changes in the absorption and distribution patterns of trimethoprim/sulfadiazine were studied following oral or subcutaneous administration of 15 mg/kg of the drug combination in calves. Following oral administration, the time course of trimethoprim/sulfadiazine appearance and dissipation in serum, synovial fluid and urine was followed for periods up to 48 hours in calves one day, one week and six weeks of age. The profiles of drug appearance-disappearance in these body fluids were also determined after subcutaneous administration in seven week old calves. The peak serum and synovial fluid levels of trimethoprim/sulfadiazine achieved following oral administration were substantially lower with increasing maturation. In ruminating (six and seven week old) calves, subcutaneous or oral administration of the combination led to high serum levels of sulfadiazine but little or no serum trimethoprim was detected in animals at this age. The data indicate that, while therapeutic concentrations and optimum ratios of the drugs may be achieved for extended time periods in neonatal life, this dosage is unable to produce optimum serum and synovial fluid concentrations as the calves mature.     

Pharmacokinetic study of chloramphenicol in calves using sensitive gas-liquid chromatographic analysis.

Chloramphenicol was given intravenously and intramuscularly to calves and the blood levels determined over 27 hours. At a dosage of 11 mg/kg chloramphenicol was detected in the blood for 25 hours after intravenous and 27 hours after intramuscular administration. The blood levels after intravenous administration indicate that chloramphenicol in animals moves in a two compartment model. Kinetic parameters were determined for intravenous but not intramuscular chloramphenicol treatment. The blood levels of chloramphenicol were higher following intramuscular than intravenous administration from five hours onward. Chloramphenicol distributed quickly and widely throughout the animal's body.     

Distribution of chloramphenicol in the genital tract of postpartum cows

Chloramphenicol was administered by constant IV infusion to 7 healthy postpartum cows at rates predicted to approach a steady-state plasma concentration of 5 micrograms/ml. After 8 hours of constant IV infusion, uterine tissues were removed surgically and were assayed for chloramphenicol concentrations. Mean plasma-to-tissue ratios of chloramphenicol concentrations were 3.05, 3.63 (6 cows only), and 3.22 for caruncles, endometrium, and uterine wall, respectively. Plasma-to-tissue ratios of the 3 tissues were not significantly different (P greater than 0.10). Intrauterine (IU) injections of chloramphenicol (20 mg/kg of body weight) were administered to 3 healthy post-partum cows. The mean value of the fraction of the drug absorbed from the uteri of these cows was 0.40. Mean concentrations of chloramphenicol were 43.8 micrograms/g in caruncles, 34.6 micrograms/g in endometrium, 2.8 micrograms/g in uterine wall, and 2.9 micrograms/ml in plasma 8 hours after IU injections. Chloramphenicol has now been banned for use in food-producing animals in the United States because of its potential for causing toxicosis in human beings. It is illegal to use chloramphenicol in food-producing animals in the United States and in some other countries as well. This includes use by the IU route of administration because chloramphenicol and most drugs are absorbed from the uterus into the bloodstream and are distributed to milk and tissues.     

Breath hydrogen concentration and small intestinal malabsorption in calves

Breath hydrogen concentrations were measured to assess intestinal carbohydrate malabsorption in preruminating calves. Oral administration of 1.25 g of lactulose (a nonabsorbable carbohydrate)/kg to calves produced breath hydrogen concentrations significantly (P less than 0.001) higher than values determined after calves were fed milk and before the treatment was given. This indicates that, in the calf, fermentation of nonabsorbed carbohydrates results in increased breath hydrogen values. To induce small intestinal malabsorption, chloramphenicol was administered orally at 50 mg/kg, 2 times a day, to 5 calves for 3 days. Before therapy was started, each calf was fitted with a duodenal cannula to facilitate collection of intestinal mucosal biopsy samples during treatment. Chloramphenicol therapy significantly (P less than 0.001) increased breath hydrogen concentrations from those values measured after calves were fed milk alone. Concurrently, chloramphenicol administration significantly decreased intestinal villous length (P less than 0.001) and D-xylose absorption (P less than 0.05), compared with those values before treatment was given. These results demonstrate that decreased intestinal absorptive capacity is associated with an increase in breath hydrogen concentrations and that breath hydrogen may be useful in evaluating malabsorption in calves with naturally occurring enteric disease.     

Pharmacokinetics of hexobarbital, sulphadimidine and chloramphencoliin neonatal and young pigs.

Half-life and apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol were investigated in newborn, 1, 3, 5 and 8 weeks old pigs. Hexobarbital sleeping time and plasma concentration of hexobarbital at recovery were measured in the same age groups. The half-life of hexobarbital and chloramphenicol was long in newborn pigs but decreased fast during the first week after birth. From 1 to 8 weeks after birth the decrease was less pronounced. The half-life of sulphadimidine increased during the first 3 weeks of life, but in 1 and 3 weeks old pigs the amount of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection was higher than in the newborn pigs.The apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol was changed in different ways from birth to 8 weeks of age.The hexobarbital sleeping time was very long in the newborn pigs and decreased until 3 weeks of age. The concentration of hexobarbital in plasma at recovery was unchanged from birth to 8 weeks of age.The concentration of chloramphenicol metabolites in plasma 100 min. after the injection increased very fast during the 8 weeks of observation. The concentration of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection increased from birth to 1 week of age, then it decreased.The data are stressing that the neonatal pig is a convenient model for pharmacokinetic testing of drugs used as pharmacotherapeutics in neonatal life.     

In vivo mechanical and in vitro electromagnetic side-effects of a ruminal transponder in cattle

This work was undertaken to assess the long-term impacts of a ruminal transponder, used for electronic identification, on ruminal motility and on health and performance of cattle, as well as to study the electromagnetic effects on ruminal bacteria in vitro. A passive transponder (51.4 g, 67 x 17 mm) was delivered into the forestomachs of 8 calves, 32 bulls, 10 heifers, and 40 dairy cows. Final readability was 87.5% in calves, 96.9% in bulls, 90% in heifers, and 100% in cows at 481, 360, 650, and 601 d, respectively, after transponder administration. The transponder did not affect production or reproduction of cows over a 2-yr period, or performance of bulls, or mortality compared with control animals. Chewing movements per bolus were lower (P <0.01) in treated animals than in controls (49.6 vs. 52.2, 51.2 vs. 63.6, and 57.0 vs. 59.7 for bulls, heifers, and cows, respectively). Regurgitation frequency (number of boluses/10 min) tended to be greater in treated cattle: 12.4 vs. 11.3 (P = 0.07), 11.3 vs. 10.6, and 11.3 vs. 10.7 (P = 0.08) for bulls, heifers, and cows, respectively. Rumination patterns of calves fitted with transponders within the first weeks of life were similar to controls. During the experiment, 43 treated animals (8 calves, 29 bulls, and 6 cows) were slaughtered. Thirty transponders were localized in the reticulum (3 calves, 24 bulls, and 3 cows), 11 in the rumen (4 calves, 4 bulls, and 3 cows), and 2 were not recovered (1 calf and 1 bull). Within the calves, 57% of the boluses were found in the rumen. In 8 reticula (2 calves and 6 bulls) and 1 rumen (1 cow), an impression left by physical contact of the transponder was observed, although histological examination did not reveal specific lesions in the mucosa of the dystrophic areas. In strained, whole ruminal contents incubated in vitro, pH values were lower after 24 and 48 h (P <0.001) of continuous exposure to an electromagnetic field induced by the transponder-reading system. After 48 h of incubation, total bacterial numbers and NH3-N concentration were greater (P <0.001) in exposed flasks than in controls. These data indicate that the transponder may alter, via mechanical action, the reticuloruminal mucosa and rumination patterns. Furthermore, the transponder may increase, via its electromagnetic action, the growth rate and metabolic activity of ruminal bacteria.     

Drug residues in food animals. I. Plasma and tissue kinetics of chloramphenicol in young cross-bred swine

Eighteen non-fasted, 12–16 week old pigs weighing between 20 and 40 kg were dosed with chloramphenicol intravenously at a dose rate of 22 mg/kg body weight. The pharmacokinetics of chloramphenicol were determined in blood plasma and sixteen selected organs and body fluids. The elimination half-life in plasma was estimated to be 2.66pL1.06 h and volume of distribution was 1.39pL0.32 I/kg. The body clearance of chloramphenicol was estimated to be 6.64pL1.52 ml/kg/min. The elimination half-life in tissue was found to range from 1.25 h in kidney to 5.89 h in fat. Most major organs ranged from 2.0 to 5.0 h. Significant correlations were found to exist between plasma concentrations and most major organ concentrations. Chloramphenicol concentrations in muscle, spleen, lung, stomach content, and large intestine content were found to exist slightly beyond the time when concentrations were negative in plasma. However, urine levels exceeded tissue levels at the last slaughter interval. It appears that serum or urine would be a good body fluid for monitoring chloramphenicol residues in tissues, whereas stomach content might be used as an indicator for chloramphenicol treatment for many days after therapy with the drug.     

A pharmacological study of chloramphenicol in horses.

Pharmacological disposition of chloramphenicol was studied in horses. Minimum levels of the antibiotic (greater than or equal to 5 mu g/ml) in blood or plasma recommended to combat infections could not be achieved by 4.4 and 8.8 mg/kg I.V. or 30 and 50 mg/kg I.M. or 30 mg/kg oral (as palmitate salt) doses of chloramphenicol. Increasing the dose to 19.8 and 26.4 mg/kg I.V. provided such levels for about two and three hours respectively. A combination of 20 mg/kg I.V. and 30 mg/kg I.M. administered simultaneously did not provide more prolonged levels than 26.4 mg/kg I.V. alone. Chloramphenicol succinate produced higher but not more prolonged levels in blood and plasma than those produced by pure chloramphenicol. Succinate salt is very little, if at all, bound to red blood corpuscles. Plasma half life and the apparent volume of distribution of chloramphenicol in horses were determined as 0.98 hours and 0.92 L/kg, respectively. At 5-10 mu g/ml concentrations in equine plasma approximately 30 percent of the chloramphenicol is bound to plasma proteins. From these studies it is concluded that the biological half life of chloramphenicol may be too short for therapeutic application against systemic infections in horses.     

Experimental myopathy in vitamin E- and selenium-depleted calves with and without added dietary polyunsaturated fatty acids as a model for nutritional degenerative myopathy in ruminant cattle

Fourteen calves, 14 weeks old, fed a low vitamin E and selenium diet based on sodium hydroxide-treated, selenium-deficient barley showed a rapid decline in plasma alpha-tocopherol, a gradual decline in erythrocyte glutathione peroxidase (GSHPX) activity, elevated plasma creatine kinase (CK) activity, teeth grinding and (in three cases) electrocardiographic changes, but no clinical abnormalities after 127 to 137 days. Necropsy of six depleted calves at that stage revealed pale muscles in two animals and mild histopathological lesions of skeletal myopathy in all six calves. Ten control calves were fed a similar diet supplemented with alpha-tocopherol and selenium. Plasma alpha-tocopherol and erythrocyte GSHPX activity remained high in these calves and no clinical abnormalities or evidence of myodegeneration were observed. When protected linseed oil was fed as a source of polyunsaturated fatty acids to the remaining eight depleted calves, rapid elevations in plasma CK activity and linolenic acid associated with a variety of cardiopulmonary and locomotory signs, electrocardiographic changes and myoglobinuria occurred within six to 11 days. Necropsy revealed widespread severe skeletal myodegeneration (eight calves) and myocardial lesions (five calves) with preferential involvement of the left ventricular myocardium. Clinical signs and pathological changes were similar to those reported in field outbreaks of nutritional degenerative myopathy in ruminant cattle and establish the experimental regime as the first successful model for reproduction of this disease.     

Pharmacokinetics of chloramphenicol in sheep after intravenous, intramuscular and subcutaneous administration

The pharmacokinetics of chloramphenicol were studied in sheep after 3 single intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations (30 mg/kg). The two extravascular routes were studied during a crossover trial for a bioequivalence test. After IV and SC administrations, the plasma-concentration time graphs were characteristic of a two-compartment model, and after IM administration it was characteristic of a monocompartment model. The two routes of absorption were not bioequivalent. Using the kinetic values, multidose regimens to maintain the therapeutic chloramphenicol blood level (5 micrograms/ml) were proposed: 60 mg/kg every 12 hours for 72 hours for the IM administration and 45 mg/kg administered subcutaneously according to the same regimen. A study of the chloramphenicol residues in tissues was carried out. Chloramphenicol residues remained at the injection site, and 400 hours would be necessary to obtain the level of 10 micrograms/kg. Determination of the creatinine phosphokinase serum values showed that the subcutaneous route induced less damage to muscle than the intramuscular route.     

D-Lactic acidosis in calves as a consequence of experimentally induced ruminal acidosis

In order to test the hypothesis that ruminal drinking in calves can lead to D-lactic metabolic acidosis, ruminal acidosis was induced in nine calves by intraruminal application of untreated whole milk via a stomach tube. The amount of the daily force-fed liquid was 3 x 1 l. The experimental design called for an end of intraruminal applications if two or more of the following signs were observed: severe depression, estimated degree of dehydration >10%, absence of sucking reflex, lack of appetite for two consecutive feedings, severe metabolic acidosis with calculated Actual Base Excess (ABE) <-15 mmol/l. The procedure was scheduled to be discontinued on the 17th day of experiment. The onset of ruminal acidification occurred rapidly, and mean pH value fell from 6.70 (+/-0.48) to 4.90 (+/-0.38) after the first application. The following days the pH values varied between 4 and 5. Rumen acidity was characterized biochemically by a significant increase in both isomers of lactic acid. The effects of the intraruminal administration on the calves were detrimental; eight of nine calves showed an acute disease process. According to the pre-established clinical standard, seven of nine calves were removed from the intraruminal feeding schedule. All but one of the calves developed severe systemic acidosis. The increase in anion gap demonstrated the net acid load. In all the calves D-lactate levels were found to show a significant and rapid increase. On the contrary, L-lactate never deviated from physiological levels. These observations confirm that, in young calves as in adult cattle, ruminal acidosis may lead to a clinically manifested D-lactic metabolic acidosis.     

Rinderpest vaccination responses among calves and adult cattle in Uganda monitored using ELISA assay

Responses to the Plowright Rinderpest vaccine by 43 calves and 70 adult cattle in Uganda in 1990, through the production of IgG antibodies, were monitored for 4 weeks using the ELISA assay. 80% of the calves were seronegative before vaccination of which 32% remained seronegative and 68% subsequently seroconverted at 2 weeks postvaccination. 20% of the calves were seropositive before vaccination but registered a decline during the 2nd and 4th weeks postvaccination. 50% of adult Ankole cattle seroconverted after 3 weeks postvaccination, while the other 50% of them, which were seropositive before vaccination, showed a decline in seronegative levels during the first 2 weeks postvaccination, but increased again at the 4th week. 90% of Friesian adult cattle were seronegative before vaccination; however, they all seroconverted within the 2nd week of postvaccination. The other 10% remained seropositive, with a slight decline of antibody levels during the 4 weeks after vaccination.     

Ontogeny of circulating B lymphocytes in neonatal calves.

The ontogeny of lymphocytes bearing surface immunoglobulin (B lymphocytes) in the peripheral blood of neonatal and young calves was determined by fluorescent antibody techniques in calves from one day to 140 days old. The percentage of B lymphocytes in neonatal calves (less than one week) was approximately 5% of the total mononuclear cell population. B lymphocytes increased steadily in the peripheral blood of calves until 20 weeks of age when values stabilised (approximately 19%) and were similar to adult levels.