Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants

Summary

Serum chloramphenicol concentrations were determined by microbiological and chemical assay methods in cows, ewes, and goats treated parenterally with seven different veterinary parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol and solutions of 20%, 25% and 50% of chloramphenicol base in various organic solvents. Serum drug concentrations were analyzed for the effect of product formulation differences, dosage, whether the drug was administered i.m. at a single body site or to two sites, and the method of assay, on the absorption from the injection site, peak drug levels, and the persistence in serum of effective concentrations of the drug i.e. 5 to 10 ug / ml. Although differences were observed among the 6 products containing chloramphenicol base in respect to absorption rate and peak serum drug levels, and although these differences significantly influenced the persistence of microbiologically‐active serum drug concentrations at the level of ≥ 10 μg / ml, they did not at the level of ≥ 5 μg / ml.

In the animal species examined, injections given at 2 sites appeared to influence the duration of predetermined serum drug levels more than the differences among the products in respect of the absorption and elimination rates from serum, the peak serum concentrations, and the dose. The shapes of the concentration‐to‐time curves in cows and ewes injected with the same dose of a given product were essentially the same, but they were different in goats. Serum chloramphenicol concentrations measured chemically after treatment with chloramphenicol base were 20% to 46% higher than those measured microbiologically.

For 60 minutes after the sodium succinate ester had been administered i.v. and i.m. to ewes, the chemically determined chloramphenicol levels were more than twice as high as the respective concentrations determined by microbiological assay, but thereafter, the magnitude of those differences was not greater than observed after treatment with chloramphenicol base.

Intramuscular bioavailability of the products containing chloramphenicol base injected at 2 sites was rather poor (51% to 80.5%ofthe dose) and even lower values were calculated after injection at a single site.

Results are briefly discussed of the effect of dosage form on the persistence of microbiologically effective serum drug levels. A dose of at least 50 mg / kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants.     

Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants

Summary Serum chloramphenicol concentrations were determined by microbiological and chemical assay methods in cows, ewes, and goats treated parenterally with seven different veterinary parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol and solutions of 20%, 25% and 50% of chloramphenicol base in various organic solvents. Serum drug concentrations were analyzed for the effect of product formulation differences, dosage, whether the drug was administered i.m. at a single body site or to two sites, and the method of assay, on the absorption from the injection site, peak drug levels, and the persistence in serum of effective concentrations of the drug i.e. 5 to 10 ug / ml. Although differences were observed among the 6 products containing chloramphenicol base in respect to absorption rate and peak serum drug levels, and although these differences significantly influenced the persistence of microbiologically-active serum drug concentrations at the level of ≥ 10 μg / ml, they did not at the level of ≥ 5 μg / ml. In the animal species examined, injections given at 2 sites appeared to influence the duration of predetermined serum drug levels more than the differences among the products in respect of the absorption and elimination rates from serum, the peak serum concentrations, and the dose. The shapes of the concentration-to-time curves in cows and ewes injected with the same dose of a given product were essentially the same, but they were different in goats. Serum chloramphenicol concentrations measured chemically after treatment with chloramphenicol base were 20% to 46% higher than those measured microbiologically. For 60 minutes after the sodium succinate ester had been administered i.v. and i.m. to ewes, the chemically determined chloramphenicol levels were more than twice as high as the respective concentrations determined by microbiological assay, but thereafter, the magnitude of those differences was not greater than observed after treatment with chloramphenicol base. Intramuscular bioavailability of the products containing chloramphenicol base injected at 2 sites was rather poor (51% to 80.5%ofthe dose) and even lower values were calculated after injection at a single site. Results are briefly discussed of the effect of dosage form on the persistence of microbiologically effective serum drug levels. A dose of at least 50 mg / kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants.     

Persistence of chloramphenicol residues in calf tissues.

Twenty-one 5 to 18 day old calves were administered 11 mg chloramphenicol in propylene glycol per kg body weight intramuscularly twice daily for three days. Groups of calves were euthanized with a barbiturate overdose at 5, 21, 42 and 70 days after the last dose was administered. Serum, kidney, analyzed for the drug using a quantitative gas chromatographic method with a detection limit of five parts per billion. After five days of withdrawal, chloramphenicol was detected in all the injection sites and in 6 out of 16 of the other samples. After 21 days of withdrawal, chloramphenicol was detected in all the injection sites and in one each of the serum, liver and muscle samples. After 42 days of withdrawal, chloramphenicol was detected in the injection sites only, and after 70 days of withdrawal it was not detected in any of the samples.     

Concentrations sériques et biodisponibilité sanguine du chloramphénicol chez les bovins

Serum concentrations and factors affecting the blood bioavailability of chloramphenicol in bovine

The authors have compared the serum concentrations and the factors affecting blood bioavailability of chloramphenicol after intramuscular administration of canadian commercial preparations containing 500 mg/mL of antibiotic.

The animals (dairy cows and heifers) received each drug (20 mg/kg) in one or two injection sites. The serum samples, analysed by colorimetric or microbiological methods, showed that considerable differences in concentration exist between the two methods.

The evolution of biodisponibility factors proved identical in both cases. It appears that therapeutic levels of chloramphenicol are reached only by drug A for four to five hours.

The usual dosage (2-10 mg/kg), by intramuscular route, is not sufficient to attain these active concentrations using the other drugs. However, the important variability obtained during the experiment and reflected in the standard deviation values, has not proved that drug A has a better bioavailability based on the criteria of the only microbiological analysis.

     

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.     

Pharmacokinetics of chloramphenicol in non-lactating cattle

The pharmacokinetics and bioavailability of a formulation of chloramphenicol base in propylene glycol were determined following administration of single intravenous (i.v.) and subcutaneous (s.c.) 50 mg/kg doses of chloramphenicol to six non-lactating Holstein cows. Mean serum concentrations of chloramphenicol following i.v. administration of 50 mg/kg declined rapidly from a peak of greater than 100 micrograms/ml to 6.9 micrograms/ml at 12 h after administration. Serum concentrations were not detectable at 24 h after administration. The curve of serum concentrations vs time was characteristic of a two-compartment open model. Mean i.v. data gave a biological half-life of 4.3 h and a volume of distribution of the central compartment of 0.44 l/kg. Serum concentrations of chloramphenicol following s.c. administration of 50 mg/kg rose slowly to a broad peak near 20 micrograms/ml from 3 to 8 h after administration and then declined. These data were also analysed according to a two-compartment open model. The biological half-life was 4.2 h and the volume of distribution of the central compartment was 0.50 l/kg. Significant adverse reactions, including acute collapse, intravascular haemolysis and haemoglobinuria, were observed in cows when dosed i.v. Cows dosed s.c. exhibited local reactions at injection sites. The disadvantages of administration of 50 mg/kg doses of chloramphenicol base in propylene glycol appear to be significant and may outweight the potential advantages of parenteral use of the drug as presently formulated.     

Chloramphenicol sodium succinate in the horse: serum, synovial, peritoneal, and urine concentrations after single-dose intravenous administration

Six healthy adult mares were given a single IV dose (25 mg/kg of body weight) of chloramphenicol sodium succinate. Chloramphenicol concentrations in serum, synovial fluid, peritoneal fluid, and urine were measured serially over a 48-hour period. The highest measured serum chloramphenicol concentration was 6.21 micrograms/ml at 0.5 hour. Chloramphenicol was detected in synovial and peritoneal fluids, with mean peak concentrations of 3.89 micrograms/ml and 3.50 micrograms/ml, respectively, at 0.5 hour. Serum and synovial concentrations declined rapidly and were not measurable at 3 hours. Chloramphenicol could not be detected in peritoneal fluid at 6 hours. The serum half-life was 0.43 hour and the apparent volume of distribution was 2.83 L/kg. Urine concentrations of chloramphenicol peaked at 0.5 hour at 106.72 micrograms/ml and also declined rapidly. The drug could not be detected in the urine at 36 hours.     

A competitive enzyme-linked immunosorbent assay for determination of chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic shown to have specific activity against a wide variety of organisms that are causative agents of several disease conditions in domestic animals. Chloramphenicol has been banned for use in food-producing animals for its serious adverse toxic effects in humans. Due to the harmful effects of chloramphenicol residues livestock products should be free of any traces of these residues. Several analytical methods are available for chloramphenicol analysis but sensitive methods are required in order to ensure that no traces of chloramphenicol residues are present in edible animal products. In order to prevent the illegal use of chloramphenicol, regulatory control of its residues in food of animal origin is essential. A competitive enzyme-linked immunosorbent assay for chloramphenicol has been locally developed and optimized for the detection of chloramphenicol in sheep serum. In the assay, chloramphenicol in the test samples and that in chloramphenicol-horseradish peroxidase conjugate compete for antibodies raised against the drug in camels and immobilized on a microtitre plate. Tetramethylbenzidine-hydrogen peroxide (TMB/H2O2) is used as chromogen-substrate system. The assay has a detection limit of 0.1 ng/mL of serum with a high specificity for chloramphenicol. Cross-reactivity with florfenicol, thiamphenicol, penicillin, tetracyclines and sulfamethazine was not observed. The assay was able to detect chloramphenicol concentrations in normal sheep serum for at least 1 week after intramuscular injection with the drug at a dose of 25 mg/kg body weight (b.w.). The assay can be used as a screening tool for chloramphenicol use in animals.     

Pharmacokinetics of chloramphenicol in normal and Escherichia coli infected chickens

1. Disposition kinetics were compared in healthy chickens and in chickens naturally infected with E. coli following the intravenous, intramuscular and oral administration of chloramphenicol in a single dose of 20 mg/kg body weight. 2. Lower serum chloramphenicol concentration in diseased chickens were reported after intravenous injection, but they were higher than normal 30 min after intramuscular and oral administration. Following intravenous injection the volume of distribution was increased in diseased chickens. 3. The biological half-life in normal chickens was 8.32 +/- 0.5 h and was prolonged in diseased birds (26.21 +/- 0.2 h). The body clearance of chloramphenicol was reduced in diseased chickens. 4. The rate of absorption of chloramphenicol was delayed after administration via the oral route but the extent of absorption was increased. The maximum concentration was higher and it was reached after a longer time in diseased than in normal chickens after administration by both intramuscular and oral routes.     

Pharmacokinetic,residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants

Summary

The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicole^®Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 μg/ml) and 36% larger areas under the plasma concentration‐ time curves than product B, whereas their absorption and elimination half‐lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug.

The maximum CAP concentration in milk was for product B equal to, and for product A 80% of the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra‐trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean‐up procedure.

Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine.

Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited. It was concluded that product A (Amicol^®Forte) had more favourable pharmacokinetic characteristics than the sodium succinate formulation.     

Pharmacokinetic, residue and irritation aspects of chloramphenicol sodium succinate and a chloramphenicol base formulation following intramuscular administration to ruminants

The disposition of chloramphenicol (CAP) and of its glucuronide metabolite in plasma and milk was studied following a single intramuscular injection of a chloramphenicol base formulation (Amicol Forte; product A) and of chloramphenicol sodium succinate (product B) to dairy cows. The dose applied of both formulations was equivalent to 50 mg CAP base/kg body weight. The HPLC determined CAP concentrations were microbiologically active. Product A revealed 30% higher plasma CAP peak concentrations (13.0 vs 9.0 micrograms/ml) and 36% larger areas under the plasma concentration-time curves than product B, whereas their absorption and elimination half-lives were of the same order of magnitude. In the onset phase (during 4 h p.i.) unhydrolysed CAP sodium succinate could be detected in plasma and the glucuronide fraction was 26% of the parent drug. After 25 h p.i. the glucuronide fraction equalled that of the parent drug. The maximum CAP concentration in milk was for product B equal to, and for product A 80% of, the CAP plasma concentration. In milk no chloramphenicol glucuronide metabolites could be detected. HPLC methods for detecting ultra-trace CAP concentrations in edible tissues were developed by the employment of extraction with or without a clean-up procedure. Seven days after i.m. administration of product A and B to calves, the CAP residue concentrations in the kidney, liver, and muscle were less than 2 nanogram/g tissue. Traces of CAP residues could be still found at the injection site and in the urine. Chloramphenicol sodium succinate (product B) caused extensive tissue irritation at the injection site, while in the case of product A the irritation was limited.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Pharmacokinetics of chloramphenicol in cows after intramuscular application

The concentrations of chloramphenicol and its water-soluble metabolites in the plasma of six clinically healthy heifers were measured at intervals during five days after intramuscular administration of free chloramphenicol (20 mg/kg) in a vehicle containing 40% of an organic solvent. Estimations were carried out by a colorimetric method and by high pressure liquid chromatography (for the very low values beyond the second day).For free chloramphenicol a peak concentration of 1.7 g/ml at 7.3 h after injection was found (MIC: 5 g/ml). Bioavailability was calculated to be 63%.It is shown that absorption was apparently not a uniform process but occurred rather slowly (t_1/2(ab)=10.2 h) for the main part of the available dose, whereas one sixth was quickly absorbed (t_1/2(ab)=0.7 h). The apparent half-time of elimination was 10.2 h for the unchanged drug. At the fifth day after administration the plasma concentration was below the limit of detectability (10 ng/ml) in all animals.     

Survey of chloramphenicol residues in diseased swine.

Tissue samples from 279 hogs suspected of having received antibiotic treatment were collected at federally-inspected abattoirs and submitted for chloramphenicol residue analysis during August and September 1984. Injection sites (when present), kidneys or muscle samples were tested by one of two gas chromatographic methods. Kidney samples were also tested at the abattoirs by the Swab Test On Premises. Thirty-one animals (11%) were found with detectable levels ranging from 1 part per billion to 5727 ppb. Highest levels were found at the injection sites, while levels in muscle tissue did not exceed 500 ppb. None of the kidneys from animals found to contain chloramphenicol residues produced a positive Swab Test On Premises result attributable to the presence of chloramphenicol. Twelve kidneys from animals free of chloramphenicol residues produced positive Swab Test On Premises results. Of these, five contained penicillin or streptomycin, but antibiotic residues were not detected in the remaining seven. In addition to the samples collected for this survey, samples from eight hogs representing a herd which had been treated for pneumonia were submitted by an abattoir in Manitoba in November 1984. Chloramphenicol levels in these animals ranged from 0.1 to 73 parts per million in the injection sites, and from 0.04 to 21 ppm in the muscle tissues. The survey data indicated that there were a significant number of animals reaching the abattoirs with detectable chloramphenicol residues, and that the Swab Test On Premises procedure was ineffective in detecting these animals.     

Effect of pyridoxine on the distribution of chloramphenicol and its residues in the chicken

1. Chickens were given either a single dose of chloramphenicol (50 mg/kg body weight per os) or a dose of chloramphenicol together with pyridoxine (25 mg/kg per os) given 1 h before or 4 h afterwards.

2. Concentrations of chloramphenicol were determined in samples of serum and the rates of distribution and elimination extrapolated. Concentrations of chloramphenicol in muscle, liver and kidney were also determined.

3. Serum concentrations of chloramphenicol were lower in chickens given both pyridoxine and chloramphenicol compared with those given only chloramphenicol.

4. Differences were most pronounced during the post‐absorptive phase. The rates of disappearance of chloramphenicol residues from tissues were enhanced by pyridoxine.

5. The biological half life of chloramphenicol and area under the concentration‐time curve were both reduced by the concurrent administration of pyridoxine.

6. Availability of pyridoxine may be a rate limiting factor in the biotransformation of xenobiotics, though its indiscriminate use could cause failure of antibiotic therapy.     

Effect of parenteral iron on serum electrolytes of the baby pig

Twenty-eight 4-d-old nursing pigs were used in two trials to evaluate the effects of im injection of iron (Fe) from Fe-dextran upon subsequent serum mineral concentrations. An im injection of 150 mg of Fe from Fe-dextran was given to all pigs (n = 17) in trial 1. Serum Fe concentration increased rapidly from an initial mean of 65 to 3,466 micrograms/dl at 6 h postinjection (PI), 5,712 micrograms/dl at 24 h PI, then fell to 317 micrograms/dl at 4 d PI, 143 micrograms/dl at 7 d PI and remained about 100 micrograms/dl at 14, 21 and 28 d PI. Concentrations of other serum minerals did not appear to be influenced by the Fe-dextran injection. Treatments of Pigs (n = 11) in trial 2 were no injection, injection of dextran only, injection of 100 mg Fe from Fe-dextran and injection of 200 mg Fe from Fe-dextran. Serum Fe concentration increased rapidly after Fe-dextran injection, rising to a peak of 11,028 micrograms/dl at 6 h PI from the 100-mg Fe injection and 17,012 micrograms/dl at 6 h PI from the 200-mg Fe injection. Serum Fe concentration dropped steadily in pigs that were given no injection or injected with dextran only. Seven days after trial 2 started, all pigs that had received no injection or dextran only were injected with 100 mg Fe from Fe-dextran.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of regional limb perfusion with chloramphenicol using the saphenous or cephalic vein in standing horses

Regional limb perfusion (RLP) significantly decreases morbidity and mortality associated with distal limb injuries in horses. There is an urgent need for finding additional effective antimicrobial drugs for use in RLP. In this study, we tested the pharmacokinetics (PK) of chloramphenicol in RLP. Eight horses participated in the study, which was approved by the University Animal Care and Use Committee. The cephalic and the saphenous veins were used to perfuse the limbs. Synovial samples were collected from the metacarpo/metatarsophalangeal (MCP/MTP) joint. The Friedman Test was applied for assessing change in PK concentration over time, for all time points. The Wilcoxon Signed Ranks Test was used to test the difference between PK concentration in joint & serum as well as concentration in joint vs. MIC. The comparison of measurements between measurements taken on hind vs. front legs was carried out using the Mann–Whitney Test. A P‐value of 5% or less was considered statistically significant. After RLP, the concentration of chloramphenicol in the synovial fluid of the MCP/MTP joint using either the cephalic or the saphenous vein was initially far above the minimal inhibitory concentration (MIC) of most susceptible pathogens and remained above the MIC for approximately 6 h. The results indicate that performing RLP using the cephalic and saphenous veins enables reaching concentrations of chloramphenicol in the MCP/MTP joint that are well above the MIC of most susceptible pathogens. The chloramphenicol concentrations achieved in the synovial fluid of the MCP/MTP joint in the current study were between 1.5 (MTP) and 7 (MCP) times the MIC of MRSA in horses. These results are encouraging since MRSA infections are becoming far more common, causing considerable morbidity. To the best of our knowledge, this is the first study to evaluate the pharmacokinetics of chloramphenicol following RLP in the horse and the results are positive.     

Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparation

The pharmacokinetics of a long‐acting oxytetracycline (OTC) formulation (Liquamycin® LA‐200®) injected intramuscularly (i.m.) at a dose of 20 mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168±14.6 (μg ? h/mL) and was significantly less than the AUC for sheep (209±43 μg ? h/mL). Using the standard two‐stage approach and a one‐compartment model, the mean Cmax for the calves was 5.2±0.8 μg/mL, and for the sheep was 6.1±1.3 μg/mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08 L/kg for the calves and sheep respectively. Analysis of the data using the standard two‐stage approach, the naive pooled‐data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20 mg/kg OTC. Half‐lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9 h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6 p.p.m.), muscle (2 p.p.m.) and kidney (12 p.p.m.) by 48 h, and in injection site muscle by 14 days after the single i.m. injection of 20 mg/kg.     

Plasma concentrations of chloramphenicol after subcutaneous administration to koalas (Phascolarctos cinereus) with chlamydiosis

Nine mature koalas with chlamydiosis, typically keratoconjunctivitis and/or urogenital tract infection, were treated with daily subcutaneous injections of chloramphenicol at 60 mg/kg for 45 days (five koalas), or for a shorter duration (four koalas). All koalas were initially positive for Chlamydia pecorum as determined by real-time polymerase chain reaction (qPCR). Plasma chloramphenicol concentrations were determined at t = 0, 1, 2, 4, 8, and 24 h after the day 1 injection (nine koalas) and after the day 15 injection (seven koalas). Chloramphenicol reached a median (and range) maximum plasma concentration of 3.03 (1.32-5.03 μg/mL) at 4 (1-8 h) after the day 1 injection and 4.82 (1.97-27.55 μg/mL) at 1 (1-2 h) after day 15. The median (and range) of AUC(0-24) on day 1 and day 15 were 48.14 (22.37-81.14 μg·h/mL) and 50.83 (28.43-123.99 μg·h/mL), respectively. The area under the moment curve (AUMC)(0-24) median (and range) for day 1 and day 15 were 530.03 (233.05-798.97 h) and 458.15 (291.72-1093.58 h), respectively. Swabs were positive for chlamydial DNA pretreatment, and all koalas except one, produced swabs negative for chlamydial DNA during treatment and which remained so, for 2-63 days after treatment, however whether chloramphenicol treatment prevented long-term recrudescence of infection was not established. At this dose and dosing frequency, chloramphenicol appeared to control mild chlamydial infection and prevent shedding, but severe urogenital disease did not appear to respond to chloramphenicol at this dosage regime. For koalas affected by severe chlamydiosis, antibiotics alone are not sufficient to effect a cure, possibly because of structural or metabolic changes associated with chronic disease and inflammation.