No abstract

The effect of bacterial infection on antibiotic activity and penetration of parenterally administered ceftiofur into implanted tissue chambers was studied in cattle. Tissue chambers were implanted subcutaneously in the paralumbar fossae of eight calves (256-290 kg body weight). Approximately 80 days after implantation, the two chambers on one side of each animal were inoculated with Pasteurella haemolytica (10(6) CFU/chamber). Eighteen hours after inoculation, ceftiofur sodium was administered intravenously (5 mg/kg) to each of the calves. Non-infected chamber fluid, infected chamber fluid and heparinized blood samples were collected immediately before and at 1, 3, 6, 12 and 24 h after drug administration. Concentrations of ceftiofur and desfuroylceftiofur metabolites and ceftiofur-equivalent microbiological activity were measured by high-pressure liquid chromatography and microbiological assay respectively. Concentrations of ceftiofur and desfuroylceftiofur metabolites and anti-microbial activity in P. haemolytica-infected tissue chambers were significantly higher than those in non-infected tissue chambers at all sampling times, indicating that ceftiofur, regardless of the method used for analysis, localizes at higher concentrations at tissue sites infected with P. haemolytica. Antibiotic activity-concentration ratios were lower in plasma and infected chamber fluid compared with non-infected chamber fluid, suggesting that antibiotic was bound to proteins. However, higher antimicrobial activity in the infected chamber fluid compared with the non-infected chamber fluid, suggests that active drug is reversibly bound to proteins. Protein-bound desfuroylceftiofur may represent a reservoir for release of active drug at the site of infection in the animal.

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.

Summary Endotoxins are non‐protein fragments of the cell wall of Gramnegative bacteria. They must be absorbed into the circulation to produce disease and systemic effects are similar, regardless of bacterial source. Absorption of endotoxins occurs in obstructive bowel disease and may play a significant part in determining the severity of the disease. Many of the responses to experimentally administered endotoxin are identical to those of bowel diseases of the horse and include circulatory, haematological and metabolic alterations. Therapeutic approaches are indirect and include many drugs currently employed in equine practice. The agents are directed toward mediators of the disease rather than the endotoxins themselves and include fluids, corticosteroids, anti‐inflammatory drugs, energy sources and vasoactive drugs. The rationale for use and dosages are discussed. Résumé Les endotoxines sont des fragments non protéiques de la paroi cellulaire des bactéries Gram‐. Ils doivent être entraînés par la circulation sanguine pour engendrer des maladies et les effets systémiques sont semblables, quelle que soit la source bactérienne. L'absorption d'endotoxines se produit lors d'obstruction intestinale et cela peut jouer une part importante dans la sévérité de la maladie, Bien des résultats faisant suite à l'administration expérimentale d'endotoxines sont identiques à ceux constatés lors d'obstruction intestinale chez le cheval, et comportent des altérations métaboliques, hématologiques et circulatoires. Les démarches thérapeutiques sont indirectes et utilisent de nombreux médicaments d'emploi courant en médecine équine. Les agents thérapeutiques sont utilisés contre les relais de la maladie à défaut de pouvoir agir contre les endotoxines elles mêmes; ils comportent des solutés, des corticostéroîdes, des anti inflammatoires, des sources énergétiques et des agents vaso actifs. On en discute les dosages et l'emploi. Zusammenfassung Endotoxine sind eiweissfreie Fragmente der Zellwand gramnegativer Bakterien. Um Krankheitszeichen hervorrufen zu können, müssen sie in die Zirkulation absorbiert werden, unabhängig von der bakteriellen Quelle. Eine Endotoxinabsorption ergibt sich bei obstruktiven Darmkrankheiten; sie kann den Grad einer Erkrankung signifikant beeinflussen. Viele der mit experimentell verabreichtem Endotoxin ausgelösten Zeichen sind mit denjenigen von Darmerkrankungen des Pferdes identisch. Sie umfassen zirkulatorische, haematologische und metabolische Veränderungen. Die Behandlung erfolgt indirekt mit vielen der in der Pferdepraxis üblichen Medikamente. Die Mittel richten sich gegen die Krankheitsmediatoren und nicht gegen die Endotoxine selbst; sie umfassen Flüssigkeiten, Corticosteroide, Entzündungshemmer, Energiespender und vasoaktive Substanzen. Die Rationalität von Gebrauch und Dosierungen wird besprochen.

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.

The disposition and urinary excretion pharmacokinetics of methylene blue were determined after its intravenous administration at 15 mg/kg to mature female sheep. Comparisons were made between methylene blue administered alone or subsequent to 50 mg/kg sodium nitrite. The overall elimination rate constant (beta) of methylene blue, 0.0076 +/- 0.0016 min-1, was not influenced by prior administration of sodium nitrite. However, the distribution rate was significantly altered by sodium nitrite. Very little of the methylene blue was eliminated in the urine either intact or as leucomethylene blue in spite of its relatively short half life. Toxicologic assessment was carried out using LD50 determination, methemoglobin production and hematologic effects as evaluation parameters. Methemoglobin production was minimal with doses as high as 50 mg/kg and no significant hematologic changes were seen up to 4 weeks after a total dose of 30 mg/kg methylene blue. The 24 h LD50 for intravenous methylene blue administered as a 3% solution was 42.3 mg/kg with 95% confidence interval limits of 37.3 to 47.9 mg/kg. From these data it appears that as conditions may warrant, the dosage of methylene blue may be safely increased up to at least 15 mg/kg in therapy of severe methemoglobinemias.

Ewing, P. J., Burrows, G., MacAllister, C, Clarke, C. Comparison of oral erythromycin formulations in the horse using pharmacokinetic profiles. J. vet. Pharmacol, Therap.17, 17–23. The pharmacokinetic properties of four erythromycin formulations were compared in six adult horses after administration of single and multiple oral doses. Formulations of erythromycin administered were estolate and phosphate given 37.5 mg/kg every 12 h and 25 mg/kg every 8 h, and stearate and ethylsuccinate given 25 mg/kg every 8 h. Areas under the curve (AUC) and maximum plasma erythromycin concentrations (Cmax) were equal or greater (P ≥ 0.05) following administration of erythromycin phosphate and stearate compared with those values following administration of erythromycin estolate or ethylsuccinate. In comparing an 8 h vs. a 12 h dosage interval for multiple doses of erythromycin phosphate or estolate, there were no significant differences observed in AUC(24–28 h), peak‐trough plasma concentrations or duration that plasma concentrations exceeded the minimal inhibitory concentration (MIC) for Rhodococcus equi. Comparisons of pharmacokinetic parameters between single and multiple doses were made for each formulation. Differences in Cmax, tmax, or t½β between single and multiple doses were demonstrated for erythromycin ethylsuccinate and estolate. Based on equivalent plasma antibiotic concentrations, erythromycin phosphate or stearate could be substituted for estolate in the treatment of Rhodococcus equi pneumonia. Furthermore, there was no advantage of an 8‐h interval, compared with an interval of 12 h.

ABSTRACr Twenty four volunteers who had been allergic to laboratory animals for some years were examined by means of a questionnaire paying particular attention to symptoms associated with rats and by serological and skin tests with extracts of rat urine (retrospective study). Nasal and eye symptoms were reported by 21 and 16 individuals respectively: 13 had asthma. Positive skin tests and high levels of specific IgE antibody to rat urine extract were found in 17 of the more severely affected individuals and this group included 12 of those with asthma. Latent periods of work with animals before symptoms appeared varied from 0*5 to 12 years. Also 148 individuals were studied during their first year of work with animals (prospective study). Symptoms developing during the year were reported by 15%, asthma by 2%. IgE antibody levels to rat urine were raised in 40% of affected and 6% of the unaffected individuals but there was no significant correlation between symptoms and either antibody levels or positive skin tests. Allergic symptoms developing during the first year of postemployment were, on the whole, much milder than those seen in the retrospective study. A tentative conclusion is that most individuals who become allergic to laboratory animals develop the condition in a mild form during their first year of employment but it appears probable that atopic individuals, although having an equal chance of developing allergy as compared with non-atopic individuals, may eventually progress to a more severe form of the disease.Allergy to laboratory animals (ALA), after a period of relative neglect, is now receiving increased attention' 1O. While all authors agree that the overall incidence of ALA in the exposed population is about 20%, there is considerable variation in terms of the percentage of individuals with ALA (table 1).A notable advance in the study of ALA resulted from the findings of Newman-Taylor etal" and Longbottom12 that a major allergen is found in the urine of rats and mice. Among other benefits these findings have facilitated the use of relevant immunological approaches to the problems presented by ALA. Despite our increased knowledge, more information is needed before a rational approach to the control of ALA can be instituted. The present study had two main aims: (1) symptoms in a group of people with established allergy to rats and (2) to study the nature and rate of development of allergy during the period of employment as an animal worker. A subsidiary aim of the study was to offer an explanation for the apparently wide differences in the reported incidence of asthma. The present paper describes our initial findings, and is presented in two parts, a retrospective study and a prospective study.The retrospective study attempted to correlate rat associated allergic symptoms with the presence of specific IgE antibody and the response in skin tests to rat urine. The volunteers included in this study were selected solely on the basis of their previous report of allergic symptoms.8 Although some of th...