Comparison of plasma and interstitial fluid concentrations of doxycycline and meropenem following constant rate intravenous infusion in dogs

OBJECTIVE: To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug. ANIMAL: 6 adult Beagles. PROCEDURE: Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods. RESULTS: Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 +/- 0.63%) and lipophilicity (partition coefficients, 0.02 +/- 0.01 vs 0.68 +/- 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 +/- 0.57 hours, 0.65 +/- 0.82 L/kg, and 1.66 +/- 2.21 mL/min/kg, respectively, for doxycycline and 0.73 +/- 0.07 hours, 0.34 +/- 0.06 L/kg, and 5.65 +/- 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 +/- 0.67 and 2.31 +/- 0.36 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The extent of protein binding determines distribution of doxycycline and meropenem into ISF. As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations.     

Evaluation of iohexol clearance used to estimate glomerular filtration rate in clinically normal foals

OBJECTIVE: To determine whether pharmacokinetic analysis of data derived from a single i.v. dose of iohexol could be used to predict creatinine clearance and evaluate simplified methods for predicting serum clearance of iohexol with data derived from 2 or 3 blood samples in clinically normal foals. ANIMALS: 10 healthy foals. PROCEDURE: Serum disposition of iohexol and exogenous creatinine clearance was determined simultaneously in each foal (5 males and 5 females). A 3-compartment model of iohexol serum disposition was selected via standard methods. Iohexol clearance calculated from the model was compared with creatinine clearance. Separate limited-sample models were created with various combinations of sample times from the terminal slope of the plasma versus time profile for iohexol. Correction factors were determined for the limited-sample models, and iohexol clearance calculated via each method was compared with exogenous creatinine clearance by use of method comparison techniques. RESULTS: Mean exogenous creatinine clearance was 2.17 mL/min/kg. The disposition of iohexol was best described by a 3-compartment open model. Mean clearance value for iohexol was 2.15 mL/min/kg and was not significantly different from mean creatinine clearance. A method for predicting serum iohexol clearance based on a 2-sample protocol (3- and 4-hour samples) was developed. CONCLUSIONS AND CLINICAL RELEVANCE: Iohexol clearance can be used to predict exogenous creatinine clearance and can be determined from 2 blood samples taken after i.v. injection of iohexol. Appropriate correction factors for adult horses and horses with abnormal glomerular filtration rate need to be determined.     

Identification of a new source of Campylobacter contamination in poultry: transmission from breeder hens to broiler chickens

Campylobacter jejuni, a foodborne pathogen closely associated with market poultry, is considered to be the most frequent agent of human gastroenteritis in the United States. The pathways involved in the contamination of poultry flocks, vertical transmission and/or horizontal transmission, are unclear. In this study, Campylobacter isolates from two independent commercial broiler breeder flocks, as well as from their respective progeny, were characterized and compared by PstI ribotype analysis and by DNA sequence analysis of the short variable region (SVR) of the flaA gene (flaA SVR). Campylobacter isolates originating from one set of breeder hens and the feces from their respective progeny demonstrated identical ribotype patterns as well as identical flaA SVR DNA sequences, thereby suggesting that these isolates were clonal in origin. Ribotype analysis of Campylobacter isolates from the second set of breeder hens and processed carcasses from their offspring resulted in two patterns. Sequence analysis placed these isolates into two closely related groups and one distant group, similar to the ribotype analysis. These results demonstrate that Campylobacter isolates from commercial broiler breeder flocks and from the respective broiler progeny may be of clonal origin and that breeder hens can serve as a source for Campylobacter contamination in poultry flocks.     

Pharmacokinetics after intravenous and oral administration of enrofloxacin in sheep

OBJECTIVE: To compare pharmacokinetics of enrofloxacin administered IV and in various oral preparations to ewes. ANIMALS: 5 mature Katahdin ewes weighing 42 to 50 kg. PROCEDURE: Ewes received 4 single-dose treatments of enrofloxacin in a nonrandomized crossover design followed by a multiple-dose oral regimen. Single-dose treatments consisted of an IV bolus of enrofloxacin (5 mg/kg), an oral drench (10 mg/kg) made from crushed enrofloxacin tablets, oral administration in feed (10 mg/kg; mixture of crushed enrofloxacin tablets and grain), and another type of oral administration in feed (10 mg/kg; mixture of enrofloxacin solution and grain). The multiple-dose regimen consisted of feeding a mixture of enrofloxacin solution and grain (10 mg/kg, q 24 h, for 7 days). Plasma concentrations of enrofloxacin and ciprofloxacin were measured by use of high-performance liquid chromatography. RESULTS: Harmonic mean half-life for oral administration was 14.80, 10.80, and 13.07 hours, respectively, for the oral drench, crushed tablets in grain, and enrofloxacin solution in grain. Oral bioavailability for the oral drench, crushed tablets in grain, and enrofloxacin in grain was 4789, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 microg/ml, respectively. Median Cmax of the multiple-dose regimen was 2.99 microg/ml. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered orally to sheep has a prolonged half-life and high oral bioavailability. Oral administration at 10 mg/kg, q 24 h, was sufficient to achieve a plasma concentration of 8 to 10 times the minimum inhibitory concentration (MIC) of any microorganism with an MIC < or = 0.29 microg/ml.     

Neuroendocrine-immune interactions in fish: a role for interleukin-1

Bi-directional communication between the hypothalamus-pituitary-adrenal (HPA)-axis and the sympathetic nervous system with the immune system is crucial to ensure homeostasis. Shared use of ligands and especially receptors forms a key component of this bi-directional interaction. Glucocorticoids (GC), the major end products of the HPA-axis differentially modulate immune function. Cytokines, especially interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), ensure immune signalling to the neuroendocrine system. In addition, hormones from leukocyte origin such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and beta-endorphin, as well as centrally synthesised and secreted cytokines, contribute to the communication network.In teleost fish cortisol is the major product of the hypothalamus-pituitary-interrenal (HPI)-axis which is the teleost equivalent of the HPA-axis. Moderate and substantial increases in cortisol during stressful circumstances negatively affect B-lymphocytes, whereas rescue of neutrophilic granulocytes may support innate immunity. Recent elucidation of lower vertebrate cytokine sequences has facilitated research into neuroendocrine-immune interactions in teleosts and the first evidence for a significant function of interleukin-1 in the bi-directional communication is discussed.     

Efficacy of extended pirlimycin hydrochloride therapy for treatment of environmental Streptococcus spp and Staphylococcus aureus intramammary infections in lactating dairy cows

Fifty-one chronically infected lactating dairy cows were used to evaluate the efficacy of extended pirlimycin therapy regimens for treatment of intramammary infections by environmental Streptococcus spp and Staphylococcus aureus. Cows (n = 47) with one or more infected mammary quarters were blocked by parity and randomly allocated to one of three groups for treatment with pirlimycin (50 mg/mammary quarter) as follows: one treatment per day for 2 days (n = 36 infected mammary quarters); one treatment per day for 5 days (n = 36 infected mammary quarters); and one treatment per day for 8 days (n = 20 infected mammary quarters). Four cows with nine infected mammary quarters were included as untreated controls. Milk samples from each mammary quarter were collected 7 days before treatment, immediately before treatment, and weekly for 4 weeks after the final treatment for microbiological evaluation. A bacteriologic cure was defined as a treated, infected quarter that was bacteriologically negative for the presence of previously identified bacteria at weekly intervals after treatment. Efficacy of pirlimycin therapy against intramammary infections caused by environmental Streptococcus spp and S. aureus was 44.4%, 61.1%, and 95.0% for the 2-, 5-, and 8-day treatment regimens, respectively. None of the infections in the untreated control quarters was cured. Significant differences in efficacy were detected between all pirlimycin groups and the untreated control group, between the 8- and 2-day treatment regimens, and between the 8-day and 5-day treatment regimens (P < or = .05). Results of this study indicate that extended pirlimycin therapy was effective in eliminating intramammary infections caused by environmental streptococci and S. aureus in lactating dairy cows.     

Frequency of isolation and antimicrobial susceptibility patterns of Staphylococcus intermedius and Pseudomonas aeruginosa isolates from canine skin and ear samples over a 6-year period (1992-1997)

Staphylococcus intermedius (S. intermedius) was isolated from 88.6% and 49.4% of skin and ear samples, respectively, during the years 1992 through 1997, and frequency of isolation remained unchanged. More than 95% of all S. intermedius isolates were susceptible to cephalothin and oxacillin, providing support for empirical treatment of canine skin and ear infections with cephalexin. Pseudomonas aeruginosa (P. aeruginosa) was isolated from 7.5% and 27.8% of skin and ear samples, respectively. The frequency of isolation from skin samples increased over the study period. Because of multidrug-resistant profiles for P. aeruginosa isolates, especially for ear isolates, empirical treatment of P. aeruginosa infections is not advisable.