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Abstract

Objective—To express a cecropin B transgene on bovine nasal mucosa and determine the effect on Mannheimia haemolytica serotype 1 (S1) colonization.

Animals—27 crossbred beef calves.

Procedure—The antibacterial efficacy of cecropin B against M haemolytica S1 was first determined by measuring its minimum inhibitory concentration (MIC). The peptide was also diluted in pooled bovine nasal secretions, and its antibacterial activity was evaluated. The nasal passages of 16 calves were aerosolized with 25, 50, or 100 µg of plasmid DNA/nostril, whereas 11 control calves were aerosolized with only the transfection reagent. In 2 of the experiments, 12 treated and 8 control calves were exposed intranasally with an aerosol of M haemolytica S1. Nasal swab specimens and secretions were collected and analyzed by use of polymerase chain reaction (PCR), real-time PCR, real-time reverse-transcriptase PCR, ELISA, and bacterial culture.

Results—In vitro, cecropin B inhibited M haemolytica S1 at an MIC of 2 µg/mL and its antibacterial activity was not affected by proteolytic activity in nasal secretions. Cecropin B transgene expression was detected in calves transfected with 50 or 100 µg of DNA/nostril. Antibacterial activity against M haemolytica S1 was observed in all calves transfected with 100 µg of DNA/nostril but in only 2 of the 4 calves transfected with 50 µg of DNA/nostril.

Conclusions and Clinical Relevance—In vitro, cecropin B has an effective antibacterial activity against M haemolytica S1 and can prevent colonization of the nasal mucosa after transfection of a vector expressing cecropin B in vivo. (Am J Vet Res 2005;66:1922–1930)

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in American Journal of Veterinary Research

Abstract

Objective—To compare concentrations of danofloxacin, enrofloxacin, and ciprofloxacin in plasma and respiratory tissues of calves treated after challenge with Mannheimia haemolytica.

Animals—75 calves.

Procedure—24 hours after challenge with M haemolytica, 72 calves with clinical signs of respiratory tract disease were randomly assigned to 1 of 12 equal treatment groups. Three nonchallenged, nontreated calves formed a control group. Challenged calves were treated with danofloxacin (6 and 8 mg/kg, SC) and enrofloxacin (8 mg/kg, SC) once. At 1, 2, 6, and 12 hours after treatment, 6 calves from each treatment group were euthanatized. Antimicrobial drug concentrations were assayed in various specimens. Peak plasma concentration (Cmax)-to-minimum inhibitory concentration (MIC; Cmax-to-MIC) ratios and the area under the concentration versus time curve over a 12-hour period-to-MIC ratios (AUC12h-to-MIC) were calculated.

Results—Danofloxacin and enrofloxacin had MICs of 0.03 µg/mL for the M haemolytica challenge isolate. Danofloxacin administered at doses of 6 and 8 mg/kg resulted in numerically higher geometric mean concentrations of danofloxacin in plasma and all respiratory tissues than geometric mean concentrations of enrofloxacin after treatment with enrofloxacin. Geometric mean concentrations of enrofloxacin were numerically higher than geometric mean concentrations of ciprofloxacin metabolite in plasma and almost all respiratory tissues. Danofloxacin and enrofloxacin achieved Cmax-to-MIC ratios > 10 and AUC12h-to-MIC ratios > 125 hours.

Conclusions and Clinical Relevance— When used to treat pneumonic pasteurellosis in calves, danofloxacin and enrofloxacin can be expected to deliver concentration-dependent bactericidal activity against M haemolytica, the bacteria most commonly associated with bovine respiratory tract disease. (Am J Vet Res 2005;66:342–349)

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in American Journal of Veterinary Research

Abstract

Objective—To determine plasma concentrations of enrofloxacin and the active metabolite ciprofloxacin after PO, SC, and IV administration of enrofloxacin to alpacas.

Animals—6 adult female alpacas.

Procedure—A crossover design was used for administration of 3 single-dose treatments of enrofloxacin to alpacas, which was followed by an observational 14-day multiple-dose regimen. Single-dose treatments consisted of IV and SC administration of injectable enrofloxacin (5 mg/kg) and PO administration of enrofloxacin tablets (10 mg/kg) dissolved in grain to form a slurry. Plasma enrofloxacin concentrations were measured by use of high-performance liquid chromatography. The multiple-dose regimen consisted of feeding a mixture of crushed and moistened enrofloxacin tablets mixed with grain. Behavior, appetite, and fecal quality were monitored throughout the 14-day treatment regimen and for 71 additional days following treatment.

Results—Mean half-life following IV, SC, and PO administration was 11.2, 8.7, and 16.1 hours, respectively. For SC and PO administration, mean total systemic availability was 90.18% and 29.31%, respectively; mean maximum plasma concentration was 3.79 and 1.81 µg/mL, respectively; and area under the curve (AUC) was 50.05 and 33.97 (µg × h)/mL, respectively. The SC or PO administration of a single dose of enrofloxacin yielded a ratio for AUC to minimum inhibitory concentration > 100 for many grampositive and gram-negative bacterial pathogens common to camelids.

Conclusions and Clinical Relevance—The administration of enrofloxacin (5 mg/kg, SC, or 10 mg/kg, PO) may be appropriate for antimicrobial treatment of alpacas. (Am J Vet Res 2005;66:767–771)

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of azithromycin and its concentration in body fluids and bronchoalveolar lavage cells in foals.

Animals—6 healthy 6- to 10-week-old foals.

Procedure—Azithromycin (10 mg/kg of body weight) was administered to each foal via IV and intragastric (IG) routes in a crossover design. After the first IG dose, 4 additional IG doses were administered at 24-hour intervals. A microbiologic assay was used to measure azithromycin concentrations in serum, peritoneal fluid, synovial fluid, pulmonary epithelial lining fluid (PELF), and bronchoalveolar (BAL) cells.

Results—Azithromycin elimination half-life was 20.3 hours, body clearance was 10.4 ml/min·kg, and apparent volume of distribution at steady state was 18.6 L/kg. After IG administration, time to peak serum concentration was 1.8 hours and bioavailability was 56%. After repeated IG administration, peak serum concentration was 0.63 ± 0.10 µg/ml. Peritoneal and synovial fluid concentrations were similar to serum concentrations. Bronchoalveolar cell and PELF concentrations were 15- to 170-fold and 1- to 16-fold higher than concurrent serum concentrations, respectively. No adverse reactions were detected after repeated IG administration.

Conclusions and Clinical Relevance—On the basis of pharmacokinetic values, minimum inhibitory concentrations of Rhodococcus equi isolates, and drug concentrations in PELF and bronchoalveolar cells, a single daily oral dose of 10 mg/kg may be appropriate for treatment of R equi infections in foals. Persistence of high azithromycin concentrations in PELF and bronchoalveolar cells 48 hours after discontinuation of administration suggests that after 5 daily doses, oral administration at 48-hour intervals may be adequate. (Am J Vet Res 2001;62:1870–1875)

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics and pharmacodynamics of danofloxacin in goats and the concentrations required to induce bacteriostasis, bactericidal activity, and bacterial elimination.

Animals—6 healthy British Saanen goats.

Procedure—Danofloxacin (1.25 mg/kg of body weight) was administered IV and IM in a cross-over design with 14 days between treatments. A tissue cage was used for evaluation of drug distribution into transudate and exudate. The ex vivo antibacterial activity of danofloxacin in serum, exudate, and transudate against a caprine isolate of Mannheimia haemolytica was determined. Pharmacokinetic and pharmacodynamic data were integrated to determine the ratio of the area under the concentration versus time curve to the minimum inhibitory concentration of danofloxacin (AUIC).

Results—Elimination half-lives of danofloxacin in serum were 4.67 and 4.41 hours after IV and IM administration, respectively. Volume of distribution was high after administration via either route, and bioavailability was 100% after IM administration. Rate of penetration into exudate and transudate was slow, but elimination half-lives from both fluids were approximately twice that from serum. Drug concentrations in serum, exudate, and transudate for 9 to 12 hours after administration induced marked ex vivo antibacterial activity. For serum, AUIC24h values required for bacteriostasis, bactericidal effect, and bacterial elimination were 22.6, 29.6, and 52.4, respectively. Similar values were obtained for exudate and transudate.

Conclusions and Clinical Relevance—Integration of danofloxacin pharmacokinetic and pharmacodynamic data obtained in goats may provide a new approach on which to base recommendations for therapeutic dosages. (Am J Vet Res 2001;62:1979–1989)

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in American Journal of Veterinary Research

Abstract

Objective—To determine pharmacokinetics and plasma concentrations of erythromycin and related compounds after intragastric administration of erythromycin phosphate and erythromycin estolate to healthy foals.

Animals—11 healthy 2- to 6-month-old foals.

Procedure—Food was withheld from foals overnight before intragastric administration of erythromycin estolate (25 mg/kg of body weight; n = 8) and erythromycin phosphate (25 mg/kg; 7). Four foals received both drugs with 2 weeks between treatments. Plasma erythromycin concentrations were determined at various times after drug administration by use of high-performance liquid chromatography. Maximum plasma peak concentrations, time to maximum concentrations, area under plasma concentration versus time curves, half-life of elimination, and mean residence times were determined from concentration versus time curves.

Results—Maximum peak concentration of erythromycin A after administration of erythromycin phosphate was significantly greater than after administration of erythromycin estolate (2.9 ± 1.1 µg/ml vs 1.0 ± 0.82 µg/ml). Time to maximum concentration was shorter after administration of erythromycin phosphate than after erythromycin estolate (0.71 ± 0.29 hours vs 1.7 ± 1.2 hours). Concentrations of anhydroerythromycin A were significantly less 1 and 3 hours after administration of erythromycin estolate than after administration of erythromycin phosphate.

Conclusions and Clinical Relevance—Plasma concentrations of erythromycin A remained > 0.25 µg/ml (reported minimum inhibitory concentration for Rhodococcus equi) for at least 4 hours after intragastric administration of erythromycin phosphate or erythromycin estolate, suggesting that the recommended dosage for either formulation (25 mg/kg, q 6 h) should be adequate for treatment of R equi infections in foals. (Am J Vet Res 2000;61:914–919)

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in American Journal of Veterinary Research

Abstract

Objective—To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs.

Animals—6 healthy adult dogs.

Procedure—Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device.

Results—Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean ± SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 ± 0.07 hours, 0.372 ± 0.053 L/kg, and 6.53 ± 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 ± 0.57 hours. Half-life after SC administration was 0.98 ± 0.21 and 1.31 ± 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%.

Conclusions and Clinical Relevance—Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 µg/mL. (Am J Vet Res 2002;63:1622–1628)

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in American Journal of Veterinary Research

Abstract

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 47.89, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 µg/ml, respectively. Median Cmax of the multiple-dose regimen was 2.99 µg/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 ≤ 0.29 µg/ml. (Am J Vet Res 2002; 63:1012–1017)

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in American Journal of Veterinary Research

Abstract

Objective—To determine the plasma pharmacokinetics of imipenem (5 mg/kg) after single-dose IV, IM, and SC administrations in dogs and assess the ability of plasma samples to inhibit the growth of Escherichia coli in vitro.

Animals—6 adult dogs.

Procedure—A 3-way crossover design was used. Plasma concentrations of imipenem were measured after IV, IM, and SC administration by use of high-performance liquid chromatography. An agar well antimicrobial assay was performed with 3 E coli isolates that included a reference strain and 2 multidrug-resistant clinical isolates.

Results—Plasma concentrations of imipenem remained above the reported minimum inhibitory concentration for E coli (0.06 to 0.25 µg/mL) for a minimum of 4 hours after IV, IM, and SC injections. Harmonic mean and pseudo-standard deviation halflife of imipenem was 0.80 ± 0.23, 0.92 ± 0.33, and 1.54 ± 1.02 hours after IV, IM, and SC administration, respectively. Maximum plasma concentrations (Cmax) of imipenem after IM and SC administration were 13.2 ± 4.06 and 8.8 ± 1.7 mg/L, respectively. Time elapsed from drug administration until Cmax was 0.50 ± 0.16 hours after IM and 0.83 ± 0.13 hours after SC injection. Growth of all 3 E coli isolates was inhibited in the agar well antimicrobial assay for 2 hours after imipenem administration by all routes.

Conclusions and Clinical Relevance—Imipenem is rapidly and completely absorbed from intramuscular and subcutaneous tissues and effectively inhibits in vitro growth of certain multidrug-resistant clinical isolates of E coli. (Am J Vet Res 2003;64:694–699)

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in American Journal of Veterinary Research

Abstract

Objective—To design short and potent analogs of bovine lactoferricin by use of the concepts of lipophilic bulk and cationic charge.

Sample Population—5 synthetic peptides of bovine lactoferricin.

Procedure—Antibacterial peptides were constructed by synthesizing several decapeptides rich in arginine and tryptophan. Basic residues of bovine lactoferricin (bLf 20-29; residues 20 to 29) were modified by substitution with arginine or lysine and nonbasic residues were modified by substitution with tryptophan, phenylalanine, or isoleucine. Synthetic peptides of bovine lactoferrin (LFB) were designated as LFB-RW (RRWWWRWRRW), LFB-KW (KKWWWKWKKW), LFB-RWa (RRWWRRWRRW), LFB-RF (RRFFFRFRRF), and LFB-RI (RRIIIRWRRI), where R, K, W, F, and I stand for arginine, lysine, tryptophan, phenylalanine, and isoleucine, respectively. Peptides were evaluated by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli, Staphylococcus aureus,and Enterococcus faecalis.

Results—LFB-RW, LFB-KW, and LFB-RWa possessed equivalent potency as bLf 20-29 against E coli. LFB-RW and LFB-RWa had a 2-fold increase in growth-inhibitory and bactericidal activity against S aureus, compared with bLf 20-29. LFB-RI had the lowest MIC value against E coli among the peptides but lost bactericidal activity. LFB-RW and LFB-KW had stronger bactericidal activities against S aureus or E faecalis, respectively, as well as E coli than the other synthetic peptides. LFB-RF also had antibacterial activity, but this was 2-fold less than that of LFBRW, as determined by MIC and MBC values.

Conclusions and Clinical Relevance—In construction of potent antibacterial peptides, inclusion of arginine, lysine, tryptophan, or isoleucine residues enhances effectiveness against certain bacteria, as measured by MIC or MBC values. (Am J Vet Res 2003;64:1088–1092)

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in American Journal of Veterinary Research