Pharmacokinetics of azithromycin in lactating dairy cows with subclinical mastitis caused by Staphylococcus aureus.

Azithromycin is a time-dependent antimicrobial with long persistence. The main characteristics of azithromycin suggest that it could be useful for treating bovine mastitis caused by Staphylococcus aureus. To investigate this possibility, its pharmacokinetic (PK) behavior was studied. Six Holstein lactating cows with subclinical mastitis were administered two 10 mg/kg intramuscular (i.m.) doses of azithromycin, with a 48-h interval. Milk and plasma concentrations were measured by microbiological assay. The MIC(90) was determined in 51 S. aureus isolations to calculate pharmacokinetic/pharmacodynamic (PK/PD) parameters. Milk maximal concentration (C(max)) was 7.76 +/- 1.76 microg/mL (16.67 h post-first administration) and 7.82 +/- 2.18 microg/mL (14 h post-2(nd) administration). In plasma C(max) was 0.18 +/- 0.03 microg/mL (2 h post-1(rst) administration) and 0.11 +/- 0.03 microg/mL (14 h post-2(nd) administration). Azithromycin was eliminated from the milk with a half-life (T(1/2)lambda) of 158.26 +/- 137.7 h after 2(nd) administration, meanwhile plasma T(1/2)lambda resulted shorter(13.97 +/- 11.1 h). The mean area under the concentration vs. time curve from 0 to 24 h (AUC(0-24h)) was 153.82 +/- 34.66 microg.h/mL in milk secretion and 2.61 +/- 0.59 microgxh/mL in plasma. Infection presence in the quarters had a significant effect (P < 0.05) on the area under the concentration vs. time curve from 0 to infinity (AUC(0-infinity)) and clearance from the mammary gland (Cl(mam)/F). Moreover, it had influence on milk bioavailability (F(milk)), T(1/2)lambda, AUC(0-infinity) and mean residence time (MRT) in milk, which values resulted increased in mastitic quarters. In this study, it was determined that the production level and the mammary health status have an influence on PK parameters of azithromycin treatments in bovine mastitis.

Pharmacokinetics of enrofloxacin after single intravenous administration in sheep.

The disposition of enrofloxacin in sheep was investigated after single-dose intravenous administration of 2.5 mg/kg body weight. Blood samples were drawn from the jugular vein at predetermined times after drug administration. Plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin were simultaneously determined by reverse-phase high performance liquid chromatography. The data collected were subjected to non-compartmental and compartmental kinetic analysis. Statistical model theory was used to determine non-compartmental pharmacokinetic parameters. Disposition of enrofloxacin was described by a three-compartment open model with elimination from the central compartment following intravascular administration. The elimination half-life, the volume of distribution, and the area under the concentration vs time curve (AUC) were 4.31 h, 1.10 l/kg and 9.24 microg x h/ml, respectively. Enrofloxacin was metabolised to ciprofloxacin and the ratio between the AUCs of ciprofloxacin and enrofloxacin was 0.26 after intravenous administration. With predictive models of efficacy (maximum plasma concentrations/minimum inhibitory concentrations [Cmax/MIC] and AUC/MIC ratios in plasma) for most of the sheep pathogen microorganisms, enrofloxacin produced scores higher than 15 and 50, respectively. After intravenous administration atthe dose of 2.5 mg/kg, enrofloxacin achieved concentrations several times above the MIC for major pathogen bacteria in plasma, and it may prove useful in the treatment of infectious diseases caused by sensitive pathogens in sheep.

Pharmacokinetic disposition of triclabendazole in cattle and sheep; discrimination of the order and the rate of the absorption process of its active metabolite triclabendazole sulfoxide.

A comparative pharmacokinetic study was conducted to determine the order and the rate of absorption of triclabendazole (TCBZ) in cattle and sheep. A commercial suspension of TCBZ (Biofasiolex, Biogénesis S.A., Argentina) was administered at a dose rate of 10 mg/kg by the oral route to six Holstein female calves and six Corriedale female sheep. The plasma concentration profiles of the metabolites triclabendazole sulfoxide (TCBZ-SO) and triclabendazole sulfone (TCBZ-SO(2)) were analysed by means of the non-compartmental method. The order of the absorption process of the active metabolite, TCBZ-SO, was determined by construction of curves of cumulative absorbed fraction of the drug by means of the Wagner-Nelson method. The appearance of TCBZ-SO in plasma of cattle and sheep resembles the entry of a constant quantity of drug into the organism per unit time. This is explained by the reservoir effect of the rumen, which acts as a biological slow-release system for TCBZ-SO and its precursor TCBZ to the posterior digestive tract where they are absorbed. The plasma concentration profiles of TCBZ-SO in both species were well described by a one-compartment open model with zero-order process of absorption and first-order process of elimination. The values of AUC(0-infinity) and C(max) of TCBZ-SO did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep. In the case of TCBZ-SO(2), t(max) was the only parameter that did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep.

Pharmacokinetics and tissue residues of an oxytetracycline/diclofenac combination in cattle.

Eight male cattle were given a combined dose containing 20 mg/kg oxytetracycline and 0.5 mg/kg diclofenac intramuscularly. Blood samples were drawn at different times until 168 h after administration. Two experimental animals were slaughtered by humane means at weekly intervals up to 28 days after administration. Samples of muscle, injection zone tissue, liver, kidney and fat were obtained. Oxytetracycline and diclofenac concentrations were determined by high performance liquid chromatography. Kinetic analysis was performed by linear regression using the CSTRIP programme. Plasma oxytetracycline concentration showed a maximum (Cmax) of 3.89 +/- 1.48 microg/ml and a prolonged elimination half-life (T1/2beta: 47.73 +/- 18.33 h). The diclofenac plasma profile showed high Cmax (577.62 +/- 238.40 ng/ml), and its T1/2beta was also prolonged (30.48 +/- 9.42 h). Oxytetracycline concentrations were measurable in liver and adipose tissue until day 21 after administration, but all tissue samples were negative for diclofenac at 21 days. The long elimination half-life of diclofenac was an unexpected finding; its T1/2beta in humans is 1.1 h.

Pharmacokinetics of ricobendazole after its intravenous, intraruminal and subcutaneous administration in sheep.

Ricobendazole (RBZ) was administered in sheep at the dose rate of 5 mg/kg by intravenous (i.v.) route as a 10% experimental solution, by the intraruminal (i.r.) route as a 10% experimental suspension, and by the subcutaneous (s.c.) route as a 10% commercial formulation available in Argentina. Blood samples were drawn during a 60 h period. Plasma concentrations of RBZ and its inactive metabolite albendazole sulphone (ABZSO2) were determined by high-performance liquid chromatography. The pharmacokinetic parameters were determined by compartmental analysis. The fitting of the data was done by weighted least-squares non-linear regression analysis. The pharmacokinetic parameters were estimated for every animal by simultaneous fitting of the plasma concentrations profiles of RBZ obtained after its administration by the three routes. The kinetic analysis of ABZSO2 was performed by a statistical moment approach. Ricobendazole bioavailability was poor after i.r. administration, whereas high and sustained plasma concentrations and higher bioavailability were obtained after s.c. administration. A simple two-compartment open model explains in a mechanical sense the pharmacokinetic behaviour of RBZ in sheep and allows us to estimate the real first-order constant rate of absorption and the loss of drug from the absorption site after its administration by s.c. and i.r. routes.

The effects of the method of calculation on the evaluation of the pharmacokinetic parameters of oxytetracycline after intravenous administration to calves.

The aim of this study was to assess the differences in the values of the pharmacokinetic parameters attributable to the use of either linear or nonlinear regression analysis and to find the effect of weighting schemes on these differences. Six calves received 20 mg/kg oxytetracycline i.v. Blood samples were drawn during 72 h. The assay of the drug was performed microbiologically. A bicompartmental pharmacokinetic model was used, kinetic analysis being carried out by linear regression (LR) and by weighted least-squares nonlinear regression (WLSNLR). Statistical analysis included a test for normality, the Kruskall-Wallis test and ANOVA with log transformation. The A0, alpha and B0 did not show any statistically significant differences attributable to the mathematical method used. On the other hand, the statistically significant differences in the beta values found using the Kruskall-Wallis test and ANOVA with log transformation could be attributed to the different methods employed. ANOVA with log transformation determined statistically significant differences between the parameters obtained by linear analysis and those obtained by WLSNLR when the weighting (w) was 1. When weights were 1/x, 1/x2 or 1/square root of x, no statistically significant differences were found. The optimal weighting scheme was w = 1/x2 because of a more homogeneous scatter and random distribution of residuals about the abcissa axis in a plot of weighted residuals in the ordinate versus time in the abcissa. It was concluded that the use of these different procedures can give major variations in the apparent value of beta, the most important pharmacokinetic parameter. The correct selection of the weighting procedure is therefore fundamental in obtaining the best estimate of this pharmacokinetic parameter in WLSNLR.

The pharmacokinetics of thiamphenicol in lactating cows.

The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives of 6.10 +/- 1.39 min and 1.60 +/- 0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9 +/- 0.077 ml/kg per min and the apparent volume of distribution was 1220.79 +/- 256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t1/2P) (serum to quarters), was found to be 36.89 +/- 11.14 min. The equivalent elimination half-life (t1/2E) (quarters to serum) from the milk was 3.62 +/- 1.06 h and the peak thiamphenicol concentration in the milk was 23.09 +/- 3.42 micrograms/ml at 2.5 +/- 0.32 h. After intramuscular injection, the elimination half-life was 2.2 +/- 0.40 h, the absorption half-life was 4.02 +/- 1.72 min and the peak concentration in the serum was 30.90 +/- 5.24 micrograms/ml at 23 +/- 8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59 +/- 6.87 min, the elimination half-life was 5.91 +/- 4.97 h and the mean peak concentration in the milk was 17.37 +/- 2.20 micrograms/ml at 3.4 +/- 0.22 h.

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains.

The objective of this study was to evaluate the interaction of the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP) when combined with different families of antimicrobial agents against isogenic strains and multidrug-resistant (MDR) Escherichia coli field strains isolated from animals. Laboratory isogenic strains of E. coli with different levels of expression of efflux pumps were used as quality controls. Ten MDR E. coli strains were collected from healthy animals in a cross-sectional study in four commercial dairy farms. The MICs of florfenicol, ciprofloxacin, tetracycline and ampicillin were determined by a serial microdilution method in Luria-Bertani broth in the presence or absence of NMP. NMP used with ampicillin exerted no effect on the isogenic or field strains. In most of the field MDRE. coli strains and in an acrAB-overexpressing (AG112) isogenic strain, the MICs of florfenicol, ciprofloxacin and tetracycline decreased at least fourfold when the antimicrobial was combined with the highest NMP concentrations. In the wild-type strain (AG100), there were no decreases of more than twice the MIC, whilst in strain AG100A, an efflux pump-deficient strain, the MIC did not change, regardless of the concentration of NMP used with these three antimicrobials. Thus, ampicillin was not affected by the efflux pump mechanism, whereas ciprofloxacin, tetracycline and florfenicol were shown to be substrates of efflux pumps, with a consequent significant reduction in MICs. Resistance could not be completely reversed in the E. coli field strains by NMP, probably because other resistance mechanisms were also present. However, in strain AG112, the MIC results demonstrated that NMP expressed an important synergistic activity with florfenicol. The reduction in florfenicol MIC value was sufficient to reverse antimicrobial resistance completely for AG112.

Personalised iron supply for prophylaxis and treatment of pregnant women as a way to ensure normal iron levels in their breast milk.

RATIONALE: Because the characteristics of all body fluids depends on patient's health status, is it possible that disadvantaged and socially vulnerable mothers may have lower amounts of iron in their breast milk, and that their babies receive lower content of the mineral for their normal growth and development. Assuring a preventive treatment of the mother might solve this problem. OBJECTIVE: To demonstrate breast milk iron content from disadvantaged mothers and impact of personalized iron supplementation program. MATERIALS AND METHODS: cross-sectional study. Breast milk samples were obtained for ferritin analysis. Health's services usually provides free folic acid and iron treatment however, treatment compliance is low. Patients were random in two groups: "A: Controls" that had free iron tablets available from Health Centre; and "B: Intervention" group where patients accepted to be periodically contacted at home by health's team for personalized iron dispensation. RESULTS: 360 patients were included. Profilaxis and treatment compliance were 100% and 97,6% for B group while for "Control" one was 63% and 34%(p0.0001). Higher breast milk iron levels were detected in Intervention's mothers compared with control's patients (p0.007). CONCLUSION: Personalized iron prophylaxis and treatment increased breast milk iron levels. Public health policy must ensure iron dispensation for each underserved mother in order to reduce children problems associate to iron deficiency during the first year of their life.

Concentrations of danofloxacin 18% solution in plasma, milk and tissues after subcutaneous injection in dairy cows.

Danofloxacin is a fluoroquinolone developed for use in veterinary medicine. Its concentrations and pharmacokinetic profile in plasma, milk and tissues of lactating dairy cows were determined, and its milk withdrawal time (WT) calculated. Twenty-one dairy cows received a single subcutaneous administration of 18% mesylate danofloxacin salt (6 mgkg(-1)). Plasma and milk samples were obtained at different times until 48 h. Groups of three animals were sacrificed at different post-administration times and tissue samples (mammary gland, uterus, duodenum, jejunum, ileum, colon and mesenteric lymph nodes) obtained. Danofloxacin concentrations were determined by liquid chromatography with fluorescence detection. The milk WT was calculated by the Time to Safe Concentration method (Software WTM 1.4, EMEA). Danofloxacin was rapidly absorbed and its distribution from plasma to all sampled tissues and milk was extensive. Milk and tissues concentrations were several times above those found in plasma. Plasma area under the curve (AUCp) was 9.69 microghmL(-1) and its elimination half life (T(beta)(1/2)) was 12.53 h. AUC values for the various tissues and milk greatly exceeded AUCp. T(beta)(1/2) from milk and tissues ranged between 4.57 and 21.91 h and the milk withdrawal time was 73.48 h. The reported results support the potential use of danofloxacin in the treatment of mastitis and other infections in milk cows with 3 days of withdrawal.

Pharmacokinetics of amoxycillin in normal horses and horses with experimental arthritis.

The serum and synovial pharmacokinetics of amoxycillin (AMX) were studied after i.v. administration at a dosage of 40 mg/kg to normal horses and horses with induced aseptic carpal arthritis. The best estimates of serum and synovial pharmacokinetic parameters were calculated by mono or bivariable non-linear regression analysis. A biexponential equation was used to describe the concentration vs. time profiles in both normal and arthritic horses. There were no serum kinetic differences between normal and arthritic horses. There were, however, major synovial kinetic changes between these groups. The rate of penetration from serum to synovial fluid was larger in arthritic animals, indicating better penetration in this case. On the other hand, the rate of disappearance from synovial fluid was larger in normal horses, indicating more persistence of the drug in the diseased joint. Synovial AMX availability increased from 21% in normal horses to 79% in arthritic horses. These findings support the use of AMX for the treatment of infectious synovial joint disease produced by susceptible organisms in horses.