Extralabel use of penicillin in food animals.

Penicillin is one of the most commonly detected drug residues in tissues and milk, and is the antimicrobial for which information is most often sought through FARAD.

Tissue penetration of cefpodoxime into the skeletal muscle and lung in rats.

PURPOSE: The aim of this study was to investigate the pharmacokinetics of cefpodoxime in interstitial tissue fluids (skeletal muscle and lung) in rats by microdialysis, and to examine the relationship between free drug levels in plasma and in tissues. METHODS: Cefpodoxime was administered to anesthetized male Wistar rats as single intravenous bolus of 10 or 20 mg/kg and constant infusion of 260 microg/h with a loading dose. The protein binding of cefpodoxime in rat plasma was determined using ultrafiltration. RESULTS: The average protein binding of cefpodoxime in rat plasma was 38%. The half-lives in plasma, muscle and lung were similar (approximately 5 h). After constant rate infusion, the free concentrations in the muscle and the lung were almost identical, but lower than total and free plasma concentrations. The data were modeled simultaneously using a two-compartmental body model. CONCLUSIONS: Free interstitial levels of cefpodoxime in muscle and lung tissue are very similar. Since muscle is more accessible than lung, free muscle concentrations may serve as a good surrogate for unbound concentrations in lung.

Short-duration mechanical ventilation enhances diaphragmatic fatigue resistance but impairs force production.

STUDY OBJECTIVE: s: Mechanical ventilation (MV) is a life-support measure for patients who cannot maintain adequate alveolar ventilation. Following prolonged MV, difficulty in weaning patients from the ventilator can occur, and it has been postulated that difficult weaning is linked to respiratory muscle dysfunction. We tested the hypothesis that 18 h of controlled MV will diminish diaphragmatic maximal tetanic specific tension (force per cross-sectional area of muscle) without impairing diaphragmatic fatigue resistance. DESIGN: To test this postulate, adult Sprague-Dawley rats were randomly classified into one of two experimental groups: (1) control group (n = 8), and (2) 18-h MV group (n = 6). MV-treated animals were anesthetized, tracheostomized, and received room air ventilation. Animals in the control group were acutely anesthetized but did not receive MV. Muscle strips from the mid-costal diaphragm were removed from both experimental groups, and contractile properties were studied in vitro to determine the effects of MV on diaphragmatic endurance and maximal force production. Diaphragmatic endurance was investigated by measuring tension development during repeated contractions throughout a 30-min fatigue protocol. RESULTS: MV resulted in a reduction (p < 0.05) in diaphragmatic maximal specific tension (control group, 26.8 +/- 0.2 Newtons/cm(2) vs MV group, 21.3 +/- 0.6 Newtons/cm(2)). Compared to the control group, diaphragms from MV-treated animals maintained higher (p < 0.05) percentages of the initial force production throughout the fatigue protocol. The observed improvement in fatigue resistance was associated with an increase in diaphragmatic oxidative and antioxidant capacity as evidenced by increases (p < 0.05) in both citrate synthase and superoxide dismutase activities. However, by comparison to the control group, diaphragms from MV-treated animals generated less (p < 0.05) absolute specific force throughout the fatigue protocol. CONCLUSIONS: These data indicate that 18 h of MV enhances diaphragmatic fatigue resistance but impairs diaphragmatic specific tension.

Microdialysis of triamcinolone acetonide in rat muscle.

The objective of this study was to compare plasma and muscle concentrations of triamcinolone acetonide (TA) in the rat by microdialysis. Microdialysis experiments were carried out at steady state in rats after an initial I.V. bolus 50 mg/kg of the phosphate ester of TA (TAP) followed by 23 mg/kg/h infusion. In vivo recovery was calculated by retrodialysis. The concentration determined at steady state in microdialysate, corrected for recovery, was 2.73 +/- 0.42 microg/mL compared to 21.9 +/- 2.3 microg/mL in plasma. The pharmacokinetics of TA in plasma was described by an open two-compartment model with a terminal half-life of 2.7 h. The clearance of TA in rats determined by compartmental analysis was 0.94 L/h/kg. The measured microdialysate levels of TA in muscle, corrected for recovery, were comparable to the predicted free drug levels in the peripheral compartment. Protein binding in rat plasma, measured by ultrafiltration, was 90.1%. The microdialysis in vivo recovery in muscle was similar to the in vitro recovery under stirred conditions. The results show the applicability of microdialysis to measure free tissue concentrations of TA in rats.

Interstitial tissue concentrations of cefpodoxime.

Microdialysis is a technique that allows the measurement of concentrations of free antibiotic in tissue. The free antibiotic concentration is responsible for the antibacterial effect at the target site. We used microdialysis in animal and human studies to investigate the tissue penetration of cefpodoxime. In the animal study, total plasma and free muscle and lung concentrations of cefpodoxime were measured after male Wistar rats had received either 10 mg/kg or 20 mg/kg i.v. cefpodoxime over 5 h or a continuous i.v. infusion of 260 microg/h cefpodoxime after a loading dose of 6 mg/kg. Free muscle concentrations of cefpodoxime were similar to free lung concentrations and therefore provided a surrogate measure of cefpodoxime concentrations at the pulmonary target site. In an open, randomized, two-way crossover, single-dose study in six healthy male volunteers, total plasma and free muscle concentrations were measured after a single oral dose of cefpodoxime 400 mg or cefixime 400 mg. The total plasma concentrations of each antibiotic were similar and higher than free muscle concentrations. The tissue penetration of cefpodoxime was, however, greater than that of cefixime, as shown by two-fold higher peak free muscle concentrations after dosing with cefpodoxime than with cefixime (2.1 mg/L versus 0.9 mg/L). In addition, the area under the curve for tissue (AUC(t)) of cefpodoxime (400 mg) was more than double that of cefixime (400 mg), based on free antibiotic concentrations (15.4 mg x h/L versus 7.3 mg x h/L). These findings indicate that, taking into account pharmacokinetic/pharmacodynamic considerations, cefpodoxime is likely to be more efficacious than cefixime, due to its greater tissue penetration.