Ascitic Fluid Cephalosporin Concentrations: Influence of Protein Binding and Serum Pharmacokinetics

Abstract

Mongrel dogs with ascites created by inferior vena cava ligation were given cephalothin, cephaloridine, cefazolin, and cefamandole to evaluate the effect of protein binding and serum pharrnacokinetics on the distribution of cephalosporins into ascitic fluid. Antibiotics were given intramuscularly (15 mg/kg) every 4 h for a total of eight doses. Antibiotic binding to dog serum and ascitic fluid was measured by ultracentrifugation. Binding of the cephalosporins to dog serum ranged from 31% for cephaloridine to 46% for cephalothin, considerably lower than human serum binding for cefazolin, cephalothin, and cefamandole. Antibiotic binding to ascitic fluid was only slightly lower than that to serum. Ascitic fluid antibiotic concentrations, which approached equilibrium at 16 to 28 h, were significantly higher for cefazolin and cephaloridine than for cephalothin and cefamandole. However, serum concentrations were also higher for cefazolin and cephaloridine, and percent penetration (ratio of serum peak to ascites peak x 100) was not statistically different among the four drugs. Binding of these cephalosporins to extravascular fluid protein was an important factor that determined the total ascitic fluid antibiotic level achieved. A formula utilizing the log mean serum level and binding to serum and extravascular fluid protein was used to accurately predict ascitic fluid drug levels at equilibrium.

Effect of method of administration on extravascular penetration of four antibiotics

“…This is due to the absence of protein to which the antibiotic can bind in the lin concentration in the serum and Viski for the constant intravenous infusion stu saline chambers. Thus, total drug concentration is less in the saline chamber than the serum chambers as has been previously reported (6,11,12). The difference is much greater for the higher protein-bound oxacillin (73%) than for the lower protein-bound ampicillin (9%).…”

“…The fact that extravascular foci exhibit peak concentrations lower than those in serum, show less peak/trough ratio fluctuation than serum, and have a longer drug elimination half-life than serum has been previously shown in a number of models (2,6,7,10 98,1981). A major advantage of the model chosen for this study is that the extravascular specimens are not contaminated by blood or serum in the sampling process.…”

Antibiotic tissue penetration and its relevance: impact of tissue penetration on infection response

“…Bile is the primary route of excretion for cefoperazone. (33,34,64) and clearly influences in vitro susceptibility testing (14,45). The effect on in vivo antibacterial activity is not as clear.…”

Role of serum protein binding and multiple antibiotic doses in the extravascular distribution of ceftizoxime and cefotaxime

“…Many investigators including ourselves, have attempted to judge whether agents with high or low levels of serum protein binding have superior extravascular penetration based on a comparison of peak extravascular-to-peak serum concentration ratios after a single antibiotic dose (1,(5)(6)(7)(8)11). The purpose of this report is to (i) describe the extravascular distribution of two extended-spectrum cephalosporins in a rabbit model after single and multiple systemic administrations and (ii) demonstrate that the major effect of a high level of serum protein binding is to delay the distribution of drug to the extravascular space, presumably by decreasing the concentration of free drug available for diffusion.…”

“…Many investigators including ourselves, have attempted to judge whether agents with high or low levels of serum protein binding have superior extravascular penetration based on a comparison of peak extravascular-to-peak serum concentration ratios after a single antibiotic dose (1, [5][6][7][8]11 surgically implanted in the subcutaneous space of the back of 3.0-to 3.4-kg female New Zealand white rabbits while the latter were anesthetized with 10 mg of xylazine hydrochloride (Cutter Laboratories, Inc., Shawnee, Kans.) plus 60 mg of ketamine hydrochloride (Bristol Laboratories, Syracuse, N.Y.).…”