Effect of protein binding on drug penetration into blister fluid

Abstract

The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ratio. Both the area under the concentration-time cu'rve ratio and the concentration ratio (by the disk method) for cefonicid were statistically lower than the ratios for ceftizoxime and cefotaxime. The high degree of protein binding of cefonicid results in the availability of less drug for diffusion to blister fluid than with the low-protein-binding ceftizoxime and cefotaxime.Drug concentrations in blister fluid are critical, since most bacterial infections occur in the interstitial space and not the intravascular space. Many investigators have tried to correlate the penetration of P-lactam antibiotics into interstitial fluid with the degree to which the drugs bind protein.However, such studies have yielded disparate results, as shown by reports of poor cefazolin extravascular penetration in one study (11,12) and of good penetration in other studies (1,4,5,7,8).Cefonicid is 98% bound to serum protein and is used for the treatment of skin and soft tissue infections (3). In view of the high degree of protein binding of this compound, the penetration of the drug into blister fluid was compared with the penetrations of ceftizoxime and cefotaxime (<40% bound) by using a modified suction blister technique (10).Six healthy volunteers (four male and two female) between the ages of 25 and 29 years and weighing 51 to 80 kg were enrolled in this study. Female volunteers were not pregnant or receiving oral contraceptives.Each subject received a single 30-mg/kg (body weight) dose of cefonicid, ceftizoxime, or cefotaxime on three occasions. A treatment schedule was assigned randomly to each subject. There was at least 1 week between doses. Drugs were given by constant intravenous infusion over 5 min into an antecubital vein via an indwelling intravenous catheter. Nornmal saline (3 ml) was injected immediately after the infusion to flush the catheter. Blood samples were obtained from the cannulus, after discarding the first 2 ml, at 0,5,10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 480, 600, 720, and 1,440 min after dosing. Each volunteer had eight skiii blisters produced on his or her forearm by the modified suction blister technique previously described by Shyu et al. (10).In the protein-binding study, cefonicid standards were prepared in freshly pooled human serum at 37°C at 450, 400, 350, 300, 250, 175, 150; 125, 100, 75, 50, 25, and 12.5 immediately after preparation. Ultrafiltration was performed at 37°C and 1,000 x g for 15 min.Cefonicid concentrations were determined by a microbiological assay with Bacillus subtilis ATCC 6633 as the test organism. Serum standards were prepared in pooled serum, and blister fluid standards were prepared in 50% pooled serum and 50% phosphate buffer (0.1 M, p...

Penetration of antibiotics into the surgical wound in a canine model

“…Our findings confirm the results of previous studies using artificially created models with a high SA/V ratio (i.e., filter paper disk, cotton thread, and an in vitro kinetic model) which noted that drug concentrations in these fluid spaces tend to parallel changes in serum (3,6,(17)(18)(19). In contrast, drug concentrations in chamber models with a low SA/V ratio (i.e., blister fluid, tissue cage), which are not representative of a surgical wound, have delayed equilibrium, lower peak levels, and prolonged concentrations in comparison with serum (1,3,4,6,20).…”

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

“…Since several blisters are formed with either of these procedures, multiple samples can be obtained by emptying the contents of individual blisters with a sterile needle and syringe at appropriate sampling times. Fluid present in the inflammatory blisters contains a higher protein content than does ECF, so the antibiotic concentration appears higher than that present in true ECF for protein-bound drugs (88,104).…”

Significance of "extravascular" protein binding for antimicrobial pharmacodynamics in an in vitro capillary model of infection

“…Studies in animals (6,19,20), in vitro models (21), and humans (16,22,25) have shown that high serum protein binding significantly affects the kinetics of extravascular drug distribution. High binding to serum proteins (e.g., albumin) in the intravascular space tends to reduce the amount of drug available for diffusion into extravascular spaces (22,25).…”

“…A 10-fold-higher dose of dicloxacillin was also studied to determine the effect of drug concentration on Studies in animals (6,19,20), in vitro models (21), and humans (16,22,25) have shown that high serum protein binding significantly affects the kinetics of extravascular drug distribution. High binding to serum proteins (e.g., albumin) in the intravascular space tends to reduce the amount of drug available for diffusion into extravascular spaces (22,25). However, a considerable amount of serum protein also is distributed to the extravascular space; for example, approximately 60% of the total exchangeable albumin in the body is found in the extravascular space, but at lower concentrations than in the intravascular space (17).…”