Suction skin blister, skin window, and skin chamber techniques to determine extravascular passage of cefotaxime in humans

Abstract

We report the results obtained in a comparative study on the extravascular passage of cefotaxime, employing three different methods: suction skin blister, skin window, and skin chamber. Applying the skin blister method in two different ways, we also studied the influence that suction pressure and time lapse between blister formation and antibiotic injection had on the results obtained in order to standardize the method and establish repeatability of the results. Using the skin chamber method, we studied the influence that the different protein contents in the fluid used to fill the skin chamber had on extravascular concentrations.The study of interstitial extravascular passage of antibiotics in humans is an interesting problem which presents considerable limitations because of the lack of material available on dosage systems for the antibiotics. In fact, it is almost impossible to obtain sufficient quantities of the interstitial fluid to make such determining possible.Studies on the extravascular passage of antibiotics in humans have been made, using the skin window (7) and skin chamber methods (10) and more recently, the skin blister method (8).From the published results of studies on this subject, the great diversity of interstitial concentrations of the same antibiotic and the kinetic difference in relation to the methods being used are evident. We found, furthermore, that this difference may be related to diverse characteristics, mainly the different protein contents of the exudates obtained by different methods (R. F. Frongillo, Relazione XX Congresso Nazionale Societa Italiana Malattie Infettive e Parass., in press). It is, therefore, clear that none of the applied methods can produce liquids comparable to the interstitial fluid, since they are, for the most part, exudates or only apparent transudates.The first problem, therefore, is to establish a method which can be standardized easily and which by assuring reproducible results makes feasible a comparative study of the influence of various factors on the extravascular passage of the antibiotics.In recent in vivo and in vitro experiments, using the new cephalosporin cefotaxime, we studied the extravascular concentrations of this antibiotic and compared the results obtained by application of the skin window and skin chamber 22 methods with those obtained by using a suction skin blister method (6). MATERIALS AND METHODSSubjects. Patients 18 to 69 years of age (average age, 56), weighing 42 to 70 kg (average weight, 58 kg), were studied in the Infectious Diseases Institute of the University of Perugia, Italy.No clinical or biochemical alterations in kidney and liver functions were found on examining the patients, who had given their consent for the experiment.Cefotaxime. Cefotaxime (HR 756; Hoechst A. G., Frankfurt, Germany), in 1-g vials diluted in 1% lidocaine for intramuscular injection, was used. Blood and extravascular fluid samples were taken 30 min and 1, 2, and 4 h after the injection.Filter paper disks used in the skin window method were applied imm...

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

“…This is particularly true of long-half-life antibiotics (30). For drugs with low protein binding (aminoglycosides, quinolones, and some 1-lactams), concentrations in ECF are virtually identical to concentrations in serum with large surface area/volume ratio models like cotton threads (28,81). The ECF penetration of cephalosporins which show relatively high protein binding is also affected by the protein concentration in ECF.…”

“…Given that distribution in extracellular fluid (ECF) is important, a variety of methods have been applied to the collection and study of data on ECF distribution. Antibiotic concentrations have been measured in the lymphatic drainage of organs and tissues (95,96), fluids obtained from tissue cage reservoirs (82,90), chemically or mechanically induced skin blisters (1,81), surgically implanted cotton threads (28,81), implanted fibrin clots (3), and directly from inflammatory exudates (72). This diversity of models has confused the interpretation of antibiotic extravascular fluid distribution, particularly in comparisons between members of the same class of compounds.…”

“…Thus, the surface area of vascular tissue in relation to the total volume of the tissue to be sampled is the most important consideration in the modeling of ECF (26). The commonly used tissue penetration models differ in the vascular tissue surface area/volume ratio at the measurement site (28,77,81,93). In addition, the inflammatory response induced by the procedure (81,104) and the presence of cellular debris in the sample (i.e., paper disks or cotton threads) (81) may influence results.…”

“…At the steady state, the free concentration of drug in serum is equal to the free concentration of drug in ECF, provided that passive diffusion is the only operational mechanism. ECF models which provide a small sampling compartment with a large diffusible surface area/volume ratio lead to rapid equilibration with serum (28,81). Examples include cotton threads and paper disks on abraded skin.…”