Simultaneous comparison of three methods for assessing ceftazidime penetration into extravascular fluid

Abstract

The penetration of ceftazidime, a new broad-spectrum cephalosporin, into fluids from subcutaneous threads, suction blisters, and cantharidin blisters was studied in eight healthy male volunteers. A pharmacokinetic analysis showed fundamental differences between the models. The results obtained with the subcutaneous thread technique were similar to those of the peripheral compartment and were characteristic of a rapidly equilibrating compartment. The results obtained with the suction and cantharidin blister techniques were characteristic of slowly equilibrating compartments. We concluded that although one model will not accurately predict the penetration of an antibiotic in all clinical situations, each model will have its own particular application.A variety of models are available for assessing extravascular penetration of antibiotics (6) without recourse to surgery or tissue extirpation. In volunteers the methods for collecting tissue fluid include dermabrasion with skin window (8) or skin chamber (13), blisters induced by cantharidin (12) or suction (5), and subcutaneous tissue cages (1) or cotton threads (9). The results obtained with these models are often used to predict antibiotic concentrations in tissue fluids in general. However, for a given antibiotic we have observed different tissue fluid-time proffles depending on the experimental model used, and this has also been reported by others (2, 15; B. Hoffstedt et al., Eur. J. Clin. Bacteriol., in press). These differences could be due either to minor modifications in technique (e.g., route and method of administration of antibiotics or the site from which the extravascular tissue was sampled), or to more fundamental physiopathological reasons.To investigate the problem we attempted to assess simultaneously as many of the available techniques as practicable under standardized conditions. We chose three methods which allowed multiple timed samples to be obtained and which were well tolerated by the volunteers. These methods were subcutaneous cotton threads, suction blisters, and cantharidin blisters. To minimize differences due to site, we chose to obtain all samples from the forearm. The antibiotic used in this study was ceftazidime, a broad-spectrum, antipseudomonal cephalosporin, given as a single 1-g bolus intravenous injection. MATERIALS AND METHODSVolunteers. Eight healthy male volunteers averaging 34 years in age (range, 26 to 49 years) and 72 kg in weight (range, 64 to 86 kg) took part in the study. Each volunteer gave written informed consent and underwent a routine medical examination before taking part. The study was approved by an ethical review committee.Threads. At 18 h before doses were given, each volunteer had 10 or 11 cotton threads of diameter of 0.90 mm inserted subcutaneously into the lateral aspect of the right forearm, using 1% lignocaine and an aseptic technique. The length of thread inserted subcutaneously was 2 to 3 cm. The arm was covered with sterile gauze which was left in place until each thread was removed.Cantharidin blister...

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

“…Based on previous experimental studies (13,33,43,40), the definitive antibiotic doses were those achieving PD parameters in TCF that were similar to human ones in serum with conventional doses. For all drugs except cloxacillin, we adjusted AUC values to obtain similar AUC/MIC ratios in animals and in humans (7,8,24,25,32,34).…”

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

“…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. Given these multiple sources of confusion, it is vital to define general principles of antibiotic extravascular fluid penetration and then interpret the outcomes of specific fluid models within this context.…”

“…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.…”

Pharmacokinetic Profile of Meropenem, Administered at 500 Milligrams Every 8 Hours, in Plasma and Cantharidin-Induced Skin Blister Fluid

“…In this study, a single 1,000-mg meropenem dose was infused over 5 min, and the mean peak concentration in blister fluid occurred at 0.75 h. The percent penetration of meropenem into blister fluid in that study was 110%; however, when corrected for an extraordinarily high value in one volunteer, the percent penetration was 100.4%. A smaller blister size may explain the higher rate and larger percent penetration of meropenem observed by Wise due to differences in blister volume (7,8).…”