To describe the epidemiology of bacteremia in a large, well defined population, the authors reviewed medical records for residents of Charleston County, South Carolina, who had bacteria isolated from blood in the period 1974 to 1976. The incidence was 80 cases per 100,000 population per year. The most common organisms were Escherichia coli, Staphylococcus aureus, Klebsiella, and Streptococcus pneumoniae. The incidence was highest for neonates, infants, and those 70 years of age and older with annualized attack rates of 1,864,250, and 446 cases per 100,000 population, respectively. The incidence was 3.2 times higher for blacks than for whites and, within races, appeared to be independent of family income. Twenty-five per cent of patients had no clinically apparent focus of infection, 26% had urinary tract infection, and 17% had pneumonia. Thirty-nine per cent of cases were nosocomial, and 30% of patients died.
The extravascular kinetics of ceftizoxime were studied both in an in vitro kinetic model and in an in vivo rabbit model. Visking tubing chambers were used in both models to provide extravascular spaces with large or small volumes and surface areas, but identical surface area/volume ratios. Four rabbits, each implanted with two large Visking chambers and four small chambers, received 50 mg of ceftizoxime per kg intramuscularly every 3 h for eight doses. In the in vitro model, 80 mg of ceftizoxime was infused over 30 min every 3 h for eight doses. Intravascular and extravascular spaces were sampled in both models after the eighth dose. Ceftizoxime had similar intravascular kinetics in both models, i.e., the peak levels, the peak-to-trough fluctuations, and the half-life were comparable. The area under the curve (AUC) for the extravascular spaces was also similar in the two models. Large and small chambers having identical surface area/volume ratios demonstrated identical kinetics. The extravascular Visking chamber spaces achieved equilibrium with the intravascular spaces in both models, i.e., the AUC for the extravascular spaces was the same (P > 0.2) as that for the serum (rabbit model) or the test chamber (in vitro model). This study illustrates (i) that our modified in vitro model is a potentially valid model for studying extravascular kinetics; (ii) that extravascular spaces with identical surface area/volume ratios show similar penetration kinetics with a freely diffusible drug, such as ceftizoxime, despite differences in size; and (iii) that the Visking chamber extravascularspace model permits the free diffusion of the antimicrobial agent and reaches equilibrium (equivalent AUC) with the intravascular space.The majority of infections in patients occur outside the vascular space. Several investigators have utilized various artificial chambers, disks, or threads to study the kinetics of antibiotic penetration into these extravascular sites both in humans (4,10,15,18) and in laboratory animals (1,2,5,6). These studies have shown that the binding of the antibiotic to serum and extravascular fluid protein is one important determinant of drug penetration. In addition, we have recently shown (17) that the surface area-to-volume (SANV) ratio of an extravascular site is another major factor governing the kinetics of drug penetration. Because the work on SA/V ratio was done in an in vitro kinetic model, we chose to study this concept further in the in vitro kinetic model and to compare it in vivo in rabbits. The purpose of this present report is (i) to show that extravascular spaces with identical SA/V ratios
The effect of both method of drug administration and serum protein binding on antibiotic penetration into subcutaneous Visking chambers was studied in rabbits. Ampicillin and oxacillin were administered by either repeated intramuscular injection of 30 mg/kg every 4 h or by constant infusion of 7.5 mg/kg per h for 24 h. Gentamicin was given by intramuscular injection of 4 mg/kg every 4 h for 28 h and by constant infusion of 1 mg/kg per h for 24 h. Amikacin was given by intramuscular injection of 8 mg/kg every 4 h for 12 h and by constant intravenous infusion of 2 mg/kg per h for 12 h. Protein binding to rabbit serum was 73% for oxacillin, 9% for ampicillin, 19% for gentamicin, and 0% for amikacin. Chamber concentrations achieved for oxacillin, gentamicin, and amikacin were not significantly different for constant infusion versus intermittent administration. For ampicillin, chamber concentration was slightly higher by constant infusion than by intermittent administration (P less than 0.02). Fluctuations in drug concentration from peak to trough values in the chambers during the intermittent administration studies were markedly dampened when compared with serum fluctuations. This study demonstrates that whereas steady state is reached more rapidly by intermittent administration, the mean steady-state concentration of an antibiotic achieved at an extravascular site is the same or greater by constant infusion than by intermittent dosing. This is true for highly protein bound antibiotics as well as those with low serum protein binding.
The extravascular penetration of ceftizoxime and cefotaxime was studied in a rabbit subcutaneous Visking chamber model. Four rabbits, implanted with four chambers each, received each drug intramuscularly at a dose of 50 mg/kg every 3 hours for eight doses. Serum drug concentrations were measured after the eighth dose, and extravascular (chamber) concentrations were measured after the first and eighth doses. Cefotaxime (93% bound to rabbit serum proteins) demonstrated a much lower peak chamber-to-peak serum percent penetration after the first dose (20/163 = 13%) than did the less-bound (32%) ceftizoxime (21/52 = 40%, P < 0.002). Similarly, the ratio of the chamber fluid area under the curve to the serum area under the curve was significantly lower for cefotaxime (15%) than for ceftizoxime (44%, P < 0.002) after the first dose. Both agents approached equilibrium conditions between the intravascular and extravascular space by the eighth dose, and the ratios of chamber area under the curve to serum area under the curve of cefotaxime (76%) and ceftizoxime (79o) were similar. The peak-topeak percent penetration of ceftizoxime (54%) was still significantly higher than that of cefotaxime (41%, P < 0.01), although the chamber concentration of cefotaxime (66.2 ,u.g/ml) was considerably higher than that of ceftizoxime (28.2 ,ug/ml). This study illustrates (i) dampened peak-to-trough antibiotic level fluctuation seen at extravascular sites as compared with measured serum concentrations, (ii) the large differences in extravascular penetration between single-and multipledose studies, and (iii) the importance of serum protein binding in the delay, but not the prevention, of extravascular drug distribution.The role of antibiotic binding to serum protein in the pharmacokinetics of extravascular distribution and in the interpretation of studies of extravascular drug penetration is important (9). 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.MATERIALS AND METHODS Animal model. The rabbit model used has been described previously (8). Tissue fluid chambers made of Visking tubing (Union Carbide Corp., Chicago, Ill.), tied off at one end and occluded at the other end by a cork through which tubing from a 21-gauge Butterfly intermittent infusion set (Abbott Hospital Products, Inc., North Chicago, Ill.) had been passed, were surgically implanted in the subcutaneous space of the b...
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