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GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most 8i-lactamases. Its in vitro activities were of the same order as those of cefotaxime against most gram-negative bacteria, were clearly inferior to cefotaxime against Staphylococcus aureus, but were significantly more active against Pseudomonas aeruginosa. Against the 25 strains used, GR 20263 was significantly more active than any of the other agents tested: piperacillin, azlocillin, gentamicin, amikacin, and carbenicillin. GR 20263 protected mice against experimental infections with P. aeruginosa more effectively than other f-lactam antibiotics; its general effectiveness in this test was comparable with gentamicin. Studies on human volunteers showed that it produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine. Intramuscular and intravenous injections were well tolerated by the volunteers, and there were no untoward side effects.Although the cephalosporins have been used in clinical medicine for many years, the usefulness of the currently available members of the group is impaired by limitations such as restricted antibacterial spectrum, susceptibility to ,8-lactamases from gram-negative organisms, and metabolic degradation in the body. Compounds such as cefuroxime (4), cefotiam (7), and cefotaxime (1,5) have overcome some of these problems, but further improvements were desirable. For example, cefuroxime has good resistance to ,8-lactamases from many gram-negative organisms and is stable to metabolic degradation, but its intrinsic antibacterial activity is not as high as that of cefotiam. The spectrum of cefotiam is rather restricted by a degree of susceptibility of the compound to many ,B-lactamases. Cefotaxime, with good enzyme resistance and very high intrinsic antibacterial activity, suffers from metabolic degradation which reduces its activity in the body. To a large extent the newly developed GR 20263

Cefuroxime axetil is a new orally absorbed prodrug of the antibiotic cefuroxime. The results of pharmacological studies in 52 healthy volunteers are presented. Intact cefuroxime axetil was not detected in the systemic circulation, indicating that deesterification to yield cefuroxime occurs rapidly after absorption. The bioavailability as measured by urinary recovery of cefuroxime was 40 to 50% if the drug was taken after food and 30% if the drug was taken after overnight fasting. Absorption was similar for three different formulations at 500 mg and independent of dose over the range of 250 mg to 1 g. When the drug was taken after food, serum levels and urinary recoveries were significantly greater for cefuroxime than for ampicillin, but when the drug was taken after fasting the values were similar for the two drugs. The kinetic behavior of cefuroxime axetil and ampicillin was not influenced by repeated dosing at 250 mg. Cefuroxime axetil was well tolerated. Although changes in bowel flora and habit were noted during repeated dosing, these changes were no greater than with ampicillin.Cefuroxime, with its relatively broad antibacterial spectrum and stability to many beta-lactamases, has an established place in antimicrobial therapy (12). However, like many cephalosporins, its application is handicapped by the need for parenteral delivery. Recent work has led to the development of cefuroxime axetil, the 1-acetoxyethyl ester of cefuroxime ( Fig. 1), a derivative which is well absorbed from the gastrointestinal tract and promptly cleaved to cefuroxime thereafter. Preliminary research on cefuroxime axetil indicated that the compound was highly labile in blood and serum, enzymatic deesterification occurring in vitro to produce cefuroxime. To investigate the absorption and pharmacokinetics of cefuroxime axetil, it was necessary to develop an assay method which would extract the drug from blood while simultaneously preventing further enzymatic hydrolysis. The current report summarizes the results of studies designed to determine the concentrations of intact ester in peripheral venous blood, serum levels, and urinary recoveries after single oral doses of 250 mg, 500 mg, and 1 g given to male and female volunteers and the effect offood on absorption. Furthermore, tolerance was assessed during repeated doses of 250 mg given every 6 h in comparison with ampicillin, and the kinetics of cefuroxime and ampicillin were compared at the 250-mg dose level. MATERIALS AND METHODSMetabolism of cefuroxime axetil in vitro. The stability of cefuroxime axetil in blood was determined by adding a known amount of drug to fresh human blood and incubating the mixture for 15 min at 37°C. At 1.5-min intervals during the incubation a sample of blood (0.25 ml) was withdrawn, mixed with acetonitrile (0.5 ml) on a Vortex mixer for 5 s, and then centrifuged at 2,000 rpm for 5 min. The supernatant was assayed for cefuroxime axetil by using high-pressure liquid chromatography (HPLC), and then a sample (0.1 ml) was transferred to another tube, diluted w...

Cefuroxime axetil is a novel oral cephalosporin. Two studies are described in which fasting male and female volunteers were given single oral doses of 1 g cefuroxime axetil in comparison with intravenous cefuroxime, and in which absorption was compared in the fasting and non-fasting states. The mean (and range) absolute bioavailability of cefuroxime axetil in the first study was 0.35 (0.26-0.44) in male volunteers and 0.32 (0.23-0.41) in female volunteers. In the second study, the bioavailability was significantly greater when cefuroxime axetil was given after food: 0.45 (0.34-0.55) in males and 0.41 (0.29-0.51) in females. There were no differences between the pharmacokinetics of cefuroxime axetil in males and females. It is recommended that patients take doses of cefuroxime axetil shortly after food.

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