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

A review of the literature shows that antibiotic concentrations in tissues and tissue fluids are often quoted as being different in profile to concurrent serum levels. To study the relationship between serum and tissue concentrations we analysed published studies where different experimental models were tested simultaneously. In some models serum levels predicted tissue levels while in others they did not. The factors likely to be responsible for the differences were examined. The most important of these factors was tissue geometry (surface area to volume ratio; SA/V). Serum levels predicted tissue levels in models where the SA/V was high (greater than 60) but not where the SA/V's were low (less than 10); here the antibiotic concentrations were lower and more prolonged than serum levels. These observations can be extrapolated to the clinical situation. In most situations involving prophylaxis or treatment of infections in non-specialised tissues (naturally high SA/V), serum levels will closely reflect levels in extracellular tissue fluid where most bacterial infections are located.

Ceftazidime was injected iv to rabbits (25 mg/kg). Samples of the whole muscle and muscle tissue fluid were removed at 0.25, 0.5, 1, 1.5, 2, 2.5 h for assay. Muscle tissue fluid was obtained using implanted cotton threads and freshly applied paper discs. The levels of ceftazidime in muscle fluid were similar to concurrent serum levels at all times tested. Ceftazidime levels in small pieces of excised muscle were significantly lower (ten-fold) than concurrent serum or tissue fluid levels. This difference between ceftazidime levels in whole tissue and tissue fluid is explained by the fact that not all antibiotics penetrate into the cellular mass of tissue but some remain confined to the much smaller interstitial tissue fluid compartment. The assumption that antibiotics will diffuse evenly throughout a tissue is an error to be avoided in the interpretation of antibiotic levels in tissues.

Cefuroxime is a new broad spectrum cephalosporin antibiotic for administration by injection. It is stable to most ~-lactamases. It is active against gram-positive organisms, including penicillinase-producing staphylococci, and has wide activity against gram-negative bacilli including Enterobacter and many strains of indole-positive Proteus spp. The substance is also highly active against Haemophilus influenzae and Neisseria gonorrhoeae. Studies on human volunteers showed that it produced high, long-lasting blood levels with virtually complete recovery of unchanged antibiotic in the urine. No evidence of toxicity due to cefuroxime was found. Slight, short-lived pain followed intramuscular injection, and the compound was well tolerated intravenously.

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