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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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...

The rodent protection test (RPT) is used in antimicrobial research to confirm the in vivo efficacy of novel antibacterial, antiviral and antifungal agents. The RPT may involve lethal infection and thus has the potential to cause significant suffering. These Guidelines recommend refinements to the RPT which reduce animal use to a minimum and suggest cardinal clinical signs which act as predictors of lethality. Early recognition of these signs is imperative to minimize suffering, allow identification of humane end points and permit timely euthanasia. Constructive suggestions for the improvement of these Guidelines are welcomed.

The pharmacokinetic properties of cefuroxime have been evaluated in laboratory animals. On injection into mice, rats, and rabbits by the subcutaneous or intramuscular routes, high serum level peaks were recorded. There was no significant absorption after oral administration. After injection, the antibiotic was excreted in large amounts in the urine. It was well distributed in the body and penetrated into the tissues at a satisfactory rate. This, coupled with a low degree of serum protein binding, was correlated with a very good protective effect in animals (mice, rats, and rabbits) experimentally infected with a wide range of bacteria, including ,B-lactamase-producing strains. It is concluded that cefuroxime should have a good potential for treating a wide range of bacterial infections in humans.It has been shown (2) that cefuroxime, a new antibiotic of the cephalosporin series, has good activity in vitro against a wide range of bacterial species, including many strains which, being producers of (8-lactamase, are resistant to many of the existing cephalosporins and penicillins.Following the in vitro work, an evaluation of the pharmacokinetic properties of the compound and of its ability to protect against a range of bacterial infections in various animal species was undertaken. The results are reported here.MATERIALS AND METHODS Cefuroxime, cephalexin, cephalothin (sodium salts), and cephaloridine were prepared in our own laboratories as pure crystalline materials. Cefazolin (Totacef intramuscular, Bristol Laboratories Inc.) was obtained commercially. The materials were all administered as solutions in physiological saline solution. In the case of the cephalosporins, which were used as sodium salts, dosages were calculated to refer to the amount of free acid present.The animals used were albino, Charles River female mice, weighing 18 to 20 g, albino female rats, Wistar strain, weighing 100 g, and Californian rabbits, weighing 2.0 to 2.5 kg. Antibiotic injections were made in 0.2-ml volumes in mice and rats and in volumes of 0.25 ml/kg in rabbits.