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

Two independent surveys have been conducted to determine the prevalent bacterial species and beta-lactamase types present in clinical populations of gram-negative, ampicillin-resistant isolates. A total of 208 isolates (112 from Nottingham Hospital and 96 from Charing Cross Hospital), all of which had been collected from out-patients suffering from urinary tract infections, were investigated. The incidence of ampicillin-resistant isolates (minimum inhibitory concentrations, 8 micrograms/ml) was 24.1% and 18.8% within the Nottingham and Charing Cross samples, respectively. The surveys gave similar results within the ampicillin-resistant samples. Escherichia coli was the prevalent bacterial species (52.9%), followed by Klebseilla pneumoniae (30.3%). The majority of isolates, at least 54.8% and possibly as high as 74.5%, owed their principal beta-lactamase activity to enzymes mediated by R-plasmids. The most prevalent beta-lactamases were TEM-1 (53.3%), SHV-1 (30.9%), and OXA-1 (11.5%). Positive associations were found between E. coli and TEM-1 or OXA-1 and between K. pneumoniae and SHV-1.

The incidence and mechanisms of ampicillin resistance (MIC greater than 1 mg/l) were investigated in 105 clinical isolates of Haemophilus influenzae collected in Edinburgh during 1983/4. Fifteen (14.3%) ampicillin-resistant strains were identified and these were non-serotypable and comprised six biotypes. Isoelectric focusing and beta-lactamase-inhibition studies demonstrated that production of the TEM-1 beta-lactamase was the principal mechanism of resistance in nine (60%) strains. Radiolabelling revealed that one beta-lactamase-positive strain also had an unusual penicillin-binding protein (PBP) profit. No beta-lactamase activity was detected in the other six (40%) ampicillin-resistant strains. Two beta-lactamase-negative ampicillin-resistant strains had atypical PBP profiles. SDS-PAGE analysis showed that four beta-lactamase-negative ampicillin-resistant strains, including one with altered PBPs, exhibited outer membrane protein profiles which differed from those of sensitive strains of the same biotype. The ampicillin-resistance mechanism of the remaining strain could not be determined. Thus, several resistance mechanisms, either acting individually or in combination, are implicated in ampicillin resistance in H. influenzae.

Ceftazidime showed a high level of in-vitro antibacterial activity against the Enterobacteriaceae with geometric mean MICs of 0.07-0.5 mg/l and at least 90% of isolates sensitive to 8 mg/l. This cephalosporin was at least as active as gentamicin against gentamicin-sensitive Enterobacteriaceae and showed no significant reduction in activity against gentamicin-resistant strains. The activity of ceftazidime against Pseudomonas species was of special note with all the 204 isolates tested sensitive to 8 mg/l and was highly active against gentamicin-resistant strains. Activity against Staphylococcus aureus was moderate, whilst streptococci were highly susceptible. Activity against Bacteroides fragilis was moderate but a range of anaerobic bacilli and cocci were sensitive. Ceftazidime showed no significant inoculum effects, was rapidly bactericidal and as stable as cefoxitin to a wide range of cell-free beta-lactamases. The spectrum and activity of ceftazidime suggest that it may replace the aminoglycosides currently in clinical use.

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