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Since the introduction of cephalothin and cephaloridine as the first parenteral cephalosporins and cephalexin as the first member of the group which is absorbed from the gastrointestinal tract, several new cephalosporin derivatives have been developed. Most of these have no major advantages over cephalothin, cephaloridine or cephalexin. Increased knowledge about the importance of beta-lactamases for bacterial resistance against beta-lactam antibiotics has focused interest on development of drugs with increased resistance to degradation by these enzymes. Among the caphalosporins, cefamandole and cefuroxime have been found to be markedly more active against beta-lactamase producing Gram-negative bacteria. A new group of beta-lactam antibiotics, the cephamycins, have been introduced with cefoxitin as the first clinically useful member. Cefoxitin has the spectrum of a beta-lactamase-resistant cephalosporin and is also active against Bacteroides fragilis. The review concentrates on the antibacterial spectrum of these three new antibiotics and on their clinical efficacy.

Bacteroides fragilis is responsible for most anaerobic infections in man. Most isolates of B. fragilis show resistance to beta-lactam antibiotics. This resistance might be due to beta-lactamase production or permeability barrier in the cell wall. B. fragilis produce beta-lactamase with mainly cephalosporinase activity. Other Bacteroides species such as B. clostridiformis, B. melaninogenicus and B. oralis also produce beta-lactamase but with different biochemical characteristics.

The antibacterial activity of cephaloridine, cephalothin, cephalexin, cephradine, cefazolin, cefamandole, cefuroxime and cefoxitin was determined for six beta-lactamase-producing gonococci isolated in Great Britain and the USA. Cefuroxime was most active against small and large inocula, then cefoxitin, while cephaloridine was least active. Cefamandole was more active than cefazolin and cephalothin, but only on small inocula, and these three antibiotics, with the slightly inferior cephalexin and cephradine, all had moderate activity against large inocula. The inoculum effect (or lack of it) with cephaloridine, cefamandole, cefoxitin, and possibly cefazolin and cephalothin, may be explicable in terms of the level of their susceptibility to enzymic degradation, but this appears not to be true of the inoculum effect with cefuroxime, cephalexin and cephradine. The enzymes from the various strains had closely similar isoelectric points, apparently the same as that for TEM I from E. coli.

The known mechanisms of beta-lactam resistance in anaerobic bacteria involve production of beta-lactamases, alteration of penicillin-binding proteins and blocked penetration of beta-lactams through the outer membranes. The most important factor in beta-lactam resistance is production of beta-lactamase. Beta-lactamases in various Bacteroides, Fusobacterium and Clostridium species have been described. Beta-lactam resistance in Bacteroides fragilis is most commonly mediated by beta-lactamase production mainly of cephalosporinase character. Recent studies have also shown that B. fragilis can produce a penicillinase which inactivates piperacillin and carbenicillin. Enzymes inactivating cefoxitin and imipenem have also been isolated from B. fragilis. The Bacteroides non-fragilis species produce beta-lactamases of mainly penicillinase character. Recently a penicillinase from Fusobacterium nucleatum has been characterized. Among the clostridia, Clostridium butyricum, C. clostridiiformis and C. ramosum have been shown to produce penicillinases.

The reason why the results of the clinical response to therapy do not always correspond to antibiotic laboratory testing include errors in performance or interpretation of test results, imprecise definition of resistance and host factors which influence the outcome of treatment regardless of the antibiotic being used. These factors are reviewed. Cephalosporins and penicillins pose problems because the prime effects of enzymes in influencing the outcome of treatment are not always clear in standard tests for susceptibility. Inter-laboratory differences in interpretation of tests makes comparisons of tests between centres difficult and the use of reference strains for validation of testing is proposed.

The rising incidence of Gram-negative bacteria resistant to ampicillin in hospitals has brought about a need to develop novel beta-lactam antibiotics. This challenge is being met in two ways. First, attempts have been made to develop compounds insensitive to beta-lactamase hydrolysis. This has proved difficult in the penicillin series, but cefuroxime and cefoxitin are cephalosporin derivatives with the necessary properties. The second approach has been to discover novel beta-lactam nuclei capable of inhibiting beta-lactamases. So far this had led to the production of the clavulins and the olivacins, the latter class of molecules being closely related chemically to thienamycin.