The antibacterial activity of the cephalosporins is dependent on multiple factors. The most important of these are : a) permeability, which is determined by charge and, in the case of gramnegative bacteria, by structures in the outer membrane of the cell wall, called porins, which aid the penetration of hydrophilic substances; b) penicillin-binding proteins (PBP's); affinity to either one or more of the PBP's IA, IB, 2 and 3 is important for activity of the ~-lactam antibiotics; c) Dlactamases, to be classified according to spectrum and genetic basis (chromosomal or plasmidal) (Richmond and Sykes, 1973; Sykes and Matthew, 1976).
The molecular structures of the new cephalosporins determine the stability to [Mactamases and also the activity range. In the cephamycin cefoxitin complete [Mactamase resistance is determined by the methoxygroup at C~. The oxa-cephem antibiotic moxalactam also contains a methoxygroup at C~ and is thereby ~-lactamase-resistant. The activity of these antibiotics against an-aerobes is also explained b~ this ~-lactamase resistance.
A m o n g the other newer parenteral [Mactamase-"resistant'" cephalosporins, ceftizoxime, cefotaxime and Ro-13-99.04 are very similar, e.g. all show high activity against Enterobacteriaceae and only marginal activity against Ps. aeruginosa (O' Callaghan, 1979; Neu et al., 1980). Cefoperazone, cefsulodin and ceftazidime (GR 20263) show higher MIC-values for Enterobacteriaceae, but are also active against Ps. aeruginosa. Ceftazidime is strongly ~-lactamase-resistant.
Except for moxalactam and cefoxitin most new cepha!osporins show some type of ~-lactamase susceptibility, although this may be reduced and specific for one type of enzyme. In a comparative study of ~-lactamase susceptibility of cefamandole, cefuroxime, cefoperazone, cefotaxime, moxalactam and cefoxitin, it was found that cefamandole and cefoperazone are of ten just as susceptible to the extrachromosomally mediated TEM-~-lactamase as cephalothin, while cefotaxime and cefuroxime may be slightly susceptible to some cephalosporinases of Richmond's class I, and to chromosomal broad-spectrum [Mactamases. Moxalactam and cefoxitin were not degraded at all. These data on 13lactamase susceptibilities do not run parallel to in vitro data on activity, which may be much higher than expected, but data from literature concerning animal experiments (Goering et al., 1978 ; Miller et al., 1979) suggest that resistance to [Mactamases is indeed important for the in vivo effect.