Beta-lactam antibiotics which affect mainly PBP 3 and are poor substrates for the cephalosporinase of Enterobacter cloacae, but tightly bind to it, are not active against cephalosporinase-overproducing variants of this organism. Attempts have been made to greatly reduce the affinity for the beta-lactamase in order to prevent both binding and hydrolysis. 3-Quaternary ammonium cephalosporins and some cephalosporin (S)-sulfoxides were seen to fit this requirement. Suitable substitution of the monocyclic beta-lactam nucleus also resulted in compounds with lower affinity than aztreonam. Temocillin, differing from ticarcillin by the 6-methoxy group, also has a lower affinity for the cephalosporinase. All compounds discussed retain the highest affinity for PBP 3 and are active against cephalosporinase-overproducing E. cloacae in contrast to compounds with high affinity for the cephalosporinase.