Emergence of resistance during beta-lactam therapy of gram-negative infections. Bacterial mechanisms and medical responses.

Some Gram-negative, non-fastidious bacilli, although classified as susceptible by conventional susceptibility testing methods, become resistant during therapy with the newer beta-lactam compounds. Emergence of resistance results primarily from the selection of resistant clones pre-existing within the susceptible bacterial populations. Most of the resistant clones produce large amounts of beta-lactamases which inhibit the beta-lactam antibiotics by hydrolysis, rather than by binding. In addition, resistant clones can limit the penetration of beta-lactam molecules through the outer membrane by a decreased expression of their porins. Less commonly, when beta-lactamase activity together with alteration of the permeability barrier does not prevent the access of the antibiotic molecules to their target, altered penicillin-binding proteins (PBPs) can produce resistance. However, the risk of resistance emerging during therapy varies with the beta-lactam drug administered. Some compounds such as cefpirome, BMY 28142, SCH 34343, or imipenem appear to be associated with a low risk. In addition, emergence of resistance can be reduced by using higher dosages of beta-lactam agents, or by combining them with other drugs such as aminoglycosides or quinolones.