Why are carbapenems active against Enterobacter cloacae resistant to third generation cephalosporins?

The broad antibacterial activity of carbapenems includes Gram-negative rods resistant to third generation cephalosporins. To increase the understanding of this improved activity, the factors involved in the efficacy of imipenem and ceftriaxone against Enterobacter cloacae have been examined. Resistance to ceftriaxone is primarily the result of a selection of resistant clones ("derepressed mutants"), pre-existing within the Enterobacter populations. Most of the resistant clones produce large amounts of beta-lactamases, and some of them show a decreased expression of porin F coupled with an increased expression of porin C. Determination of outer membrane permeability, as calculated in intact cells using a HPLC-based technique, showed that imipenem penetrated three times faster than ceftriaxone. Moreover, unlike ceftriaxone, imipenem penetration was not affected in a porin F deficient mutant. This suggests that imipenem has an additional pathway not available for ceftriaxone, possibly porin C. The rate of beta-lactamase hydrolysis in experimental conditions thought to be physiologically relevant, and the affinity for PBPs, estimated by calculation, were similar for the two antibiotics. Thus, the activity of imipenem against ceftriaxone resistant E. cloacae seems to result mainly from a selective permeability of the outer membrane.