Activity of cefepime and other beta-lactam antibiotics against permeability mutants of Escherichia coli and Klebsiella pneumoniae.

Permeability mutants were obtained, under selection pressure with cefoxitin, from five strains each of Escherichia coli and Klebsiella pneumoniae. Most mutants showed alterations to their outer membrane protein profiles. In general, the porins OmpC and F were lost from E. coli mutants, and one or both components of a 40 kD doublet were lost from K. pneumoniae mutants. Additional minor changes to outer membrane proteins, of unknown significance, were detected in many of the mutants. MICs of cefepime, ceftazidime and cefpirome for the porin-deficient mutants were up to 128-fold above those for their parent strains, but remained < or = 4 mg/L, whereas those of cefoxitin, cefuroxime, and penicillins were raised above accepted breakpoints. The detection of reduced susceptibility to third- and fourth-generation cephalosporins is in contrast to the findings of other groups. Most (9/10) mutants with high-level cefoxitin resistance were reasonably stable during sequential batch culture in rich media, but susceptible variants tended to overgrow under nutrient depletion in continuous culture. These variants were not true revertants, having failed to regain the major porins: rather they appeared to have undergone compensatory mutations. Their instability probably explains why porin-deficient enterobacteria have not become a significant clinical problem, despite the ease with which they can be selected in vitro.