Characterization of FCE 22101-resistant Enterobacteriaceae and the effect of FCE 22101 upon the activity of anti-pseudomonal β-lactams for Pseudomonas aeruginosa

Abstract

Twenty-five strains of Enterobacteriaceae (five each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii, and Providencia stuartii) were exposed to FCE 22101 in agar containing 3, 5, or 10 x the MIC. Any putative mutant with a greater than or equal to four-fold increase in the MIC was examined for beta-lactamase expression and outer membrane protein (OMP) profile. Mutant colonies were selected at a frequency of 10(-7)-10(-11) with decreased susceptibility to FCE 22101 and other beta-lactams, but after one subculture on antibiotic-free agar the mutants from 13 of the 25 strains reverted to wild-type. Only 19 stable mutants were selected from the other 12 wild-type strains, of which 15 lacked an OMP of similar molecular size to OmpF, and/or a low size OMP of approximately 18 kDa. None of the mutants had a significant alteration in expression of Richmond & Sykes class I beta-lactamase. In a separate section of the study in which 50 strains of Pseudomonas aeruginosa were examined, it was found that FCE 22101, at a concentration of 4 mg/L, induced beta-lactamase expression such that, after 24 h exposure, 24 of the 50 strains had a greater than or equal to four-fold rise in the MIC of several anti-pseudomonal beta-lactams.

Relative importances of outer membrane permeability and group 1 beta-lactamase as determinants of meropenem and imipenem activities against Enterobacter cloacae

“…This latter property appears to be peculiar to these antibiotics, since carbapenems have been shown to penetrate rapidly through the outer membrane of Pseudomonas aeruginosa via a specific porin pathway (32), and in Escherichia coli, too, in which a specific pathway is apparently absent (7), the permeability coefficients of meropenem and imipenem are 5 and 14 times higher, respectively, than that of cephaloridine, one of the noncarbapenem ␤-lactams endowed with the highest penetration rates (7). Less information is available on the mechanism by which carbapenems penetrate in other species of the family Enterobacteriaceae, although a considerable amount of evidence suggests that in many species the lack of certain outer membrane proteins is associated with the acquisition of resistance to these antibiotics (5,10,12,16,20,24,25,33). A study of carbapenem influx under conditions which, as far as possible, preserve the physiological status of the cells seems to be of great importance for comparing carbapenem permeation in different species and for assessing the respective weights of permeability and other periplasmic factors, such as ␤-lactamase activity, in determining susceptibility or resistance to these antibiotics.…”