Background: Fourth-generation cephalosporins have been developed to improve their potency, that is, low minimal inhibitory concentrations (MICs) and to prevent resistance selection of derepressed AmpC-producing mutants in comparison to third-generation cephalosporins as ceftazidime. Objectives: We investigated the role of the administered cefpirome dose on the efficacy of treatment of a Klebsiella pneumoniae lung infection as well as in the selection of resistant Enterobacter cloacae isolates in the intestines of rats treated for a K. pneumoniae lung infection. Materials and Methods: Rats with K. pneumoniae lung infection received therapy with cefpirome doses of 0.4 to 50 mg/kg/day b.i.d. for 18 days. Resistance selection in intestinal E. cloacae was monitored during 43 days. Mutants were checked for β-lactamase activity, mutations in their structural ampC gene, ampD gene, and omp39-40 gene. Results: A 45% and 100% rat survival rate was obtained by administration of 3.1 and 12.5 mg/kg b.i.d. of cefpirome. A significant correlation was demonstrated in the reduction of the susceptible E. cloacae isolates with %fT>MIC at days 7, 14, 22, and 29. Cefpirome E. cloacae mutants, with increased cefpirome MICs, were obtained in only four rats. Conclusions: The treatment with cefpirome resulted in less selection of derepressed mutants in comparison to ceftazidime as shown by their low number per gram of feces and in a limited number of animals.

Additional Metadata
Keywords cefpirome, derepressed mutants, mutant selection window
Persistent URL dx.doi.org/10.1089/mdr.2018.0473, hdl.handle.net/1765/126367
Journal Microbial drug resistance (Larchmont, N.Y.)
Citation
Gautam, V. (Vikas), Mouton, J.W, ten Kate, M.T, Bakker-Woudenberg, I.A.J.M, Van Burgh, S, Strepis, N. (Nikolaos), … Goessens, W. (Wil). (2020). Cefpirome Treatment Results in Limited Selection of Stable Derepressed Enterobacter cloacae Mutants in the Intestinal Flora of Rats Treated for an Experimental Klebsiella pneumoniae Pulmonary Infection. Microbial drug resistance (Larchmont, N.Y.), 26(4), 341–348. doi:10.1089/mdr.2018.0473