Differential selection of single-step AmpC or efflux mutants of Pseudomonas aeruginosa by using cefepime, ceftazidime, or ceftobiprole.
Single-step Pseudomonas aeruginosa mutants, selected with ceftobiprole, ceftazidime, or cefepime, were generated at frequencies of 10(-6) to <10(-9) at two and four times the MIC. The chromosomal AmpC β-lactamase activity was increased in all ceftazidime-selected mutants. Mutants selected with cefepime either increased AmpC activity or upregulated expression of the mexXY efflux genes. Mutants selected with ceftobiprole did not overexpress AmpC; 90% of these produced elevated levels of mexXY RNA, indicating that increased efflux, not AmpC derepression, is the predominant response to ceftobiprole during first-step mutations in P. aeruginosa.
Queenan
Anne Marie
AM
Johnson & Johnson Pharmaceutical Research and Development, LLC, 1000 Route 202 South, Raritan, NJ 08869, USA. aqueenan@its.jnj.com
Shang
Wenchi
W
Bush
Karen
K
Flamm
Robert K
RK
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D000077723:Cefepime; D002442:Ceftazidime / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification*; D001618:beta-Lactamases / Q000235:genetics*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; C443755:ceftobiprole; D000077723:Cefepime; D002442:Ceftazidime; C048795:AmpC beta-lactamases; D001618:beta-Lactamases