The mutation frequency for carbapenem resistance in Pseudomonas aeruginosa strains that were selected with carbapenems was enhanced in the presence of subinhibitory concentrations of fluoroquinolones. The mutants showed either a loss of OprD activity or increased mexAB-oprM expression. The highest mutant isolation frequency was obtained by selection with meropenem, while doripenem inhibited mutant growth.The carbapenem group of -lactam antibiotics is highly active against Pseudomonas aeruginosa. In the absence of the carbapenem-hydrolyzing enzyme metallo--lactamase, carbapenem resistance mechanisms include reduced expression of OprD (3, 24, 32, 33) and increased expression of mexAB-oprM (6,11,13,17,23) or AmpC cephalosporinase (14,15,23). The interplay between AmpC cephalosporinase and the loss of OprD is an essential element of carbapenem resistance (14). The reduction in OprD expression found in P. aeruginosa is the result of a spontaneous mutation lacking the D2 (OprD) porin outer membrane protein (3,24,32,33). The isolation frequency of carbapenem resistance in P. aeruginosa clinical iso-* Corresponding author. Mailing address: