Development of resistance in Pseudomonas aeruginosa to broad-spectrum cephalosporins via step-wise mutations

Step-wise resistance to cefepime, ceftazidime, cefotaxime, and cefpirome were determined for 16 Pseudomonas aeruginosa strains by daily transfer for 7 days to fresh media containing two-fold serial dilution of antibiotic. By the third transfer 4 of 16 strains (25%) were resistant (MIC ≥ 32 mg/L) to ceftazidime compared with none, five (31%) and ten (60%) strains becoming resistant to cefepime, cefpirome and cefotaxime (MIC ≥ 64 mg/L), respectively. At the end of the 7 day serial transfer, only four (25%) of the 16 strains were resistant to cefepime, in contrast to nine (56%) cefpirome resistant, 12 (75%) ceftazidime resistant and 13 (81%) cefotaxime resistant. These results are consistent with the infrequent, single-step development of resistance to cefepime, and this may also explain the frequent cefepime susceptibility of cefotaxime/ceftazidime-resistant clinical isolates of P. aeruginosa.