Delayed resistance selection for doripenem when passaging Pseudomonas aeruginosa isolates with doripenem plus an...

Doripenem (formerly S-4661), a parenteral carbapenem, was tested in combination with an aminoglycoside (gentamicin) to determine the resistance selection of these codrugs during subinhibitory passaging using 6 Pseudomonas aeruginosa isolates. The organisms were selected based on doripenem and gentamicin MIC values to include isolates with MIC values near the susceptible breakpoints of both compounds and 1 strain highly resistant to gentamicin. Baseline MIC values were established for doripenem (2-8 microg/mL) and gentamicin (4 to >256 microg/mL) using reference broth microdilution methods, and passaging was carried out over 7 consecutive days. Doripenem MIC values increased 2 to >/=8-fold in 4 isolates, whereas 2 strains maintained the baseline doripenem MIC. When the experiment was performed with doripenem plus gentamicin, 3 strains maintained the original doripenem MIC values, 2 strains had a 2-fold increase, and only 1 strain showed a 4-fold increase in the doripenem MIC values. Previous studies have demonstrated doripenem to be more potent than other members in its class when tested against P. aeruginosa. The combination of doripenem and an aminoglycoside may be an effective treatment of infections caused by P. aeruginosa with elevated carbapenem MIC values with lower risk of selecting further resistance.