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.