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Antimicrobial Agents and Chemotherapy, August 2004, p. 3086-3092, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.3086-3092.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection Potential

Antibiotic Resistance Monitoring & Reference Laboratory, Specialist & Reference Microbiology Division, Health Protection Agency, Colindale, London, NW9 5HT, United Kingdom,¹ Peninsula Pharmaceuticals Inc., Alameda, California 94502²

Received 30 October 2003/ Returned for modification 28 January 2004/ Accepted 14 April 2004

Doripenem is a broad-spectrum parenteral carbapenem under clinical development in Japan and North America. Its activities against (i) Pseudomonas aeruginosa isolates with graded levels of intrinsic efflux-type resistance, (ii) mutants with various combinations of AmpC and OprD expression, (iii) PU21 transconjugants with class A and D ß-lactamases, and (iv) P. aeruginosa isolates with metallo-ß-lactamases were tested by the agar dilution method of the National Committee for Clinical Laboratory Standards. Selection of resistant P. aeruginosa mutants was investigated in single- and multistep procedures. Doripenem MICs for isolates without acquired resistance mostly were 0.12 to 0.5 µg/ml, whereas meropenem MICs were 0.25 to 0.5 µg/ml and imipenem MICs were 1 to 2 µg/ml. The MICs of doripenem, meropenem, ertapenem, and noncarbapenems for isolates with increased efflux-type resistance were elevated, whereas the MICs of imipenem were less affected. The MICs of doripenem were increased by the loss of OprD but not by derepression of AmpC; nevertheless, and as with other carbapenems, the impermeability-determined resistance caused by the loss of OprD corequired AmpC activity and was lost in OprD^– mutants also lacking AmpC. The TEM, PSE, PER, and OXA enzymes did not significantly protect P. aeruginosa PU21 against the activity of doripenem, whereas MICs of 16 µg/ml were seen for clinical isolates with VIM and IMP metallo-ß-lactamases. Resistant mutants seemed to be harder to select with doripenem than with other carbapenems (or noncarbapenems), and the fold increases in the MICs were smaller for the resistant mutants. Single-step doripenem mutants were mostly resistant only to carbapenems and had lost OprD; multistep mutants had broader resistance, implying the presence of additional mechanisms, putatively including up-regulated efflux. Most mutants selected with aminoglycosides and quinolones had little or no cross-resistance to carbapenems, including doripenem.

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