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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

Shazad Mushtaq,1 Yigong Ge,2 and David M. Livermore1*

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.

* Corresponding author. Mailing address: Antibiotic Resistance Monitoring & Reference Laboratory, Specialist & Reference Microbiology Division, Health Protection Agency Colindale, London NW9 5HT, United Kingdom. Phone: 44 (0)20-8327-7223. Fax: 44 (0)20-8327-6264. E-mail: david.livermore{at}hpa.org.uk.

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.



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