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Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection Potential
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
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| Personen und Körperschaften: | , , |
| In: | Antimicrobial Agents and Chemotherapy, 48, 2004, 8, S. 3086-3092 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>ABSTRACT</jats:title> <jats:p> Doripenem is a broad-spectrum parenteral carbapenem under clinical development in Japan and North America. Its activities against (i) <jats:italic>Pseudomonas aeruginosa</jats:italic> 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 β-lactamases, and (iv) <jats:italic>P. aeruginosa</jats:italic> isolates with metallo-β-lactamases were tested by the agar dilution method of the National Committee for Clinical Laboratory Standards. Selection of resistant <jats:italic>P. aeruginosa</jats:italic> 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 <jats:sup>−</jats:sup> mutants also lacking AmpC. The TEM, PSE, PER, and OXA enzymes did not significantly protect <jats:italic>P. aeruginosa</jats:italic> PU21 against the activity of doripenem, whereas MICs of ≥16 μg/ml were seen for clinical isolates with VIM and IMP metallo-β-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. </jats:p> |
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| Umfang: | 3086-3092 |
| ISSN: |
0066-4804
1098-6596 |
| DOI: | 10.1128/aac.48.8.3086-3092.2004 |