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Antimicrobial Agents and Chemotherapy, June 2007, p. 2065-2069, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01198-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Tigecycline Efflux as a Mechanism for Nonsusceptibility in Acinetobacter baumannii{triangledown}

Anton Y. Peleg,* Jennifer Adams, and David L. Paterson

Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Received 24 September 2006/ Returned for modification 5 November 2006/ Accepted 24 March 2007

Tigecycline has an extended spectrum of in vitro antimicrobial activities, including that against multidrug-resistant Acinetobacter. After identifying bloodstream isolates of Acinetobacter with reduced susceptibilities to tigecycline, we performed a study to assess tigecycline efflux mediated by the resistance-nodulation-division-type transporter AdeABC. After exposure of two tigecycline-nonsusceptible isolates to the efflux pump inhibitor phenyl-arginine-ß-naphthylamide (PABN), a fourfold reduction in the tigecycline MIC was observed. Both tigecycline-susceptible and -nonsusceptible isolates were found to carry the gene coding for the transmembrane component of the AdeABC pump, adeB, and the two-component regulatory system comprising adeS and adeR. Previously unreported point mutations were identified in the regulatory system in tigecycline-nonsusceptible isolates. Real-time PCR identified 40-fold and 54-fold increases in adeB expression in the two tigecycline-nonsusceptible isolates compared to that in a tigecycline-susceptible isolate. In vitro exposure of a tigecycline-susceptible clinical strain to tigecycline caused a rapid rise in the MIC of tigecycline from 2 µg/ml to 24 µg/ml, which was reversible with PABN. A 25-fold increase in adeB expression was observed in a comparison between this tigecycline-susceptible isolate and its isogenic tigecycline-nonsusceptible mutant. These results indicate that an efflux-based mechanism plays a role in reduced tigecycline susceptibility in Acinetobacter.

* Corresponding author. Present address: Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, 110 Francis St., LMOB Suite GB, Boston, MA 02215. Phone: (617) 632-0233. Fax: (617) 632-7626. E-mail: apeleg{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 9 April 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2065-2069, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01198-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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