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Antimicrobial Agents and Chemotherapy, September 2006, p. 2946-2950, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00103-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Heteroresistance to Colistin in Multidrug-Resistant Acinetobacter baumannii

Jian Li,1* Craig R. Rayner,1 Roger L. Nation,1 Roxanne J. Owen,1 Denis Spelman,2 Kar Eng Tan,1 and Lisa Liolios2

Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia,1 Department of Microbiology and Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria, Australia2

Received 25 January 2006/ Returned for modification 3 May 2006/ Accepted 13 June 2006

Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as "salvage" therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of colistin against A. baumannii ATCC 19606 and clinical isolate 6 were investigated, and population analysis profiles (PAPs) were conducted. Resistance development was investigated by serial passaging with or without exposure to colistin. Five different PFGE banding patterns were found in the clinical isolates. MICs of colistin against all isolates were within 0.25 to 2 µg/ml. Colistin showed early concentration-dependent killing, but bacterial regrowth was observed at 24 h. PAPs revealed that heteroresistance to colistin occurred in 15 of the 16 clinical isolates. Subpopulations (<0.1% from inocula of 108 to 109 CFU/ml) of ATCC 19606, and most clinical isolates grew in the presence of colistin 3 to 10 µg/ml. Four successive passages of ATCC 19606 in broth containing colistin (up to 200 µg/ml) substantially increased the proportion of the resistant subpopulations able to grow in the presence of colistin at 10 µg/ml from 0.000023 to 100%; even after 16 passages in colistin-free broth, the proportion only decreased to 2.1%. This represents the first demonstration of heterogeneous colistin-resistant A. baumannii in "colistin-susceptible" clinical isolates. Our findings give a strong warning that colistin-resistant A. baumannii may be observed more frequently due to potential suboptimal dosage regimens recommended in the product information of some products of colistin methanesulfonate.

* Corresponding author. Mailing address: Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Phone: 61 3 9903 9702. Fax: 61 3 9903 9629. E-mail: Jian.Li{at}vcp.monash.edu.au.

Antimicrobial Agents and Chemotherapy, September 2006, p. 2946-2950, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00103-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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