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Antimicrobial Agents and Chemotherapy, August 2008, p. 2898-2904, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01309-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii{triangledown}

Tze-Peng Lim,1 Kimberly R. Ledesma,2 Kai-Tai Chang,2 Jing-Guo Hou,2 Andrea L. Kwa,1 Michael Nikolaou,3 John P. Quinn,4 Randall A. Prince,2 and Vincent H. Tam2*

Singapore General Hospital, Singapore, Singapore,1 College of Pharmacy,2 Department of Chemical & Biomolecular Engineering, University of Houston, Houston, Texas,3 John H. Stroger, Jr. Hospital, Rush University, Chicago, Illinois4

Received 10 October 2007/ Returned for modification 9 December 2007/ Accepted 18 May 2008

Treatment of multidrug-resistant bacterial infections poses a therapeutic challenge to clinicians; combination therapy is often the only viable option for multidrug-resistant infections. A quantitative method was developed to assess the combined killing abilities of antimicrobial agents. Time-kill studies (TKS) were performed using a multidrug-resistant clinical isolate of Acinetobacter baumannii with escalating concentrations of cefepime (0 to 512 mg/liter), amikacin (0 to 256 mg/liter), and levofloxacin (0 to 64 mg/liter). The bacterial burden data in single and combined (two of the three agents with clinically achievable concentrations in serum) TKS at 24 h were mathematically modeled to provide an objective basis for comparing various antimicrobial agent combinations. Synergy and antagonism were defined as interaction indices of <1 and >1, respectively. A hollow-fiber infection model (HFIM) simulating various clinical (fluctuating concentrations over time) dosing exposures was used to selectively validate our quantitative assessment of the combined killing effect. Model fits in all single-agent TKS were satisfactory (r2 > 0.97). An enhanced combined overall killing effect was seen in the cefepime-amikacin combination (interactive index, 0.698; 95% confidence interval [CI], 0.675 to 0.722) and the cefepime-levofloxacin combination (interactive index, 0.929; 95% CI, 0.903 to 0.956), but no significant difference in the combined overall killing effect for the levofloxacin-amikacin combination was observed (interactive index, 0.994; 95% CI, 0.982 to 1.005). These assessments were consistent with observations in HFIM validation studies. Our method could be used to objectively rank the combined killing activities of two antimicrobial agents when used together against a multidrug-resistant A. baumannii isolate. It may offer better insights into the effectiveness of various antimicrobial combinations and warrants further investigations.

* Corresponding author. Mailing address: University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030. Phone: (713) 795-8316. Fax: (713) 795-8383. E-mail: vtam{at}uh.edu

{triangledown} Published ahead of print on 27 May 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2898-2904, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01309-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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