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Antimicrobial Agents and Chemotherapy, April 2005, p. 1483-1494, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1483-1494.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phenotypic Tolerance: Antibiotic Enrichment of Noninherited Resistance in Bacterial Populations

C. Wiuff,1* R. M. Zappala,1 R. R. Regoes,1 K. N. Garner,1 F. Baquero,2 and B. R. Levin1

Department of Biology, Emory University, Atlanta, Georgia,1 Department of Microbiology, Ramón y Cajal University Hospital, Madrid, Spain2

Received 16 July 2004/ Returned for modification 7 October 2004/ Accepted 28 December 2004

When growing bacteria are exposed to bactericidal concentrations of antibiotics, the sensitivity of the bacteria to the antibiotic commonly decreases with time, and substantial fractions of the bacteria survive. Using Escherichia coli CAB1 and antibiotics of five different classes (ampicillin, ciprofloxacin, rifampin, streptomycin, and tetracycline), we examine the details of this phenomenon and, with the aid of mathematical models, develop and explore the properties and predictions of three hypotheses that can account for this phenomenon: (i) antibiotic decay, (ii) inherited resistance, and (iii) phenotypic tolerance. Our experiments cause us to reject the first two hypotheses and provide evidence that this phenomenon can be accounted for by the antibiotic-mediated enrichment of subpopulations physiologically tolerant to but genetically susceptible to these antibiotics, phenotypic tolerance. We demonstrate that tolerant subpopulations generated by exposure to one concentration of an antibiotic are also tolerant to higher concentrations of the same antibiotic and can be tolerant to antibiotics of the other four types. Using a mathematical model, we explore the effects of phenotypic tolerance to the microbiological outcome of antibiotic treatment and demonstrate, a priori, that it can have a profound effect on the rate of clearance of the bacteria and under some conditions can prevent clearance that would be achieved in the absence of tolerance.

* Corresponding author. Mailing address: Department of Biology, Emory University, 1510 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-2956. E-mail: cwiuff{at}emory.edu.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1483-1494, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1483-1494.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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