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Antimicrobial Agents and Chemotherapy, November 2009, p. 4718-4725, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00802-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Impact of Spore Biology on the Rate of Kill and Suppression of Resistance in Bacillus anthracis{triangledown}

G. L. Drusano,1* O. O. Okusanya,2 A. O. Okusanya,2 B. van Scoy,1 D. L. Brown,1 C. Fregeau,1 R. Kulawy,1 M. Kinzig,3 F. Sörgel,3,4 H. S. Heine,5 and A. Louie1

Ordway Research Institute,1 Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, New York,2 IBMP—Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg,3 Department of Pharmacology, University of Duisburg—Essen, Essen, Germany,4 United States Army Research Institute for Infectious Diseases, Fort Detrick, Maryland5

Received 16 June 2009/ Returned for modification 7 August 2009/ Accepted 11 August 2009

Bacillus anthracis is complex because of its spore form. The spore is invulnerable to antibiotic action. It also has an impact on the emergence of resistance. We employed the hollow-fiber infection model to study the impacts of different doses and schedules of moxifloxacin on the total-organism population, the spore population, and the subpopulations of vegetative- and spore-phase organisms that were resistant to moxifloxacin. We then generated a mathematical model of the impact of moxifloxacin, administered by continuous infusion or once daily, on vegetative- and spore-phase organisms. The ratio of the rate constant for vegetative-phase cells going to spore phase (Kvs) to the rate constant for spore-phase cells going to vegetative phase (Ksv) determines the rate of organism clearance. The continuous-infusion drug profile is more easily sensed as a threat; the Kvs/Ksv ratio increases at lower drug exposures (possibly related to quorum sensing). This movement to spore phase protects the organism but makes the emergence of resistance less likely. Suppression of resistance requires a higher level of drug exposure with once-daily administration than with a continuous infusion, a difference that is related to vegetative-to-spore (and back) transitioning. Spore biology has a major impact on drug therapy and resistance suppression. These findings explain why all drugs of different classes have approximately the same rate of organism clearance for Bacillus anthracis.

* Corresponding author. Mailing address: Ordway Research Institute, 150 New Scotland Ave., Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6403. E-mail: gdrusano{at}ordwayresearch.org

{triangledown} Published ahead of print on 17 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4718-4725, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00802-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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