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Impact of Resistance Selection and Mutant Growth Fitness on the Relative Efficacies of Streptomycin and Levofloxacin for Plague Therapy

Arnold Louie,^* Mark R. Deziel, Weiguo Liu, and George L. Drusano

Emerging Infections and Host Defense Section, Ordway Research Institute, Albany, New York 12208

Received 17 January 2007/ Returned for modification 27 March 2007/ Accepted 12 May 2007

Yersinia pestis, the bacterium that causes plague, is a potential agent of biowarfare and bioterrorism. The aminoglycoside antibiotic streptomycin is the gold standard for treatment. However, this recommendation is based on scant animal and clinical data. We used an in vitro pharmacodynamic infection model to compare the efficacies of 10-day regimens of streptomycin versus the fluoroquinolone antibiotic levofloxacin for the treatment of Y. pestis infection and to evaluate for emergence of resistance. The human serum concentration-time profiles for standard clinical regimens of 1 g of streptomycin given every 12 h and 500 mg of levofloxacin given every 24 h were simulated. The growth fitness of drug-resistant mutants was examined in neutropenic and immunocompetent mouse thigh infection models. In the in vitro infection system, untreated bacteria grew from 10⁷ to 10¹⁰ CFU/ml. Streptomycin therapy caused a 10⁵ CFU/ml reduction in the number of bacteria over 24 h, followed by regrowth with streptomycin-resistant mutants. Levofloxacin resulted in a 10⁷ CFU/ml reduction in the number of bacteria within 12 h, ultimately sterilizing the culture without resistance selection. In both the normal and neutropenic mouse infection models, streptomycin-resistant and wild-type strains were equally fit. However, 90% of levofloxacin-resistant isolates, cultured from the control in vitro infection arm, did not proliferate in the mouse models. Thus, the fluoroquinolone antibiotic levofloxacin was superior to streptomycin in our in vitro infection model. The majority of levofloxacin-resistant mutants were less fit than streptomycin-resistant and wild-type Y. pestis.

Published ahead of print on 21 May 2007.

Deceased.