Impact of Resistance Selection and Mutant Growth Fitness on the Relative Efficacies of Streptomycin and Levofloxacin for Plague Therapy
- 1 August 2007
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 51 (8), 2661-2667
- https://doi.org/10.1128/aac.00073-07
Abstract
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 10 7 to 10 10 CFU/ml. Streptomycin therapy caused a 10 5 CFU/ml reduction in the number of bacteria over 24 h, followed by regrowth with streptomycin-resistant mutants. Levofloxacin resulted in a 10 7 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 .Keywords
This publication has 33 references indexed in Scilit:
- Pharmacokinetic Considerations and Efficacy of Levofloxacin in an Inhalational Anthrax (Postexposure) Rhesus Monkey ModelAntimicrobial Agents and Chemotherapy, 2006
- Treatment of Plague with Gentamicin or Doxycycline in a Randomized Clinical Trial in TanzaniaClinical Infectious Diseases, 2006
- Effective Antimicrobial Regimens for Use in Humans for Therapy of Bacillus anthracis Infections and Postexposure ProphylaxisAntimicrobial Agents and Chemotherapy, 2005
- Selection of a Moxifloxacin Dose That Suppresses Drug Resistance inMycobacterium tuberculosis,by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical ModelingThe Journal of Infectious Diseases, 2004
- Gentamicin and Tetracyclines for the Treatment of Human Plague: Review of 75 Cases in New Mexico, 1985–1999Clinical Infectious Diseases, 2004
- Hollow‐Fiber Unit Evaluation of a New Human Immunodeficiency Virus Type 1 Protease Inhibitor, BMS‐232632, for Determination of the Linked Pharmacodynamic VariableThe Journal of Infectious Diseases, 2001
- Multidrug Resistance inYersinia pestisMediated by a Transferable PlasmidNew England Journal of Medicine, 1997
- Doxycycline or ciprofloxacin prophylaxis and therapy against experimental Yersinia pestis infection in miceJournal of Antimicrobial Chemotherapy, 1996
- PlagueAnnual Review of Microbiology, 1955
- The Chemotherapy of Experimental Plague in the Primate HostThe Journal of Infectious Diseases, 1953