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Antimicrobial Agents and Chemotherapy, August 2005, p. 3178-3181, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3178-3181.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Evidence that Ciprofloxacin Failure against Tuberculosis Is Not Due to Poor Microbial Kill but to Rapid Emergence of Resistance

Tawanda Gumbo, Arnold Louie, Mark R. Deziel, and George L. Drusano*

Emerging Infections and Pharmacodynamics Laboratory, Emerging Infections and Host Defenses Theme, Ordway Research Institute, Albany, New York 12208

Received 16 February 2005/ Returned for modification 24 March 2005/ Accepted 10 April 2005

Studies of early bactericidal activity provide a fast and economic way to evaluate the clinical efficacy of potential agents for the treatment of tuberculosis. Based on good early bactericidal activity data, ciprofloxacin entered further studies and is now recommended as part of treatment for multidrug-resistant tuberculosis. We examined the relationship between ciprofloxacin bactericidal activity and the emergence of resistance in an in vitro pharmacodynamic infection model in which we exposed Mycobacterium tuberculosis to simulated free-drug ciprofloxacin serum concentration-time profiles that mimic those encountered in humans treated with ciprofloxacin orally for 2 weeks. Mycobacterium tuberculosis cultures were sampled during the experiment in order to determine the effect of therapy on the total microbial population as well as the drug-resistant population. The ciprofloxacin regimen, which achieved a ratio of the area under the concentration time curve from 0 to 24 h to MIC of 80.4, resulted in a rapid microbial kill similar to that encountered in humans during studies of early bactericidal activity. However, despite this impressive bactericidal activity, resistance emerged quickly. By the end of the first week, most of the microbial population had been replaced by a ciprofloxacin-resistant population. Given the MICs encountered in clinical isolates of M. tuberculosis, we estimate that most clinically tolerable doses of ciprofloxacin will lead to emergence of resistance, especially when used as the only effective component of regimens given for treatment of multidrug-resistant tuberculosis. One of the explanations for why early bactericidal activity fails to predict sterilization may be the emergence of a resistant subpopulation, which only becomes ≥1% at the end of the early bactericidal activity studies.

* Corresponding author. Mailing address: Emerging Infections and Host Defense Theme, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641 6434. Fax: (518) 641-6304. E-mail: gdrusano{at}ordwayresearch.org.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3178-3181, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3178-3181.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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