Pharmacodynamic Evidence that Ciprofloxacin Failure against Tuberculosis Is Not Due to Poor Microbial Kill but to Rapid Emergence of Resistance
Open Access
- 1 August 2005
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 49 (8), 3178-3181
- https://doi.org/10.1128/aac.49.8.3178-3181.2005
Abstract
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 By the end of the first week, most of the microbial population had been replaced by a ciprofloxacin-resistant population.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.Keywords
This publication has 18 references indexed in Scilit:
- 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
- Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'Nature Reviews Microbiology, 2004
- Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: a Prospective, Randomized StudyAntimicrobial Agents and Chemotherapy, 2004
- The Rapid Development of Fluoroquinolone Resistance inM. tuberculosisNew England Journal of Medicine, 2003
- A multicentre comparison of a novel surrogate marker for determining the specific potency of anti-tuberculosis drugsJournal of Antimicrobial Chemotherapy, 2003
- The Hunt for the Elusive Surrogate Marker of Sterilizing Activity in Tuberculosis TreatmentAmerican Journal of Respiratory and Critical Care Medicine, 2003
- Studies of the Early Bactericidal Activity of New Drugs for TuberculosisAmerican Journal of Respiratory and Critical Care Medicine, 2002
- Bactericidal Activity of Increasing Daily and Weekly Doses of Moxifloxacin in Murine TuberculosisAntimicrobial Agents and Chemotherapy, 2002
- Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutationsAntimicrobial Agents and Chemotherapy, 1994
- The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: a new method of drug assessmentJournal of Antimicrobial Chemotherapy, 1993