Ciprofloxacin dosage and emergence of resistance in human commensal bacteria

Abstract

Background: Although optimization of the fluoroquinolone dosage increases the efficacy of this class of drugs against bacterial infections, its impact on the emergence of resistance in commensal bacteria is unknown.

Methods: Six different 14-day dosages of oral ciprofloxacin were randomly assigned to 48 healthy volunteers. Individual pharmacokinetic and pharmacodynamic parameters combining antibiotic exposure in plasma, saliva, and stool specimens and ciprofloxacin minimum inhibitory concentrations (MICs) and mutant prevention concentrations against viridans group streptococci in the pharyngeal flora and Escherichia coli in the fecal flora were estimated. Their links with the emergence of resistance to nalidixic acid or ciprofloxacin in the fecal flora and to levofloxacin in the pharyngeal flora 7, 14, or 42 days after ciprofloxacin initiation were investigated.

Results: Resistance emerged in the fecal and pharyngeal flora of 25% and 33% of the subjects, respectively, mainly when local concentrations of ciprofloxacin were less than the MIC. No variable that integrated pharmacokinetic data and pharmacodynamic parameters was found to differ significantly between the subjects in whom resistance emerged and those in whom it did not. Probabilities of the emergence of resistance were not significantly different across the different antibiotic dosages.

Conclusions: Selection of resistant commensals during ciprofloxacin therapy is a frequent ecological side effect that is not preventable by dosage optimization. Trial registration. Clinical Trials.gov identifier: NCT00190151.

Figure 1

Number of subjects harbouring strains of Escherichia coli in fecal flora that were resistant to nalidixic acid or ciprofloxacin (top left) or strains of viridans group streptococci in pharyngeal flora that were resistant to levofloxacin (bottom left) and their corresponding MIC values (mg/L) for nalidixic acid (Nal, white circles) and ciprofloxacin (Cip, black circles) (top right) and levofloxacin (bottom right) in healthy subjects receiving various dosing regimens of ciprofloxacin from day 1 to day 14. Strains that were resistant to ciprofloxacin also appear among strains resistant to nalidixic acid. There were 48 subjects at the start of therapy and 47 subjects later because of one subject discontinuing therapy. In addition, there was no pharyngeal sample to perform measurement at day 0 for one patient.

Figure 2

Mean concentration profiles of ciprofloxacin at steady state in plasma and saliva from healthy subjects receiving ciprofloxacin from day 1 to day 14, according to dosing regimens, and boxplot of the distribution of the fecal concentration at day 7 and day 14. Horizontal lines represent median MIC (mg/L) (full line) and MPC (mg/L) (dotted line) of ciprofloxacin against the dominant flora in each commensal flora.

Figure 3

Distribution of the area under the ciprofloxacin concentration-time curve from 0 to 24 h (AUC)/MIC ratio in plasma (top and bottom left) and saliva (bottom right) and of the fecal concentrations of ciprofloxacin/MIC ratio (top right) in healthy subjects receiving various regimens of ciprofloxacin from day 1 to day 14 and in whom no resistant strains were detected at day 0. Results are presented according to the emergence or not of strains of Escherichia coli resistant to nalidixic acid or ciprofloxacin in fecal flora (top, n=40) or of strains of viridans group streptococci that were resistant to levofloxacin in pharyngeal flora (bottom, n=45), from day 7 to day 42. The solid line represents the median in each group. Each circle represents a subject.