In vitro induction of resistance by tissue concentrations of azithromycin, clarithromycin, cefixime and amoxicillin/clavulanate in clinical isolates of Streptococcus pyogenes

This study evaluated the effects of exposure to serum, tonsils and breakpoint drug concentrations of clarithromycin, azithromycin, cefixime and amoxicillin/clavulanate on Streptococcus pyogenes susceptibility. Frequency of mutation and development of resistance after ten passages on antibiotic gradient plates, followed by ten passages without antibiotic, were determined. Phenotypes of macrolide-resistant strains grown at the end of multi-step selection were also determined. Azithromycin induced a surge of resistant strains more rapidly and frequently than clarithromycin, particularly at tonsils concentrations. With amoxicillin/clavulanate no strains showed minimum inhibitory concentrations (MICs) higher than the susceptibility breakpoint. Mutational frequencies were higher for azithromycin, at serum and breakpoint drug concentrations, than for the other drugs. Most of the macrolide resistant strains showed an MLSB, phenotype. In conclusion, the ability to prevent the occurrence of resistance in clinical isolates of S. pyogenes was similar for amoxicillin/clavulanate and clarithromycin followed by cefixime > azithromycin when tonsil drug concentrations were considered, and greater for amoxicillin/clavulanate followed by clarithromycin > cefixime > azithromycin, at breakpoint and serum concentrations.