ABSTRACT
BACKGROUND: The antihypertensives reserpine and verapamil are also inhibitors of pneumococcal efflux pumps. We addressed the following questions: (i) Do verapamil and reserpine influence the mutation ratio of pneumococci in the presence of ciprofloxacin? (ii) At which concentrations does this occur? (iii) Is this limited to isolates with efflux phenotype? METHODS: 14 clinical isolates, nested in 6 genetically similar clusters, were used, 7 strains with efflux and 7 without. The mutation ratio in the presence of ciprofloxacin (3 × MIC) and increasing concentrations of reserpine and verapamil was determined and the quinolone-resistance determining regions (QRDR) of selected mutants were sequenced. Analysis of the efficacy was performed using a mixed linear model, supported by descriptive statistics. RESULTS: Reserpine and verapamil reduced the mutation ratio of QRDR in the presence of ciprofloxacin with the required concentration for a reduction ≥ 50% of 1mg/l for reserpine and 50mg/l for verapamil. The mutation prevention effect is not limited to, but is more pronounced in efflux positive phenotypes. CONCLUSION: Reserpine and verapamil can prevent the selection of ciprofloxacin resistant isolates by reduction of the mutation ratio, particularly in strain with an efflux phenotype. However, the required concentrations are too toxic for clinical use.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antihypertensive Agents/metabolism , Drug Resistance, Bacterial/drug effects , Fluoroquinolones/pharmacology , Mutation Rate , Streptococcus pneumoniae/drug effects , Ciprofloxacin/pharmacology , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Humans , Pneumococcal Infections/microbiology , Reserpine/metabolism , Sequence Analysis, DNA , Streptococcus pneumoniae/isolation & purification , Verapamil/metabolismABSTRACT
A few international pneumococcal clones dominate the population of antibiotic-resistant pneumococci. Despite the scientific paradigm that a loss in fitness is the price for acquisition of resistance, these clones spread successfully. One hundred fifty-four isolates from adult patients with community-acquired pneumonia (CAP) were analyzed. Thirty percent showed a close relationship to international clones and had fitness equal to or exceeding that of other strains (P = 0.015); these factors may result in the endurance of these strains despite a reduction of antibiotic usage.
