title: Antihypertensives suppress the emergence of fluoroquinolone-resistant mutants in pneumococci: an in vitro study.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany. mathias.pletz@med.uni-jena.de
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Pletz
authors.forename: Nikolay
authors.initials: N
authors.lastname: Michaylov
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schumacher
authors.forename: Mark
authors.initials: M
authors.lastname: van der Linden
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Duesberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuehner
authors.forename: Keith P
authors.initials: KP
authors.lastname: Klugman
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Oliwia
authors.initials: O
authors.lastname: Makarewicz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000378:metabolism*; D002939:Ciprofloxacin / Q000494:pharmacology; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D059645:Mutation Rate; D011008:Pneumococcal Infections / Q000382:microbiology; D012110:Reserpine / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D014700:Verapamil / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000959:Antihypertensive Agents; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D012110:Reserpine; D014700:Verapamil