title: Theory of antimicrobial combinations: biocide mixtures - synergy or addition?
abstract: OBJECTIVE
  To demonstrate the effect that non-linear dose responses have on the appearance of synergy in mixtures of antimicrobials.
  
  
  RESULTS
  A mathematical model, which allows the prediction of the efficacy of mixtures of antimicrobials with non-linear dose responses, was produced. The efficacy of antimicrobial mixtures that would be classified as synergistic by time-kill methodology was shown to be a natural consequence of combining antimicrobials with non-linear dose responses.
  
  
  CONCLUSIONS
  The effectiveness of admixtures of biocides and other antimicrobials with non-linear dose responses can be predicted. If the dose response (or dilution coefficient) of any biocidal component, in a mixture, is other than one, then the time-kill methodology used to ascertain the existence of synergy in antimicrobial combinations is flawed.
  
  
  CONCLUSIONS
  The kinetic model developed allows the prediction of the efficacy of antimicrobial combinations. Combinations of known antimicrobials, which reduce the time taken to achieve a specified level of microbial inactivation, can be easily assessed once the kinetic profile of each component has been obtained. Most patented cases of antimicrobial synergy have not taken into account the possible effect of non-linear dose responses of the component materials. That much of the earlier literature can now be predicted, suggests that future cases will require more thorough proof of the alleged synergy.
authors.affiliation: R2-Scientific, 5 Station Rd, Sharnbrook, Bedfordshire MK44 1PT, UK. rjwlambert@r2scientific.co.uk
authors.forename: R J W
authors.initials: RJ
authors.lastname: Lambert
authors.forename: M D
authors.initials: MD
authors.lastname: Johnston
authors.forename: G W
authors.initials: GW
authors.lastname: Hanlon
authors.forename: S P
authors.initials: SP
authors.lastname: Denyer
mesh_terms: D003408:Cresols / Q000494:pharmacology; D004202:Disinfectants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D003408:Cresols; D004202:Disinfectants; D004338:Drug Combinations; C006984:chlorocresol