The synergistic effect of EDTA/antimicrobial combinations on Pseudomonas aeruginosa.
OBJECTIVE
To demonstrate that the nonlinear concentration-dependent inhibition of Pseudomonas aeruginosa to EDTA can be used to successfully model and predict the potentiation of antimicrobials by EDTA.


RESULTS
A model used successfully to describe the concentration-dependent inhibition of bacterial growth caused by many antimicrobials was unable to describe the inhibition of P. aeruginosa by EDTA. Examination of the inhibition profiles for EDTA against P. aeruginosa revealed a biphasic inhibitory pattern suggesting different mechanisms of action at different concentrations. A modelled, two-stage inhibitory process was shown to fit the observations. This model was then used to examine the effect of combining EDTA with other antimicrobials. The apparent synergy of mixtures of EDTA with quaternary ammonium surfactants (QAC) and specific antibiotics was successfully modelled. Minimum inhibitory concentrations (MIC) of the QAC and that of oxacillin and cefamandole were reduced by a factor of 3-10, whereas ampicillin was reduced by a factor of 70 from an MIC of 1524 to 21 mg l(-1) in the presence of 500 mg l(-1) of EDTA.


CONCLUSIONS
A nonlinear concentration-dependent inhibition of P. aeruginosa by EDTA gives rise to apparent observation of synergy with other antimicrobials.


CONCLUSIONS
This is a further example where the current methodology for the examination of antimicrobial synergy (the summed fractional inhibitory concentrations) leads to false conclusions.
Lambert
R J W
RJ
R2-Scientific, Bedfordshire, UK. rjwlambert@r2scientific.co.uk
Hanlon
G W
GW
Denyer
S P
SP
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002435:Cefamandole / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000379:methods; D008954:Models, Biological; D010068:Oxacillin / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013501:Surface-Active Agents / Q000494:pharmacology; D050337:Trimethyl Ammonium Compounds
D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; D050337:Trimethyl Ammonium Compounds; C013912:decyltrimethylammonium; D002435:Cefamandole; D000667:Ampicillin; D004492:Edetic Acid; C022806:dodecyltrimethylammonium; D010068:Oxacillin; C009410:tetradecyltrimethylammonium