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Synergism : what does it mean?

Synergism : what does it mean?. JW Mouton Dept Medical Microbiology Canisius Wilhelmina Hospital Nijmegen, The Netherlands. RATIONALE FOR ANTIMICROBIAL COMBINATIONS. Extension of spectrum Minimization of resistance Minimization of toxicity Synergism. Classical definition of Synergism.

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Synergism : what does it mean?

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  1. Synergism : what does it mean? JW Mouton Dept Medical Microbiology Canisius Wilhelmina Hospital Nijmegen, The Netherlands

  2. RATIONALE FOR ANTIMICROBIAL COMBINATIONS • Extension of spectrum • Minimization of resistance • Minimization of toxicity • Synergism

  3. Classical definition of Synergism A combination of two drugs is synergistic if the effect of the combination is more than it would be if the concentration of the second drug is replaced by the first drug.

  4. SYNERGISM • Increase killing rate • Potentiation of a drug • Prevention of elimination • metabolic (enzyme inhibitors) • renal function (e.g. probenicide) • Significant better outcome in vivo

  5. SYNERGISM : IN VITRO METHODS • Checkerboard titrations • Time-kill curves • Diffusion methods • disks • paperstrips • E-test

  6. SYNERGISM DEFINITIONSTIME KILL CURVES • >100 fold killing then most active agent after 6 or 24h • >1000 fold killing then most active agent after 6 or 24h • significant earlier reduction to 99% or 99.9% cfu

  7. SYNERGISM DEFINITIONSTIME KILL CURVES • >100 fold killing then most active agent after 24h or 48h • >1000 fold killing then most active agent after 24h or 48h • significant earlier reduction to 99% or 99.9% cfu

  8. Synergism, time kill

  9. Reasons for Combination Therapy

  10. Synergism by E-testWhite et al, 1996

  11. Functions of drug concentration • Two fold checkerboard dilutions, FIC • advantage : easy to perform • disadvantage : • very crude, hardly informative • only with steep effect curves • Effect function • advantage : • uniformly applicable if effect function is known • disadvantage : extensive calculations

  12. Synergy, Checkerboard FICi = FICa + FICb MIC of drug A, tested in combination MIC of drug A, tested alone + MIC of drug B, tested in combination MIC of drug B, tested alone

  13. Simple Isobole Constraints 1= [drug1] + [drug2] Conc d1 Conc d2 Where Conc d is concentration that would individually produce the same effect as the combination

  14. URSAUniversal Response Surface Approach • Loewe constraints • Berenbaum constraints • URSA possible if effect measured quantitatively (Greco, 1990)

  15. URSA 1 =

  16. Bliss Independence Effects Equation

  17. Zero Surface Substraction Bliss exp2

  18. SYNERGISM DEFINITIONScheckerboard • FIC index • <0.5 to <1 for synergism • >1 to >2 for antagonism • at least 3 different methods to calculate FICi • Isoboles • by eye • math expression • Universal Response Surface

  19. SYNERGISM EXPRESSIONScheckerboard • FIC index • <0.5 to <1 for synergism • >1 to >2 for antagonism • Isoboles • by eye • math expression • Function of Effect • Universal Response Surface (Greco, based on Loewe and Berenbaum) • Interaction (Bliss)

  20. PREDICTION OF EFFICACYcombination regimens • determine slope and intercept of the pdi best explaining efficacy for each single drug • time > (0.25 *) MIC for beta-lactams • log (AUC) for aminoglycosides and quinolone • calculate efficacy of the combination as a function of the two slopes and intercepts • determine the coefficient of determination between predicted and measured values

  21. Predicted efficacy of ticarcillin and tobramycin pseudomonas Mouton et al, AAC 1999

  22. CONCLUSIONS • Pharmacodynamic indices can be used to predict efficacy of combination therapy in vivo • These are the same indices as during single drug therapy • These indexes vary over classes, one index for all classes is not proper

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