You perform a checkerboard assay and obtain the following FIC indices: Drug X + Drug Y = 0.40, Drug X + Drug Z = 1.20, Drug Y + Drug Z = 0.60. Which pairing shows the strongest synergy, which is indifferent, and what is the best interpretation regarding which mechanism to investigate first?

• A. All combinations are equivalent because FIC values are not interpretable without time-kill data; therefore no follow-up experiments are warranted and clinical decisions should be based solely on monotherapy MICs.
• B. X+Z shows strongest synergy because any FIC above 1 indicates potentiation; therefore pursue mechanistic studies of enzymatic inhibition for X+Z first.
• C. X+Y shows strongest synergy (FIC 0.40); X+Z is indifferent (1.20). Investigate uptake/permeability or sequential-target interactions for X+Y first since strong synergy commonly arises from those mechanisms.
• D. Y+Z is strongest because 0.60 is closer to zero than 0.40 and therefore indicates a more reliable synergistic effect; investigate efflux pump induction for Y+Z as the first experiment.

Answer: (C)