To measure the effect of probenecid, fasting and fed, on flucloxacillin pharmacokinetic and pharmacodynamic endpoints.

Flucloxacillin 1000 mg orally was given to 11 volunteers alone while fasting (‘flucloxacillin alone’), and with probenecid 500 mg orally while fasting (‘probenecid fasting’) and with food (‘probenecid fed’). Flucloxacillin pharmacokinetic and pharmacodynamic endpoints were compared.

Probenecid, fasting and fed, increased free plasma flucloxacillin area under the concentration-time curve (zero to infinity) ∼1.65-fold (p < 0.01) versus flucloxacillin alone. Probenecid fed prolonged time to peak flucloxacillin concentrations ∼2-fold versus the other two regimens (p < 0.01). Probenecid fasting or fed increased free flucloxacillin concentrations exceeding 30%, 50% and 70% of the first 6, 8 and 12 h post-dose by 1.58- to 5.48-fold compared with flucloxacillin alone. As an example of this pharmacodynamic improvement, the probability of target attainment of free concentrations above the minimum inhibitory concentration for Staphylococcus aureus (0.5 mg/L) for 50% of a 6-hour dose interval was > 80% for flucloxacillin plus probenecid (fasting or fed) and < 20% for flucloxacillin alone.

Probenecid increased flucloxacillin exposure, with predicted pharmacodynamic effects greater than pharmacokinetic effects because of the altered shape of the concentration-time curve. Probenecid may improve the applicability of oral flucloxacillin regimens.