None listed
Conditions
Brief summary
Introduction and methods Flucloxacillin is the first-line antibiotic agent in many parts of the world, including NZ and Australia, for treating Staphylococcus aureus and skin infections. It is often given by 24-hour intravenous (IV) infusion to outpatients with moderately severe infections, but this costs NZ$150-200/day and sometimes causes problems with the IV catheter. It is often given by mouth to patients with mild infections, but this requires four-times-daily dosing and is recommended to be taken 1 hour before or 2 hours after a meal. It would be very useful if there was a more effective and convenient oral flucloxacillin regimen that could be taken with or without food. In the early 1950s, probenecid was developed as a penicillin ‘booster’. In this study, we evaluated the effect of low dose probenecid (500 mg), with or without a small meal, on oral flucloxacillin pharmacokinetics in 11 healthy volunteers. We used modern testing methods, measured free flucloxacillin concentrations, and evaluated the results in terms of modern PK/PD targets for the likely bacteria involved. Results Probenecid delayed clearance of flucloxacillin from the body, approximately doubling the time the flucloxacillin was above the target minimum inhibitory concentration (MIC90 = 0.5 mg/L for Staphylococcus aureus. Food delayed the absorption of flucloxacillin but did not reduce it.. For a target of time above 0.5 mg/L for more than 50% of the day (e.g. for a deep S. aureus bone or joint infection), modeling at steady state showed that flucloxacillin 1 g with probenecid 500 mg taken 6- or 8-hourly with or without food would achieve this in almost all cases. For a target of time above 0.5 mg/L for more than 30% of the day (e.g. for a mild skin infection), modeling at steady state showed that flucloxacillin 1 g with probenecid 500 mg taken twice daily with or without food would achieve this in almost all cases. Conclusion These results show that probenecid is a powerful booster of flucloxacillin and that food did not negatively affect the relevant results. Taking probenecid and flucloxacillin together could enable patients with mild infections to have a more convenient twice daily regimen and could enable patients with moderate deep serious gram-positive infections to avoid home intravenous infusions.
Interventions
Volunteers were administered flucloxacillin 1000 mg orally on three study days separated by a 7-day ‘washout period’.
Arm 1: Flucloxacillin 1000 mg orally, single dose while fasting
Arm 2: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose while fasting
Arm 3: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose with food
On each study day, participants fasted for eight hours (overnight) but had free access to water. On fasting days only wa
Volunteers were administered flucloxacillin 1000 mg orally on three study days separated by a 7-day ‘washout period’. Arm 1: Flucloxacillin 1000 mg orally, single dose while fasting Arm 2: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose while fasting Arm 3: Flucloxacillin 1000 mg orally plus probenecid 500 mg orally, both single dose with food On each study day, participants fasted for eight hours (overnight) but had free access to water. On fasting days only water could be consumed until two hours after receiving the study medication. On the fed day, each participant ingested two scrambled eggs made with two tablespoons of milk (full cream), two slices of mixed grain and toasted sesame bread with margarine and 250 mL of orange juice. Each meal contained 492 kcal of energy, 21.8 g of protein, 22 g of fat and 52.6 g of carbohydrate. Caffeine was permitted only after the 4-hour blood sample, and alcohol was forbidden until completion of the study. Adherence to fasting was assessed verbally.
Sponsors
Richard Everts
Study design
Allocation
Non-randomised trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy volunteer
Exclusion criteria
Food intolerance, pregnancy, chronic illness, renal impairment (creatinine clearance < 80 mL/min by Cockcroft-Gault formula), liver dysfunction, malabsorption or known intolerance of flucloxacillin or probenecid. Volunteers were excluded from the study if they took any regular medications (other than a hormonal oral contraceptive pill) or were intolerant of fasting for up to 10 hours.
Outcome results
None listed