Abstract
It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70–0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42–0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87–2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63–0.87, fed inferior p<0.01), 0.95 (0.81–1.11, bioequivalent) and 1.15 (0.97–1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-∞ and Cmax, and prolonged the Tmax of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances.
Highlights
Flucloxacillin is used in many parts of the world for treating infections due to methicillinsusceptible Staphylococcus aureus and Streptococcus pyogenes
The advice to take flucloxacillin in a fasting state is based on studies conducted in the 1970s, and warrants reconsideration in light of the demonstration that the primary determinant of bacterial killing for β-lactam antimicrobials is the time above the minimum inhibitory concentration (MIC)
Values for pharmacokinetic parameters for total and free flucloxacillin concentrations for fed and fasting states are shown in Table 1, along with the within-subject changes with and without food ie. paired t-test of the ratio of the fed to fasting states
Summary
Flucloxacillin is used in many parts of the world for treating infections due to methicillinsusceptible Staphylococcus aureus and Streptococcus pyogenes. Patients (rather than healthy volunteers) receiving oral flucloxacillin every 8 hours therapeutically, administered after food, had mean peak serum concentrations 25–30% lower than when taken fasting [7]. These studies indicated that food decreased the area under the concentration-time curve (AUC) and the maximum concentration (Cmax), and prolonged the time to maximum concentration (Tmax) of the concentration-time curve of total flucloxacillin. These findings have been interpreted to mean that efficacy would be greater in the fasted state. The data in the original publications cannot be accurately re-evaluated according to current pharmacodynamic end points as free flucloxacillin concentrations (i.e. appropriate for comparison against MICs) were not measured directly, and sampling times were short
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