Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections

TL;DR

This study explores combining probenecid with penicillin-V to improve its effectiveness against bacterial infections by boosting its concentration in the blood.

Contribution

The study demonstrates that probenecid significantly increases penicillin-V concentrations and improves its pharmacodynamic target attainment.

Findings

Probenecid significantly increased total and free serum concentrations of penicillin-V at both 45 and 180 minutes.

Pharmacokinetic modeling showed a fourfold increase in MIC cover when penicillin-V was combined with probenecid.

The combination of probenecid and penicillin-V was safe and well tolerated in healthy volunteers.

Abstract

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p < 0.001, 180 min 2.2 (1.58–3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88–1.42) mg/L p < 0.001, 180 min 0.5 (0.35–0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

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