Enhancing Amoxicillin Pharmacokinetics and Pharmacodynamics Parameters With Probenecid in Bone and Joint Infections

Condition(s) studied

Investigational drug(s) / intervention(s)

Oral probenecid added to oral amoxicillin for osteoarticular infections: Adjunctive oral probenecid (500 mg every 8 hours ± 1 hour) added to ongoing oral amoxicillin in adult patients treated for microbiologically documented osteoarticular infections. Probenecid is administered for pharmacokinetic assessment to evaluate its effect on amoxicillin exposure and PK/PD target attainment. Amoxicillin dosing (2 or 3 g every 8 hours ± 1 hour) remains unchanged before and after probenecid administration. Probenecid will be administered for 24-72 hours for pharmacokinetic assessment. It may subsequently be continued until the end of antibiotic treatment if the amoxicillin trough concentration is below 10 × MIC without probenecid but reaches the target with probenecid, in accordance with the protocol.

Study summary

Osteoarticular infections (OAIs) are common, with Streptococcus spp. and Enterococcus spp. being the second most common causative pathogens after Staphylococcus aureus. High-dose oral amoxicillin is recommended as first-line treatment for susceptible infections caused by Streptococcus spp., Enterococcus faecalis and anaerobic bacteria. However, treatment failure remains frequent despite appropriate therapy, with reported rates ranging from 25% to 48%.

The efficacy of β-lactam antibiotics is closely related to PK/PD target attainment, particularly the time during which free drug concentrations remain above the minimum inhibitory concentration (fT \> MIC). For severe infections such as OAIs, maintaining antibiotic concentrations above the MIC throughout the dosing interval is considered the optimal PK/PD target. Because amoxicillin penetration into bone is limited (bone-to-plasma concentration ratio 0.1-0.3), a trough plasma concentration (Cmin) ≥10 × MIC has been proposed to ensure adequate exposure at the site of infection. Achieving this target is particularly challenging for E. faecalis because of its higher MICs and the saturable oral absorption of amoxicillin at doses ≥2 g. Accordingly, the French Infectious Diseases Society (SPILF) recommends PK/PD-guided dose optimization and therapeutic drug monitoring when oral amoxicillin doses exceed 9 g/day.

Probenecid inhibits the renal tubular secretion of β-lactams through inhibition of OAT1 and OAT3 transporters, thereby increasing plasma amoxicillin concentrations and prolonging its elimination half-life. This pharmacokinetic interaction has been well documented and may improve PK/PD target attainment without increasing the amoxicillin dose. Current national recommendations advocate high-dose amoxicillin but propose heterogeneous dosing regimens, resulting in substantial variability in prescribing practices. The AMPHORE study aims to generate clinical PK/PD data to establish standardized dosing strategies for oral amoxicillin, with or without adjunctive probenecid.

Hypothesis : In patients with osteoarticular infections treated with oral amoxicillin, the addition of probenecid may improve amoxicillin PK/PD target attainment by increasing trough plasma amoxicillin concentrations.

Objective : To evaluate the effect of adding oral probenecid on the trough plasma amoxicillin concentration in patients receiving oral amoxicillin monotherapy for osteoarticular infection.

Method : Prospective, multicentre, quasi-experimental before-and-after study conducted in eight French hospitals. Fifty-seven patients with microbiologically confirmed osteoarticular infections caused by amoxicillin-susceptible pathogens (Enterococcus spp., Streptococcus spp., Cutibacterium spp. or other amoxicillin-susceptible anaerobic bacteria) receiving oral amoxicillin monotherapy will be included. Following baseline pharmacokinetic sampling, patients will receive oral probenecid (500 mg every 8 hours), with repeat pharmacokinetic assessment.

Eligibility

Primary outcome measure(s)

• Achievement of the amoxicillin PK/PD target (Cmin ≥ 10 × MIC) — At baseline before probenecid initiation and after 24-72 hours of probenecid treatment.
  The proportion of patients achieving a trough plasma amoxicillin concentration ≥ 10 × the MIC of the causative bacterium (corresponding to 100% of the time spent at concentrations ≥ 10 × MIC in plasma between two amoxicillin doses), with or without probenecid.

Trial sites (8)

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