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

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.