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.

Inclusion Criteria: * Age ≥ 18 years old * Effective contraception throughout the study period for women of childbearing potential. * Ongoing oral amoxicillin monotherapy for the treatment of a documented osteoarticular infection, including: osteoarticular infection without implanted material (arthritis, osteitis, osteomyelitis), osteoarticular infection involving implanted material (osteoarticular prosthesis, osteosynthesis hardware, external fixator, or arthrodesis material excluding spinal instrumentation), or spondylodiscitis with or without implanted material, defined by the following criteria: * Microbiological documentation of one or more pathogens for which amoxicillin is the recommended antibiotic treatment (Enterococcus spp. susceptible to ampicillin, Streptococcus spp., Cutibacterium spp., and other anaerobic bacteria susceptible to amoxicillin), obtained from blood cultures, disco-vertebral biopsy, bone biopsy, joint aspiration, and/or intraoperative samples. * Treatment with oral amoxicillin monotherapy for the management of this osteoarticular infection, with the diagnosis established based on the following criteria: * Clinical signs, with one or more of the following: fever, hypothermia, chills, pain, spinal pain, arthritis, inflammatory or dehiscent scar over osteoarticular hardware, fistula, purulent drainage, and/or * Suggestive radiological findings (X-ray, CT scan, or MRI): bone lysis, periosteal reaction, sequestrum, soft tissue collection, joint effusion, radiolucent line around osteoarticular hardware suggestive of loosening. In cases of spondylodiscitis: T2 hyperintensity of the disc, T1 hypointensity of adjacent vertebral endplates on MRI, posterior facet joint arthritis, and/or * Final diagnosis of osteoarticular infection established by the treating medical or multidisciplinary surgical team based on a combination of clinical, microbiological, radiological, or other relevant findings. Patients with a history of one or more previous osteoarticular infections are eligible. * Oral amoxicillin treatment permitted based on clinical and biological improvement. * Planned hospitalization duration ≥4 days after inclusion. * Patient informed and having provided written informed consent to participate. Exclusion Criteria: * Pregnancy or breastfeeding. * Severe allergy to β-lactams or documented allergic contraindication to penicillins confirmed by allergy testing. * Contraindication to probenecid, including: hypersensitivity to probenecid, an ongoing acute gout attack, nephrolithiasis, secondary hyperuricemia due to chemotherapy, radiotherapy, or myeloproliferative syndrome because of the increased risk of uric acid nephropathy, and primary hyperuricemia due to uric acid overproduction. * Ongoing treatment, which cannot be discontinued, with a medication known to interact with probenecid: methotrexate, diprophylline, cholestyramine, phenobarbital, and zidovudine. If treatment discontinuation is possible, the washout period will be left to the investigator's discretion. * Renal impairment defined by an estimated glomerular filtration rate (eGFR) \130 mL/min/1.73 m² according to the CKD-EPI equation, based on the most recent value available during hospitalization before inclusion. * Body weight \110 kg. * Severe hepatic impairment defined by prothrombin time (PT) \