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

August 11, 2026 updated by: Assistance Publique - Hôpitaux de Paris

Impact du probénécide Sur Les paramètres pharmacocinétiques et Pharmacodynamiques de l'Amoxicilline Chez Des Patients traités Par Voie Orale Pour Une Infection ostéo-articulaire : étude Quasi-expérimentale Multicentrique Preuve de Concept

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
57

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • France
      • Chesnay, France, 78150
        • Hôpital André Mignot, Centre Hospitalier de Versailles
        • Contact:
      • Clichy, France, 92110
      • Créteil, France, 94010
        • Hôpital Henri-Mondor, AP-HP
        • Contact:
      • Paris, France, 75 014
      • Paris, France, 75010
      • Paris, France, 75012
      • Paris, France, 92100
      • Tours, France, 37000

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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) <60 mL/min/1.73 m² according to the CKD-EPI equation, based on the most recent value available during hospitalization before inclusion.
  • Augmented renal clearance defined by an 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 <40 kg or >110 kg.
  • Severe hepatic impairment defined by prothrombin time (PT) <50%, based on the most recent value available during hospitalization before inclusion.
  • Patients under legal guardianship, curatorship, judicial protection, or deprived of liberty.
  • Patients with cognitive impairment or who, in the investigator's opinion, are unable to understand the study, participate in all study visits considering the treatments and procedures required by the protocol, and/or provide informed consent.
  • Patients not affiliated with a social security system or another health insurance scheme, including patients covered by State medical aid (AME).
  • Concomitant participation in another clinical trial involving a medicinal product for human use, a clinical investigation of a medical device, or any interventional research involving human participants.
  • Participation in non-interventional research is permitted

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Amoxicillin-probenecid combination therapy
Addition of probenecid to oral amoxicillin therapy.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Achievement of the amoxicillin PK/PD target (Cmin ≥ 10 × MIC)
Time Frame: 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.
At baseline before probenecid initiation and after 24-72 hours of probenecid treatment.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinical and biological treatment success at end of treatment and 6-month follow-up
Time Frame: At the end of antibiotic treatment and 6 months ± 7 days after treatment completion.
Quantification of the number of patients achieving clinical and biological success at the end of antibiotic therapy and 6 months after treatment completion.
At the end of antibiotic treatment and 6 months ± 7 days after treatment completion.
Comparison the complete pharmacokinetic parameters of amoxicillin in normorenal adults treated for osteoarticular infection with amoxicillin without and with probenecid.
Time Frame: 24-72 hours after probenecid initiation
Quantification of Cmin of amoxicillin without and with probenecid.
24-72 hours after probenecid initiation
Comparison the complete pharmacokinetic parameters of amoxicillin in normorenal adults treated for osteoarticular infection with amoxicillin without and with probenecid.
Time Frame: 24-72 hours after probenecid initiation
Cmax of amoxicillin without and with probenecid.
24-72 hours after probenecid initiation
Comparison the complete pharmacokinetic parameters of amoxicillin in normorenal adults treated for osteoarticular infection with amoxicillin without and with probenecid.
Time Frame: 24-72 hours after probenecid initiation
AUC0-8h of amoxicillin without and with probenecid.
24-72 hours after probenecid initiation
Comparison the complete pharmacokinetic parameters of amoxicillin in normorenal adults treated for osteoarticular infection with amoxicillin without and with probenecid.
Time Frame: 24-72 hours after probenecid initiation
t1/2 of amoxicillin without and with probenecid.
24-72 hours after probenecid initiation
Comparison the complete pharmacokinetic parameters of amoxicillin in normorenal adults treated for osteoarticular infection with amoxicillin without and with probenecid.
Time Frame: 24-72 hours after probenecid initiation
Renal clearance of amoxicillin without and with probenecid.
24-72 hours after probenecid initiation
Establishment a population-based pharmacokinetic/pharmacodynamic (PK/PD) model adapted to patient characteristics incorporating covariates of interest for oral amoxicillin in osteoarticular infections, whether or not associated with probenecid
Time Frame: Through study completion, an average of 2 years
Population PK/PD analysis: development and validation of a nonlinear mixed-effects model incorporating relevant covariates and Bayesian estimation of individual parameters.
Through study completion, an average of 2 years
Simulation of dosage regimens to calculate the probabilities of achieving targets based on MICs, and propose an oral amoxicillin dosage regimen-with or without probenecid-for the treatment of osteoarticular infections specific to each pathogen.
Time Frame: Through study completion, an average of 2 years
Monte Carlo simulations to determine the probability of target attainment according to MIC values, dosing regimen, and the presence or absence of probenecid.
Through study completion, an average of 2 years
Assessment of the saturability of amoxicillin absorption at doses of 2 g or 3 g per administration.
Time Frame: Through study completion, an average of 2 years
Comparison of Cmax and AUC0-8h of oral amoxicillin administered at doses of 2 or 3 g.
Through study completion, an average of 2 years
Analysis of adherence of oral amoxicillin monotherapy versus the combination of oral amoxicillin and probenecid.
Time Frame: Through study completion, an average of 2 years
Assessment of adherence
Through study completion, an average of 2 years
Analysis of clinical and biological tolerability of oral amoxicillin monotherapy versus the combination of oral amoxicillin and probenecid.
Time Frame: Through study completion, an average of 2 years
Description of adverse events
Through study completion, an average of 2 years
Description of the complete pharmacokinetic parameters of oral probenecid (500 mg every 8 hours ± 1 hour) in adults with normal renal function treated for Osteoarticular Infections with amoxicillin monotherapy.
Time Frame: 24-72 hours after probenecid initiation
Quantification of probenecid Cmin.
24-72 hours after probenecid initiation
Description of the complete pharmacokinetic parameters of oral probenecid (500 mg every 8 hours ± 1 hour) in adults with normal renal function treated for Osteoarticular Infections with amoxicillin monotherapy.
Time Frame: 24-72 hours after probenecid initiation
Quantification of probenecid Cmax.
24-72 hours after probenecid initiation
Description of the complete pharmacokinetic parameters of oral probenecid (500 mg every 8 hours ± 1 hour) in adults with normal renal function treated for Osteoarticular Infections with amoxicillin monotherapy.
Time Frame: 24-72 hours after probenecid initiation
Quantification of probenecid AUC0-8h.
24-72 hours after probenecid initiation
Description of the complete pharmacokinetic parameters of oral probenecid (500 mg every 8 hours ± 1 hour) in adults with normal renal function treated for Osteoarticular Infections with amoxicillin monotherapy.
Time Frame: 24-72 hours after probenecid initiation
Quantification of probenecid half-life (t1/2).
24-72 hours after probenecid initiation
Description of the complete pharmacokinetic parameters of oral probenecid (500 mg every 8 hours ± 1 hour) in adults with normal renal function treated for Osteoarticular Infections with amoxicillin monotherapy.
Time Frame: 24-72 hours after probenecid initiation
Quantification of probenecid renal clearance.
24-72 hours after probenecid initiation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Souhail Bérénice, AP-HP. Hôpitaux Universitaires Henri Mondor

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2029

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 31, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 11, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 13, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 13, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 11, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2026

More Information

Terms related to this study

Keywords

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • APHP251229
  • 2026-525404-95-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Datas are own by assistance publique - hopitaux de paris, please contact sponsor for further information.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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