Osteomyelitis, Prosthetic Joint Infection, Staphylococcal Infections
Conditions
Keywords
Rifampicin, Levofloxacin, Ciprofloxacin, Population Pharmacokinetic, Biofilm
Brief summary
Staphylococcal osteoarticular infections (OAIs), including prosthetic joint infections and chronic osteomyelitis, represent a major cause of morbidity. Rifampicin is a key bactericidal antibiotic effective against staphylococcal biofilm. However, its pharmacokinetics exhibit substantial inter-individual variability due to complex hepatic metabolism and drug interactions. Currently, no prospective population pharmacokinetic (PopPK) model of rifampicin combined with levofloxacin or ciprofloxacin exists in patients with OAIs. Objectives: The primary objective of this study is to develop a population pharmacokinetic model of oral rifampicin in patients undergoing medico-surgical treatment for staphylococcal osteoarticular infections. Secondary objectives include evaluating the pharmacokinetics of the partner antibiotic (levofloxacin or ciprofloxacin), investigating the correlation between antibiotic exposure metrics (AUC, Cmax, AUC/MIC) and clinical/biological tolerance, and assessing 1-year infection relapse-free survival and resistance emergence. Study Design: Prospective, single-center, interventional study with minimal risks and constraints (RIPH 2) involving 40 participants recruited at the Reference Center for Complex Osteoarticular Infections (CRIOAC).
Detailed description
Study Workflow and Pharmacokinetic Sampling Protocol: Screening and Baseline: Adult patients hospitalized for staphylococcal prosthetic joint infection, chronic osteomyelitis, or native joint infection sensitive to rifampicin and levofloxacin/ciprofloxacin are screened. Clinical, demographic (age, sex, actual and ideal body weight), and biological data (renal function, liver function, serum albumin) are collected. Pharmacokinetic Blood Sampling (12 samples total, 60 mL total volume): Day 2 / Day 3: 5 blood samples (5 mL each) collected pre-dose (t0, fasting) and at 1h, 2h, 4h, and 8h post-dose of rifampicin. Day 8 / Day 10: 5 blood samples (5 mL each) collected pre-dose (t0, fasting) and at 1h, 2h, 4h, and 8h post-dose of rifampicin and partner antibiotic (levofloxacin or ciprofloxacin). Day 28 / Day 32 (1-month follow-up visit): 2 blood samples (5 mL each) collected pre-dose and 2 hours post-dose during outpatient consultation. Pharmacokinetic and Statistical Modeling: Population PK parameters (CL/F, V/F, ka) and inter-individual variability will be estimated using non-linear mixed-effects modeling (NONMEM v7.5). Influence of covariates (age, sex, weight, renal function, serum albumin) will be evaluated. One-Year Follow-up: Clinical follow-up at 12 months post-treatment initiation to evaluate infection relapse, tolerance, and microbiological
Interventions
DRUGThis study focuses on the pharmacokinetics of rifampicin and levofloxacin or ciprofloxacin, which are used in the treatment of osteoarticular infections caused by susceptible staphylococci as part of
This study primarily aims to evaluate the pharmacokinetics of rifampicin, but also of one of the two partner antibiotics, levofloxacin or ciprofloxacin, used in the treatment of staphylococcal osteoarticular infections, whether or not they are present in the body. To this end, 12 blood samples, totaling 60 ml per patient, will be required. These samples will be collected specifically for this clinical research. The remainder of the study will be conducted as part of standard patient care.
Sponsors
Groupe Hospitalier Diaconesses Croix Saint-Simon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient informed about the study and signed written consent obtained * Male or female participant aged 18 years or older * Staphylococcal osteoarticular infection (prosthetic joint infection of hip, knee, or shoulder; chronic osteomyelitis; or native joint infection) susceptible to rifampicin and levofloxacin or ciprofloxacin * Indication for combined medico-surgical treatment of the osteoarticular infection
Exclusion criteria
* Septic shock requiring vasopressor support * Prior rifampicin treatment within 1 month preceding inclusion * Contraindication to rifampicin (known allergy, major drug interaction, or hepatic cirrhosis) * End-stage renal disease on chronic dialysis * Pregnant or breastfeeding woman * Adult patient unable or unfit to give informed consent * Subject deprived of liberty by judicial or administrative decision * Subject not affiliated with or beneficiary of a national social security scheme
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) of Rifampicin | Day 2/3, Day 8/10, and Day 28/32 post-initiation of antibiotic therapy | Maximum observed plasma concentration (Cmax) of oral rifampicin, measured following administration. |
| Apparent Oral Clearance (CL/F) of Rifampicin | Through 4 weeks post-initiation of antibiotic therapy | Apparent oral clearance (CL/F) of rifampicin estimated using a population pharmacokinetic model (NONMEM), including evaluation of inter-individual variability and covariate effects. |
| Apparent Volume of Distribution (V/F) of Rifampicin | Through 4 weeks post-initiation of antibiotic therapy | Apparent volume of distribution (V/F) of rifampicin estimated using a population pharmacokinetic model (NONMEM), including evaluation of inter-individual variability and covariate effects. |
| Area Under the Plasma Concentration-Time Curve (AUC) of Rifampicin | Day 2/3, Day 8/10, and Day 28/32 post-initiation of antibiotic therapy | Area under the plasma concentration-time curve of oral rifampicin, estimated using a population pharmacokinetic non-linear mixed-effects model (NONMEM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Emergence of Rifampicin Resistance at Relapse | 12 months post-initiation of antibiotic therapy | Assessment of rifampicin MIC (determined by E-test) at the time of infection relapse compared to baseline, evaluated according to Cmax/MIC and AUC/MIC ratios. |
| Peak Plasma Concentration (Cmax) of Partner Antibiotic | Day 8/10 and Day 28/32 post-initiation of antibiotic therapy | Maximum observed plasma concentration (Cmax) of the partner antibiotic (levofloxacin or ciprofloxacin) administered in combination with rifampicin. |
| Apparent Clearance (CL/F) of Partner Antibiotic | Day 8/10 and Day 28/32 post-initiation of antibiotic therapy | Apparent clearance (CL/F) of the partner antibiotic (levofloxacin or ciprofloxacin) administered in combination with rifampicin. |
| Trough Plasma Concentration (Cmin) of Partner Antibiotic | Day 8/10 and Day 28/32 post-initiation of antibiotic therapy | Trough plasma concentration (Cmin) of the partner antibiotic (levofloxacin or ciprofloxacin) measured prior to the next scheduled dose. |
| Area Under the Plasma Concentration-Time Curve (AUC) of Partner Antibiotic | Day 8/10 and Day 28/32 post-initiation of antibiotic therapy | Area under the plasma concentration-time curve (AUC) of the partner antibiotic (levofloxacin or ciprofloxacin) administered in combination with rifampicin. |
| Incidence of Clinical and Biological Adverse Events Related to Rifampicin Exposure | Through 4 weeks post-initiation of antibiotic therapy | Proportion of patients experiencing clinical or biological adverse events (recorded in CRF) evaluated in relation to rifampicin Cmax and AUC. |
| Infection Relapse-Free Survival at 1 Year Relative to Rifampicin AUC/MIC Ratio | 12 months post-initiation of antibiotic therapy | Time to staphylococcal infection relapse over a 1-year follow-up period, analyzed in relation to the rifampicin AUC/MIC (Minimum Inhibitory Concentration) ratio. |
Countries
France
Outcome results
None listed