Rifabutin Versus Rifampicin for Treatment of Staphylococcal PJI Treated With DAIR

Study Overview
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Brief Summary
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Rifampicin, is key in the treatment of staphylococcal PJIs. Rifabutin has a better profile of tolerance than rifampicin regarding the risk of interaction with concomitant medications and liver disorders. The hypothesis is that rifabutin may be an alternative antibiotic option as efficient as rifampicin for the treatment of staphylococcal PJIs, with a better safety profile. The investigator aim to demonstrate the non-inferiority of rifabutin as compared with rifampicin prescribed in combination treatment for PJIs.

Official Title
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Rifabutin Versus Rifampicin for Treatment of Staphylococcal Prosthetic Joint Infection Treated With Debridement, Antibiotics and Implant Retention (DAIR Strategy): a Multicenter Randomized, Open-label, Non-inferiority Trial

Conditions
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Prosthetic Infection

Intervention / Treatment
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* Drug: Rifabutin
* Drug: Rifampicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hip or knee Prosthetic joint infection treated by debridement, antibiotic therapy initiation and retention of prothesis (DAIR strategy) Infected with at least one of the following microorganisms: Staphylococcus aureus Coagulase-negative staphylococci Microorganisms susceptible to rifampicin and at least one other antibiotic suitable for the treatment of PJI (e.g., penicillin, fluoroquinolone, (doxy/mino)cycline, oxazolidinone, cotrimoxazole, daptomycin, glycopeptide, macrolide, fusidic acid), regardless of sensitivity to methicillin. Age ≥ 18 years At least 2 days of appropriate (i.e., covering pathogen(s) identified in the intraoperative samples) empirical agents are needed. Pre-randomization antimicrobial therapy could be: flucloxacillin, oxacillin, vancomycin, daptomycin. β-lactam plus β-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, teicoplanin, ceftaroline, ceftobiprole. Signed Inform consent Patient having the rights to French social insurance For women of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile and excluding oestroprogestative-based contraception, any effective contraceptive: vasectomy (for men), intrauterine device copper, feminine sterilization, condom, sexual abstinence is required. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause Exclusion Criteria: Suspicion of reduce absorption of oral treatment due to abdominal disorder Known or suspected malabsorption (imperfect absorption of food material by the small intestine) Polymicrobial infection due to other than staphylococcus species susceptible to rifampicin Known or suspected allergy to rifabutin and/or rifampicin Diagnosis of endocarditis associated to PJI Renal transplant or Chronic kidney disease with an eGFR of less than 30ml/min/1.73m² Other Solid Organ Transplant Liver cirrhosis, Child-Pugh score C Any other concomitant infection which required a prolonged course of intravenous antibiotic therapy Oestroprogestative-based contraception Oral anticoagulant drugs Other drug-drug interaction that contraindicated rifampicin or rifabutin Porphyria Unable to take oral treatment Receive empirical postoperative antibiotic treatment by rifampicin or rifabutin prior to randomization Pregnancy or lactating women Curator or guardianship or patient placed under judicial protection Participation in other interventional research during the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RIFAMPICIN<br>Patient with staphylococcal PJI, treated with DAIR strategy, and randomized in the control group will receive rifampicin in association with another antibiotic except rifabutin, as-per recommendations for 12 weeks. | Drug: Rifampicin<br>* 10 mg/kg per day (range 600 mg to 1,200 mg) rifampicin tablet in 1 daily dose for 12 weeks with a companion treatment<br>|
| Experimental: RIFABUTIN<br>Patient with staphylococcal PJI treated with DAIR strategy, and randomized in the experimental group, will receive rifabutin in association with another antibiotic except rifampicin, as-per recommendations for 12 weeks. | Drug: Rifabutin<br>* 2 tablets of 150 mg per day rifabutin tablet daily for 12 weeks in 1 administration with a companion treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | Treatment failure defined as one of following events: The need for any further surgical procedure - i.e. implants removal, implants exchange or amputation; And/or PJI related death; And/or use of suppressive antibiotic therapy that was not planned before randomization | At one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of serious adverse events (SAEs), including death (i.e. all cause) | Proportion of patient which are free from SAEs occurrence, as defined by: -Patients who completed the entire 12 weeks duration of antibiotic treatment planned initially and; xWho did not experience grade 3-4 adverse events, including death, regardless of the link with antibiotic therapy; xWho did not experience adverse events which led to either to: Reduce the dosage or split the treatment to two take/day; Or stop any component of the antibiotic treatment. | At the end of 12 weeks duration of antibiotic treatment planned | 
| Occurrence of any adverse event that could be related to rifampicin or rifabutin | Number and rate of patients in each arm who experiences: Liver cytolysis (>=2N for ALT AND/OR AST) Acute Kidney failure as defined by serum creatinine increase in KDIGO Digestive symptoms, including diarrhea Who required a modification of antibiotic dosage during the 12 weeks' period of antibiotic treatment Uveitis/ophthalmologic disorder Neurological disorder | At the end of 12 weeks duration of antibiotic treatment planned | 
| Proportion of patients from each arm who will complete the 12-week duration of rifampicin/rifabutin treatment, early termination of the planned 12 weeks' period of antibiotics | Early termination rate will be measured in each arm, as the number of patients having stopped rifampicin or rifabutin before the planned 12 weeks period over the total number of patients enrolled in the studied arm. | At the end of 12 weeks duration of antibiotic treatment planned | 
| Adherence to antibiotics regimen | Adherence rate to medication will be measured as the number of days on which all doses were missed over the number of days of planned antibiotic therapy. Patients enrolled in the study will have to fill their pill count in a daily notebook. | At the end of 12 weeks duration of antibiotic treatment planned | 
| Quality of life, as evaluated by EQ 5D 3L questionnaire | Quality of life, as evaluated by the use EQ 5D 3L auto-questionnaire as used in previous randomized clinical trial on bone and joint infection | At the end of the study follow up, an average of 24 months | 
| Functional prognosis using Oxford questionnaire evolution according to location of PJI | Oxford Scores as used in previous randomized clinical trial on bone and joint infection | At the end of the study follow up, an average of 24 months | 
| Long term efficacy of rifampicin and rifabutin treatment | Long term efficacy: treatment failure, as defined for primary outcome, at 24 months | At the end of the study follow up, an average of 24 months |