In this Dutch multicenter clinical trial, patients with a staphylococcal prosthetic joint infection, will, in the oral antibiotic treatment phase, be randomized between clindamycin monotherapy and rifampicin / levofloxacin combination therapy. The clinical endpoint will be treatment success one year after finishing antimicrobial treatment.

This is a pragmatic, multicenter, randomized controlled open label trial with a non-inferiority design, comparing the efficacy of rifampicin-based combination antimicrobial therapy versus antimicrobial monotherapy with clindamycin during the oral treatment phase of prosthetic joint infection caused by Staphylococcus spp. The total duration of follow-up will be 15 months from the initial DAIR.

All adult patients, aged 18 years or older, diagnosed and hospitalized with hip- or knee PJI caused by Staphylococcus spp and treated by the DAIR strategy (see Interventions), are eligible for inclusion. The diagnosis of PJI is defined according to the EBJIS 2021 criteria. Exclusion criteria are a contra-indication for rifampicin (due to a resistant strain, a proven allergic reaction, difficult drug-drug-interactions or other contra-indications as listed in the SmPC's of the antibiotics), a contra-indication for levofloxacin and clindamycin and cotrimoxazole and tetracyclines (due to a resistant strain, a proven allergic reaction, difficult drug-drug-interactions or other contra-indications as listed in the SmPC's of the antibiotics), (iii)complicated S. aureus bacteremia or concurrent endocarditis requiring long-term iv antibiotic treatment > 3 weeks , (iv) an infection for which there are no suitable antibiotic choices to permit randomization between the two arms of the trial (for instance, where organisms are only sensitive to intravenous antibiotics), (v) treatment failure before the start of oral therapy, (vi) more than two separate surgical debridements , (vii)an unsatisfactory response to initial treatment leading to continuation of intravenous therapy beyond day 21, (viii) patients with an expected life expectancy <12 months, (ix) patients with a tumor prosthesis , (x) patients receiving chemotherapy for active malignancy in the next 12 months, (xi) patients who are scheduled in advance for chronic suppressive antibiotic therapy after the initial 12 weeks of antibiotic treatment, (xii) The patient is unlikely to comply with trial requirements following randomization in the opinion of the investigator, (xiii) Pregnancy or breastfeeding, (xiv) Patients who are not able to read or communicate in Dutch or English will be excluded from participating in this study.

The main trial endpoint is treatment success 15 months after DAIR (=1 year after finishing antibiotic treatment). Treatment success will be defined as absence of all of the following:

(I) Infection related re-surgery of the initially affected prosthetic joint (II) New antibiotic treatment for suspected or proven infection of the index joint.

(III) Ongoing use of antibiotics for the index joint at the end of follow-up. (IV) Death

Secondary outcomes are (a) Quality of life, measured with the 5-level EQ-5D version (EQ-5D-5L) questionnaires. The EQ-5D-5L is a standardized and validated measure of health status developed by the EuroQol Group to provide a comprehensive generic measure of health for clinical and economic appraisal. This 'quality of life' questionnaire will be scored at the time of randomization, at week 6 after the initial surgical debridement and after 3 months.

(b) Adverse events. The number of SAEs during antimicrobial treatment and follow up ii. The number of switches to a different oral regimen, iii. The number of antibiotic associated AEs (classified by the modified Hartwig and Siegel scale). (c) The number of patients developing Clostridioides difficile infection during treatment. (d) The occurrence of rifampicin resistance in bacteria in patients with a microbiologically confirmed failure of treatment.

Inclusion Criteria:

• >18 years of age
• Confirmed staphylococcal prosthetic hip or knee joint infection according to the current EBJIS 2021 definition of PJI
• The causative agents are (or include) S. aureus or and/or Coagulase-negative staphylococci (CNS)
• Treatment is according to the DAIR-procedure

Exclusion Criteria:

(i) a contra-indication for rifampicin (e.g. a resistant strain or proven allergic reaction or difficult drug-drug-interactions) (ii) complicated S. aureus bacteremia or concurrent endocarditis requiring long-term iv antibiotic treatment > 2 weeks (iii) An infection for which there are no suitable antibiotic choices to permit Randomization between the two arms of the trial (for instance, where organisms are only sensitive to intravenous antibiotics) (iv) treatment failure before the start of oral therapy, (v) an unsatisfactory response to initial treatment leading to continuation of intravenous therapy beyond day 21, (vi) patients with an expected life expectancy <12 months, (vii) patients with a tumor prosthesis (viii) patients receiving chemotherapy for active malignancy in the next 12 months (ix) patients who are scheduled in advance for chronic suppressive antibiotic therapy for >12 months, (x) The patient is unlikely to comply with trial requirements following Randomization in the opinion of the investigator (xi) Pregnancy (xii) Patients who are not able to read or communicate in Dutch or English will be excluded from participating in this study