We investigated the effects of non-steroidal anti-inflammatory drugs (NSAIDs) with different cyclooxygenase (COX) selectivity on orthopaedic device-related infections (ODRIs) in a rat model. We aimed to measure the impact of NSAID therapy on bone changes, bacterial load, and cytokine levels after treatment with antibiotics. We also compared the effects of long vs short-term celecoxib (a COX-2 inhibitor) treatment on the same outcomes. Skeletally mature female Wistar rats were implanted with Staphylococcus epidermidis- contaminated polyetheretherketone (PEEK) screws in the proximal right tibia and monitored for 7 days. All animals received subcutaneous antibiotics (rifampicin plus cefazolin) for two weeks from day 7 to 21. In phase I of the study, rats were randomly assigned to receive 28 days of oral treatment with acetylsalicylic acid, ibuprofen, celecoxib, or vehicle control. In phase II, an additional group received seven days of celecoxib treatment from day 0 to 7. Bone changes were monitored using in vivo micro-CT and histology. Quantitative bacteriology was performed at euthanasia. Plasma samples were collected to measure cytokine levels on days 0, 6, 20, and 28. Combination antibiotic therapy resulted in treatment success in 85.71% of cases, while the addition of long-term celecoxib treatment reduced it to 45.45%. Long-term celecoxib treatment significantly reduced bone loss (33.85% mean difference [95% CI 14.12–53.58], p=0.0004 on day 6 bone fraction) and periosteal reaction (0.2760 μm mean difference [95% CI 0.2073–0.3448], p<0.0001 on day 14 periosteal thickness) during early infection compared to the control group. Short- term celecoxib treatment showed similar radiological results without a reduction in treatment success (88.9%). No differences in the inflammatory markers were observed. Our findings highlight the potential benefits of short-term use of celecoxib in improving bone fraction during the early post-infection period without impairing the efficacy of antibiotic therapy

Aim. Antibiotic concentration at the infected site is a relevant information to gain knowledge about deep-seated infections. The combination of antibiotic therapy and debridement is often indicated to treat these infections. At University Hospital Basel the most frequently administered antibiotic before debridement is amoxicillin in combination with clavulanic acid. Amoxicillin is a fragile beta-lactam antibiotic that brings multiple challenges for its quantification. As for many sample materials only little material is available, the aim of this work was to establish a sensitive and reliable quantification method for amoxicillin that only requires a small sample mass. We did not quantify clavulanic acid as we focused on the drug with antibiotic action. Method. Usually discarded sample material during debridement was collected and directly frozen. The thawed tissues were prepared using simple protein precipitation and manual homogenization with micro pestles followed by a matrix cleanup with online solid-phase extraction. Separation was performed by HPLC followed by heated electrospray ionization and tandem mass spectrometry. Results. During method development, amoxicillin showed partial formation of a covalent methanol adduct when performing protein precipitation. Furthermore, multiple in-source products of amoxicillin during ionization could be observed. Adding an aqueous buffer to the samples before protein precipitation and summing up the signals of amoxicillin and its in-source acetonitrile-sodium-adduct led to successful method validation for a calibration range of 1–51 mg/kg using 10 mg of each tissue sample. The imprecision was < 8% over the entire concentration range and the bias was ≤ 10 %. The quantitative matrix effect was < 6 % in six different tissue samples. Until now we measured amoxicillin in samples from nine patients with prosthetic joint infection, bursitis, or an abscess who obtained amoxicillin between 5 hours and 15 minutes before sampling and found concentrations between 1.4 and 35 mg/kg. Conclusions. With this method, we developed a fast, simple, and sensitive quantification assay for amoxicillin in tissue samples with little material that can now be applied to different study samples

Aim. In this study we investigated the effects of non-steroidal anti-inflammatory drugs (NSAIDs) with different cyclooxygenase (COX) selectivity on orthopaedic device-related infections (ODRIs) in a rat model. Specifically, we aimed to measure the impact of NSAID therapy on bone changes, bacterial load, and cytokine levels after treatment with antibiotics. In addition, we compared the effects of long vs short-term celecoxib (a COX-2 inhibitor) treatment on the same outcomes. Method. Skeletally mature female Wistar rats were implanted with Staphylococcus epidermidis-contaminated polyetheretherketone (PEEK) screws (1.5 × 10. 6. CFU per screw) in the proximal right tibia and monitored for 7 days. All animals received subcutaneous antibiotics (rifampicin plus cefazolin) for two weeks from day 7 to 21. In phase I of the study, rats were randomly assigned to receive 28 days of oral treatment with acetylsalicylic acid, ibuprofen, celecoxib, or vehicle control. In phase II, an additional group received seven days of celecoxib treatment from day 0 to 7. After implantation, bone changes were monitored using in vivo micro-CT and histology. Quantitative bacteriology was performed at euthanasia. Plasma samples were collected to measure cytokine levels at four time points (day 0, 6, 20, and 28). Results. The combination of antibiotic therapy resulted in treatment success in 85.71% of cases, while the addition of long-term celecoxib treatment reduced it to 45.45%. Long-term celecoxib treatment significantly reduced bone loss (33.85% mean difference [95% CI 14.12–53.58], p=0.0004 on day 6 bone fraction) and periosteal reaction (0.2760 μm mean difference [95% CI 0.2073–0.3448], p<0.0001 on day 14 periosteal thickness) during the early post-infection period compared to the control group. Short-term celecoxib treatment showed similar radiological results, however, there was no significant reduction in treatment success in the celecoxib group (88.9%). No differences in the selected inflammatory markers were observed. Conclusion. Our findings highlight the potential benefits of short-term use of celecoxib in improving bone fraction during the early post-infection period without impairing the efficacy of antibiotic therapy. This study suggests that celecoxib may be a useful addition to the multimodal approach to pain management in orthopaedic device-related infections

Aim. Treatment of chronic prosthetic joint infection (PJI) combines exchange arthroplasty and effective antibiotic therapy. Staphylococci are the most frequent microorganism isolated in PJIs, with resistance to methicillin found in 15–50% of the cases. Data from randomized trials on treatment of methicillin-resistant staphylococci are lacking and the choice of antibiotic(s) and recommendations vary according to authors. To date, combination therapy including vancomycin is the treatment of choice. Minocycline, a cyclin antibiotic, is naturally effective against methicillin-resistant staphylococci. We use this antibiotic since many years in combination with vancomycin for the treatment of multi-drug resistant staphylococcal bone and joint infections. The aim of this study is to analyze the outcome of patients treated with combination antibiotic therapy including minocycline for the treatment of chronic methicillin-resistant staphylococcal PJI. Method. We conducted a cohort study between 2004 and 2014 in our referral center for bone and joint infections. Data were extracted from the prospective database. All the patients receiving an initial combination therapy including at least 4 weeks of minocycline, given orally, and another IV antibiotic, usually high-dose continuous IV vancomycin, for chronic MR staphylococcal PJI and who underwent one or two stage exchange arthroplasty, were included. They were followed prospectively for at least 2 years. Results. We included 42 patients: 26 patients (62%) had one-stage, 16 patients (38%) had two stage exchange arthroplasty. Median duration of IV and total antibiotic therapy was 42 [40–44] days and 84 [84–88] days, respectively. 41 patients (98%) received vancomycin as associated initial therapy. Thirty-six patients received 100mgx3 per day of minocycline. Six received >300mg per day because of low serum concentrations. Median follow-up was 48 months (IQR 27–58). Survival rate without infection was 84,5% at 2 years, 70.2% at 6 years. Four patients reported adverse events due to minocycline: one had grade 4 thrombopenia leading to minocycline withdrawal, two had grade 2 liver toxicity. One patient had grade 1 nauseas. Two patients with MR Staphylococcus epidermidis knee arthroplasty experienced relapse. Three patients with hip arthroplasty infection developed a new infection within 2 year due to MSSA, Pseudomonas aeruginosa, and plurimicrobial for the last one. Three further patients developed a new infection 3 (n=2) and 4 years later. They were all acute haematogenous infections. Conclusions. Our data support the use of minocycline combination therapy with high-dose IV vancomycin for the treatment of chronic PJI due to methicillin-resistant Staphylococci