Introduction: When undergoing total joint replacement surgery, antibiotic against methicillin-resistant staph aureus (MRSA) is vancomycin, which is a frequently used prophylaxis. According to recent research, intraosseous (10) infusions can deliver systemic levels comparable to subjects where intravenous (IV) access was used. Thus, many surgeons started to think about intra osseous infusions as a better option to deliver prophylactic surgical antibiotics. Low-dose intra osseous vancomycin produced concentrations in tissues that were on par with or better than those of systemic administration, according to a prospective randomised research conducted in Australia that compared the local and systemic concentrations of the antibiotic following intra osseous versus intra venous administration. According to the authors, intra osseous route maximises the vancomycin delivery duration, and may lessen the possibility of adverse systemic effects due to the reduced dosage while offering equal or enhanced prophylaxis in total knee replacement (TKR). Even patients with a higher BMI has similar benefits as shown in literature. intra osseous infusions have demonstrated good efficacy in improving antibiotic tissue concentrations at the surgical site with decreased systemic concentrations and reduced infection rates in primary TKR. Park et al. did a study and stated, patients who received antibiotics intraoperatively (IO) had significantly reduced incidence of periprosthetic joint infections (PJI) at 90 days after surgery compared to those subjects who got intra venous antibiotics. Nevertheless, the use of intra osseous vancomycin in total knee replacement (TKR) has not been examined in any research. This randomised prospective single-blinded control study aims to assess the safety and effectiveness of antibiotic distribution during TKR and determine whether intra osseous methods are a practical option for vancomycin administration prior to the surgery.
Rationale of the study supported by cited literature: Rationale of this study is to demonstrate the utility of intra osseous vancomycin over Intra venous Vancomycin in primary TKR with improved local tissue concentration and decreased systemic concentrations. With positive findings, intra osseous route may be considered for alternative procedures for antibiotic delivery.
Hypothesis: decreased serum vancomycin levels is expected when intra osseous vancomycin is administered at both the start of the procedure and also at the end of the procedure. All local tissue samples are expected to have higher concentrations of vancomycin when intraosseous vancomycin is administered.
Research questions: to determine if any difference exists between the concentration of antibiotic administered by intraosseous or oral route in patients undergoing total knee replacement
Aims and Objectives: Aim - To determine the serum and tissue concentration of intra osseous vancomycin and IV Vancomycin in primary TKA Objectives - 1. To measure serum vancomycin levels and compare intra osseous to IV vancomycin at both the start of the procedure and also at the end of the procedure 2. To measure vancomycin levels in local tissue samples and compare intra osseous to IV vancomycin
Detailed methodology: After a patient was randomly assigned to one of the two subject groups, the remaining protocol followed the same steps. During the trial period, both groups receive weight-based preoperative IV cephazolin in order to ensure adequate preoperative antibiotic compliance in the event that the intervention group is not successful. Group 1: Following the incision, the intervention group will get an intra osseous injection of vancomycin into the femur and tibia’s medial condyles (prior to capsulotomy). Subsequently, the surgery will proceed according to the operating surgeon’s protocol. All patients will have the same samples obtained during the operation. Group 2: Before the procedure, an IV injection of vancomycin will be administered to this group, and their levels will be evaluated in a similar manner. Serum vancomycin levels are assessed by drawing blood samples following incision (prior to capsulotomy) and at the beginning of closure. During the case, soft tissue samples are obtained from the following areas: the infrapatellar fat pad, the suprapatellar synovium, the medial and lateral meniscus, and the ACL. Samples of bone are obtained from the distal femur and proximal tibia cuts, as well as intramedullary bone obtained following the establishment of a canal. Vancomycin levels are reported in these samples.
Sample Preparation Samples will be weighted and minced after collection. To digest the materials, 20 mg/ml of collagenase I in PBS will be employed (overnight at 36 °C). Phosphate buffered saline (PBS) will be used to prepare the working solution (1 mg/ml) and stock solution (10 mg/ml) of vancomycin (VANC). The preparation of calibration standard solutions will involve serial dilution using PBS. The calibration standard solutions will have final concentrations of 500, 250, 125, 62.5, 31.25, 15.63, and 7.81 mg/L. Ultimately, a homogenizer is used to homogenise the samples. In the vial containing the digested sample, caffeine is added as an internal control at a final concentration of 2 mg/ml. The various samples will be centrifuged for five minutes at 15,000 rpm, and the supernatant will be collected and filtered before being injected into the HPLC apparatus. Phosphoric acid is used to alter ph. At room temperature, isocratic separation will be performed using a flow rate of 0.36 ml/minute and UV detection at 205 nm. Every sample has a 25-minute run time. Vancomycin’s distinctive elution peak occurs at minute 11, whereas the internal standard, caffeine, has an elution peak at minute 20
Inclusion criteria: Any subject more than 18 years of age who is undergoing a primary TKR for osteoarthritis and given consent for the procedure.
Exclusion criteria: Past knee surgery (including knee scopes), allergy, patients with bleeding disorder and immunocompromised and/or immunosuppressed patients (HIV, Hepatitis B/C, end stage renal disease (ESRD), post-transplant, chemotherapy or radiation therapy, medications which are immunomodulating).
Data analysis plan: Age, surgery date, date of discharge, sex, side operated, Adverse local and systemic reaction, 30-day and 90 day complication, time from antibiotic administration to incision, and surgery time were recorded.
Review of literature: Harper et al demonstrated the efficacy and utility of intraosseous delivery of vancomycin in patients of primary Total hip replacement with improved local tissue concentration and reduced systemic concentration[1] Both increased concentrations in tissues and reduced systemic concentrations of antibiotics are shown in previous studies performed exclusively within total knee replacement patients [[2], [3], [4]]. Studies have shown reduced systemic complications and infection rates due to these concentrations [5,6]. Study done by Young et al demonstrated that deflated torniquet in total knee replacement patients had increased concentrations within the tissues [3]. Administration of antibiotics 1 hour prior to incision has shown to decrease surgical site infections [7]. In patients allergic to penicillin, those with MRSA colonisation and those considered high risk for infection, antibiotic prophylaxis of choice is Vancomycin [7,8]. However, multiple studies has shown that a large population who receive vancomycin as a preoperative antibiotic are underdosed based on their weight or the dose received is incomplete [8,9]. Feder et al did a study and showed that patients who were readmitted for infection concern and diagnosed as PJI recieved vancomycin prophylaxis <30 minutes from incision time [8]. Incomplete administration of the appropriate dose was the cause in majority. Kheir et al did a study and concluded that patients had increase risk of developing MRSA PJI who received a standard 1g of vancomcyin (rather than a weight-based dose) and therefore underdosed [9]. A study by Pai et al showed obese patients are at higher risk for underdosing and thus carry with them higher baseline infection risk [10]. The delivery of vancomycin using IO infiltration has shown statistically significant increase in tissue concentrations above IV in all locations including bone, therefore the risk of underdosing patients will be decreased. [7] The relevance and expected outcome of the proposed study: 1 Decreased serum vancomycin levels is expected to be seen when comparing intra osseous to IV vancomycin at both the start of the procedure and also at the end of the procedure. All local tissue samples are expected to have higher concentrations of vancomycin in the intra osseous group. A significant increase levels is expected to be present within the bone samples. Details of funding sought: non funded project Timelines: data collection - 6 months, data analysis and interpretation - 1.5 years
References [1]Harper KD, Park KJ, Brozovich AA, Sullivan TC, Serpelloni S, Taraballi F, Incavo SJ, Clyburn TA. Otto Aufranc Award: Intraosseous Vancomycin in Total Hip Arthroplasty - Superior Tissue Concentrations and Improved Efficiency. J Arthroplasty. 2023 Jul;38(7S):S11-S15. doi: 10.1016/j.arth.2023.04.028. Epub 2023 Apr 23. PMID: 37088221. [2] Jaimovich DG, Kumar A, Francom S. Evaluation of intraosseous vs intravenous antibiotic levels in a porcine model. Am J Dis Child 1991;145:946e9. [3] Young SW, Zhang M, Freeman JT, Mutu-Grigg J, Pavlou P, Moore GA. Higher tissue concentrations of vancomycin with low-dose intraosseous regional versus systemic prophylaxis in TKA: a randomized trial. Clin Orthop Relat Res 2014;472:57e65. [4] Chin SJ, Moore GA, Zhang M, Clarke HD, Spangehl MJ, Young SW. Intraosseous regional prophylaxis Provides higher tissue concentrations in high BMI patients in total knee arthroplasty: a randomized trial. J Arthroplasty 2018;33(7S):S13e8. [5] Park KJ, Chapleau J, Sullivan TC, Clyburn TA, Incavo SJ. 2021 Chitranjan S. Ranawat Award: intraosseous vancomycin reduces periprosthetic joint infection in primary total knee arthroplasty at 90-day follow-up. Bone Joint J 2021;103-B(6 Supple A):13e7. [6] Harper KD, Lambert BS, Sullivan T, Incavo SJ. Clinical outcome evaluation of intraosseus vancomycin in total knee arthroplasty. Arthroplast Today 2020;6: 220e3. https://doi.org/10.1016/j.artd.2020.02.001. [7] Yusuf E, Croughs P. Vancomycin prophylaxis in prosthetic joint surgery? Clin Microbiol Infect 2020;26:3e5. [8] Feder OI, Yeroushalmi D, Lin CC, Galetta MS, Meftah M, Lajam CM, et al. Incomplete administration of intravenous vancomycin prophylaxis is common and associated with increased infectious complications after primary total hip and knee arthroplasty. J Arthroplasty 2021;36: 2951e6. S14 K.D. Harper et al. / The Journal of Arthroplasty 38 (2023) S11eS15 [9] Kheir MM, Tan TL, Azboy I, Tan DD, Parvizi J. Vancomycin prophylaxis for total joint arthroplasty: incorrectly dosed and has a higher rate of periprosthetic infection than cefazolin. Clin Orthop Relat Res 2017;475: 1767e74. [10] Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy 2007;27:1081e91.
|