The Impact of Pathogen Sensitivity to Antibiotics Loaded in Cement on the Number of Revisions and Costs in the Treatment of Periprosthetic Knee Infection

The Impact of Pathogen Sensitivity to Antibiotics Loaded in Cement on the Number of Revisions and Costs in the Treatment of Periprosthetic Knee Infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Impact of Pathogen Sensitivity to Antibiotics Loaded in Cement on the Number of Revisions and Costs in the Treatment of Periprosthetic Knee Infection CUMHUR DENIZ DAVULCU, METE OZER, MUHAMMED YUSUF AFACAN, CANSU ELIBOLLAR, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5270598/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Dec, 2024 Read the published version in European Journal of Orthopaedic Surgery & Traumatology → Version 1 posted 7 You are reading this latest preprint version Abstract Objective: This study aims to evaluate the impact of the pathogen's sensitivity to the loaded antibiotics on infection resolution, the number of revisions, and the associated costs in patients undergoing revision total knee arthroplasty (rTKA) due to PJI. Material and Methods: We reviewed the treatment and follow-up processes of 61 patients who underwent rTKA for late-stage PJI following primary total knee arthroplasty (pTKA) in our clinic. The study included 11 patients in the resistant group and 50 in the sensitive group in line with the power analysis results. Patients' demographic characteristics and comorbidities were recorded. All patients received dual antibiotic-loaded cement. Microbiological examinations of patients were analyzed, and the number of revision surgeries each patient underwent was determined. We analyzed all surgeries related to infection treatment, including open irrigation, debridement, polyethylene exchange, implant extractions, antibiotic-loaded cement spacer placements, spacer changes, and debridements, and the implantation of revision prostheses, including tumor prostheses. The total number of surgeries each patient underwent was recorded. We also reviewed hospital system records of total protocol costs during patient admissions. Results: Of 61 patients undergoing revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI), 11 had antibiotic-resistant infections and 50 had antibiotic-sensitive infections. The groups had similar demographics. Polymicrobial infections were more frequent in the resistant group (p=0.017), with all resistant cases showing gentamicin resistance and two showing teicoplanin resistance. The resistant group required more surgeries (average 3.91±2.7 vs. 2.34±1.3, p=0.043) compared to the sensitive group, with teicoplanin resistance doubling revision surgeries (p=0.005). Costs were similar between groups, averaging $6279.74. Gram-negative infections led to more revisions (p=0.013). Polymicrobial infections did not significantly affect the number of surgeries or costs compared to single-strain infections. Conclusions: Our study demonstrates that in rTKA surgeries using dual antibiotic-loaded bone cement, infections caused by antibiotic-resistant microorganisms are more challenging and time-consuming to treat. This underscores the necessity of exploring new methods to enhance local efficacy by loading cement with antibiotics based on specific pathogen culture and sensitivity results, while also providing clinical evidence of the effectiveness of current treatment methods against sensitive microorganisms. Pathogen sensitivity antibiotic-loaded cement infection resolution revision total knee arthroplasty periprosthetic joint infection antibiotic resistance polymicrobial infections Gram-negative infections surgical revisions treatment costs gentamicin resistance teicoplanin resistance dual antibiotic-loaded bone cement Figures Figure 1 Figure 2 INTRODUCTION Primary total knee arthroplasty (pTKA) has become a highly effective procedure for treating knee osteoarthritis, significantly improving patients' functional capacity and quality of life. With the projected annual volume of pTKA cases expected to rise between 1.3 to 3.5 million, the demand for revision total knee arthroplasty (rTKA) is also predicted to surge by approximately 300% by 2030, primarily due to periprosthetic joint infections (PJIs) [ 1 , 2 ]. Periprosthetic knee infections present significant challenges, often necessitating complex and costly revision surgeries. The standard treatment protocol for late PJIs involves a two-stage revision approach. The initial stage includes removing the infected implant, performing extensive debridement, and placing an antibiotic-loaded cement spacer [ 3 , 4 ]. This spacer not only helps maintain the joint space but also delivers high local concentrations of antibiotics directly to the infection site, which is crucial for effective infection control [ 1 , 5 – 7 ]. According to a study by Lim et al. (2009), the two-stage reimplantation protocol showed a high rate of treatment failure in patients with infections caused by resistant microorganisms, highlighting the importance of selecting effective antibiotic regimens [ 8 ]. Although the gold standard method is reported to be two-stage revision surgery, with appropriate patient selection, one-stage revision has also been reported to be associated with successful results comparable to two-stage procedures [ 9 ]. Antibiotic-loaded bone cement (ALBC) has been a pivotal element in orthopedic surgery for both prophylactic and therapeutic purposes. Its introduction by Buchholz and Engelbrecht in the 1970s marked a significant advancement, as it allowed for high local antibiotic concentrations that surpass those achievable through systemic administration alone​​ [ 1 ]. This innovation has proven particularly valuable in the context of PJIs, where high local antibiotic concentrations are essential to combat the infection effectively [ 5 , 7 , 10 ]. Despite the widespread use of ALBC, there remains ongoing debate about its optimal application, particularly concerning the selection of appropriate antibiotics and their dosages. Studies have shown varying outcomes regarding the efficacy of ALBC in preventing and treating PJIs. Some research highlights the benefits of using dual or multiple antibiotic-loaded spacers, which can enhance the antimicrobial spectrum and reduce the risk of developing resistant bacterial strains [ 2 , 6 , 7 , 10 , 11 ]. However, concerns about the potential for antibiotic resistance and the economic implications of ALBC use persist, necessitating further investigation into cost-effective and clinically effective strategies [ 1 , 5 , 12 ]. The objective of this study is to evaluate the impact of the pathogen's sensitivity to antibiotics loaded in cement on infection management, the number of revision surgeries required, and the overall cost analysis in patients undergoing rTKA due to PJIs. By analyzing the outcomes of patients treated with antibiotic-loaded cement spacers, we aim to provide insights into optimizing treatment protocols and improving patient outcomes in the context of periprosthetic knee infections​. MATERIAL AND METHODS In our clinic, the treatment and follow-up processes of 61 patients who underwent revision total knee arthroplasty due to late periprosthetic joint infection (PJI) after primary total knee arthroplasty were examined. When deciding on the diagnosis of PJI, the diagnostic criteria of the Musculoskeletal Infection Society were used. Criteria include 2 positive cultures with the same microorganism, sinus tract associated with the joint, serum c-reactive protein (CRP), sedimentation, d-dimer values, synovial fluid analysis and peroperative findings [ 4 ]. Synovial fluid samples were repeated at 2-week intervals in cases where the diagnostic criteria were doubtful, due to continued clinical suspicion. In antibiogram studies of the infective agent produced in accordance with the diagnostic criteria, sensitivity to teicoplanin or gentamicin enabled grouping. Patients were grouped based on the sensivity of their isolated pathogens to antibiotics (teicoplanin and gentamicin) loaded in the cement. We sought resistance to at least one antibiotic. In the resistant group, all pathogens were resistant to gentamicin, and two were additionally resistant to teicoplanin in antibiogram examinitions. Conversely, in the susceptible group, all pathogens were sensitive to both antibiotics. 11 patients were included in the resistant group, and 50 patients were included in the sensitive group. The demographic characteristics and comorbidities of the patients were recorded. It was observed that all patients had dual (by adding teicoplanin to antibiotic cement with gentamicin) antibiotic-loaded cement. Microbiological examinations of the patients were screened. Patients who underwent revision surgeries due to late PJI were included in the study. Patients who underwent surgery due to early PJI or could not complete their follow-up were not included. All surgeries performed for infection management, including single-stage or two-stage procedures, implant extraction, and antibiotic-loaded cement spacer application, cement spacer exchange and debridement surgery, revision prostheses (including tumor prostheses) implantations, were individually analyzed, and the number of revision surgeries performed for each patient throughout the process was examined. In our clinic, we generally prefer a two-stage revision procedure for the treatment of PJE. However, single-stage revision surgery may be preferred in selected patients. Single-stage revision is considered in patients with antibiotic-sensitive microorganisms in preoperative cultures, absence of sepsis signs, uninfected neurovascular bundles, good soft tissue condition and no soft tissue infections hindering wound closure [ 9 ]. Whether the causative organism was detected in the joint samples taken before surgery was screened. The total cost amounts recorded in the hospital system during the patients' admissions were examined. Costs were calculated in dollars based on the exchange rate of the period and compared. Sensitive and resistant groups were compared. The relationship between gram staining characteristics, the presence of polymicrobial agents, patient factors, the number of surgeries, and costs were examined. STATISTICAL ANALYSIS Statistical analyses were performed using SPSS 26.0 (Armonk, New York: IBM Corp.) software package. The sample size was calculated using G*Power 3.1 software, determining that 11 cases in the antibiotic-resistant group and 40 in the sensitive group were sufficient to achieve 80% power (α = 0.05). Descriptive statistics for continuous variables were expressed as mean (Mean), standard deviation (SD), median, while categorical variables were expressed as frequency (n) and percentage (%). Histogram, Kolmogorov-Smirnov, or Shapiro-Wilk tests were used to assess whether continuous variables followed a normal distribution, and Leven’s t-test was used to evaluate group homogeneities. T-test was used for quantitative comparisons between groups, and Mann-Whitney U test was used for categorical comparisons. A 5% of Type 1 error (p < 0.05) was used for statistical significance in all analyses. RESULTS The follow-up processes of 61 patients were examined. It was observed that the groups were homogeneously distributed. The demographic characteristics of the patients, gram staining characteristics of the isolated causative microorganism, polymicrobial infection rate in the groups, antibiotic resistances, number of surgeries, and total costs are shown in Table 1. Figure 1 depicts the distribution of causative microorganisms in our PJI cases. The demographic data of the groups were found to be similar. It was observed that factors related to age, gender, and number of comorbidities did not affect the number of surgeries and antibiotic resistance. Polymicrobial agents were more frequently encountered in the resistant group (p:0.017). Resistance to gentamicin was present in all cases in the resistant group. Resistance to teicoplanin was observed in only 2 cases. It was found that the number of surgeries in the resistant group was higher than in the sensitive group (p:0.043) (Figure 2). The presence of teicoplanin resistance doubled the number of revision surgeries required (p:0.005). Antibiotic resistance did not affect the number of surgeries in groups where single strain or polymicrobial agents were detected. Similar total costs were observed in both groups. The average cost in the entire cohort was $6279.74. The gram staining characteristic of the causative agent was unrelated to age, number of comorbidities, and cost. However, it was found that in patients infected with gram-negative agents, the number of revisions required for infection management was significantly higher (p:0.013) (Table 2). The presence of polymicrobial agents did not cause a change in age, number of comorbidities, number of surgeries, and cost compared to the group where a single strain was detected. However, the number of surgeries and costs were relatively higher in the polymicrobial group. (Table 3) In the preoperative sampling, it was observed that the causative agent could not be cultured in only one case in the resistant group. DISCUSSION Our study highlights the significant challenges posed by antibiotic resistant pathogens in PJIs after TKA. Patients in the resistant group had more and more complex surgeries than those with antibiotic sensitive infections, 3.91 vs 2.34 on average. We believe that the high average of 3.91 surgeries in the resistant group, indicating a higher failure rate, may be attributed to the resistance of the causative microorganisms to the antibiotics loaded in the cement. Presence of polymicrobial infections and gram-negative bacteria increased the number of surgeries. Despite similar demographics and comorbidities between the two groups, the higher revision rates and longer treatment duration for resistant infections shows the need for pathogen specific antibiotic in ALBC. These results highlight the need to optimize treatment protocols to get better infection resolution and reduce the economic burden of resistant PJIs. Our findings are consistent with previous research indicating the complexities of managing PJIs, particularly those caused by resistant organisms [7,11]. Studies have shown that antibiotic-loaded bone cement is effective in reducing infection rates in both primary and revision arthroplasty [1,13]. However, the appropriate selection and concentration of antibiotics are crucial for effective treatment [11,14]. The increased surgical burden associated with resistant infections observed in our study aligns with reports highlighting the challenges and higher complication rates in such cases [11,13]. The study's finding that antibiotic-resistant microorganisms, particularly those resistant to gentamicin and teicoplanin, result in a higher number of revision surgeries is consistent with previous literature. Perry et al. [15] reported that patients referred with an antibiotic knee spacer for PJI have a high rate of positive cultures at the time of re-debridement, with Staphylococcus aureus being the most common organism identified. This aligns with our observation of gentamicin resistance in all cases within the resistant group and the higher number of surgeries required. The presence of polymicrobial infections was significantly higher in the resistant group, and although this did not directly correlate with increased surgical interventions, it did contribute to the complexity of treatment. Shahpari et. al. [16] noted the challenges of using antibiotic-impregnated cement spacers in treating infected joint replacements, emphasizing the need for high local antibiotic concentrations to combat such infections effectively. Thus, the systemic antibiotic adverse effects may also be reduced. Furthermore, the study's observation that the presence of gram-negative organisms significantly increases the number of required revisions corroborates the findings of Bos et al. [17], who highlighted the impact of pathogen type on the success of revision surgeries using antibiotic-loaded bone cement. The increased number of revisions for gram-negative infections underscores the necessity for targeted antibiotic strategies in these cases. The study underscores the importance of antibiotic selection based on specific pathogen culture and sensitivity results to enhance the efficacy of local antibiotic delivery. Anagnostakos et. al. [18] discussed the need for optimal antibiotic impregnation in bone cement to achieve high local antibiotic concentrations and improve infection control rates. The effectiveness of dual antibiotic-loaded bone cement in our study aligns with the findings of Sanz-Ruiz et al. [19], who reported that dual antibiotic-loaded bone cement is more effective and cost-efficient in preventing PJI compared to single antibiotic-loaded bone cement. Our findings are consistent with those findings that the optimal dual antibiotic impregnation may show better results. Martos et al. [20] reviewed the principles and limitations of local antibiotic delivery using ALBC, emphasizing that high local antimicrobial concentrations are needed to overcome the recalcitrance of PJIs. Those findings support the necessity for effective antibiotic delivery systems to achieve high local concentrations, reducing the risk of antimicrobial resistance. This aligns with our study's emphasis on tailoring antibiotic-loaded cements based on specific pathogen sensitivity to improve outcomes. Gandhi et. al. [21] highlighted the controversy surrounding the use of ALBC in primary and revision joint arthroplasty. While the prophylactic use in primary TKA remains debated, its routine use in revision procedures, especially in septic revisions, is well-supported. This supports our approach of using dual antibiotic-loaded cement in rTKA for managing PJIs. The study by Kim et al. [22] highlights the effectiveness of antifungal-impregnated cement spacers in treating chronic fungal PJIs after TKA, with no recurrent infections over a mean follow-up of 66 months. This supports our findings on the necessity of pathogen-specific antimicrobial strategies to manage complex PJIs, reduce revision surgeries, and enhance patient outcomes through targeted antibiotic-loaded bone cement. Another important aspect of Kim’s study [22] is Amphotericin B was heat stable and available in powder form, making it preferable to other antifungal agents. Sometimes, very rare organisms can cause PJIs. For instance, a case report documented an infection caused by SDSD in a farmer identified using VITEK MS [3]. In such rare instances, techniques like VITEK MS become especially important to accurately diagnose the microorganism, emphasizing the need for pathogen-specific antibiotic loading and tailored treatment approaches to effectively manage these uncommon infections [23,24]. The economic analysis revealed similar total costs between the resistant and sensitive groups, with an average cost of $6279.74 for the entire cohort. This finding suggests that while antibiotic resistance increases the number of surgical interventions, the overall treatment costs remain comparable. This is in line with the study by Hoskins et al. [25], which found no significant cost difference between ALBC and plain bone cement in preventing infections. Despite the supporting literature for the use of ALBC in PJI, Hao-Qian Li et. al. conducted a meta-analysis on the prophylactic use of ALBC in primary TKA, finding no significant difference in peri-prosthetic infection rates compared to plain cement. However, the analysis noted that ALBC was associated with longer hospital stays and increased risks of acute renal failure and readmission [26]. These findings highlight the need for careful consideration of ALBC's benefits and potential risks, particularly in the context of prophylaxis versus treatment. Concluding from our study that loading merely the pathogen’s susceptible antibiotic to the cement with controlled and appropriate dosage may prevent such negative effects. This study has several limitations, including its retrospective nature and potential selection bias. The sample size, while adequate according to the power analysis, may not fully represent the broader patient population undergoing TKA revisions. Additionally, despite minimizing the differences in patients, variations in surgical techniques and post-operative care could influence the outcomes. Future research should focus on prospective, randomized controlled trials to validate these findings and explore the long-term benefits of specific antibiotic regimens in ALBC. CONCLUSION In conclusion, our study demonstrates that infections caused by antibiotic-resistant microorganisms pose significant challenges in the treatment of PJI following rTKA. The necessity for multiple surgical interventions in resistant cases highlights the importance of selecting appropriate antibiotics based on pathogen sensitivity. The clinical implications of our findings are significant, advocating for the use of pathogen-specific antibiotics in ALBC to improve infection control outcomes and to reduce the economic impact of these infections on healthcare systems. Future research should focus on developing advanced antibiotic delivery systems and exploring alternative antibiotics to enhance treatment outcomes for resistant infections. These findings provide valuable clinical evidence supporting the current treatment methods for PJI and emphasize the need for ongoing improvements in antibiotic-loaded bone cement formulations. There is also a need for studies exploring novel antimicrobials and combination therapies to enhance infection control strategies. Additionally, improving diagnostic tools to identify infections early and accurately will allow for timely and appropriate interventions. Declarations Compliance with ethical standards Conflict of interests All the authors declare no conflict of interest. Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. Ethical approval Application Date: 26.03.2024 Approval Number: E-83045809-604.01-1001730 All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical committee approved the study. Funding None. Author Contribution All authors contributed to the study conception and design. All authors read and approved the final manuscript.Authors' contributions:C.D.D. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.O. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.Y.A. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.C.E. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.G.K. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.C.U. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.All authors read and approved the final manuscript.Availability of data and material: The data that support the findings of this study are available from the corresponding author, C.D.D. upon reasonable request. 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(p: p-value) Variable Sensitive Group Resistant Group All Patients p Number of Patients (N) 50 11 61 - Mean Age 67.52 ± 10.2 69 ± 5.44 67.79 (38-87) 0.504 Gender (M/F) 10 / 40 3/8 13 / 48 0.78 Number of Comorbidities 1.32 ± 1.58 0.64 ± 1.28 1.2 ± 1.54 0.18 Gram Staining (-/+) 5 / 45 2 / 11 7 / 61 0.46 Polymicrobial Infection (%) 21% 11% 32% 0.017 Teicoplanin Resistance (N) 0 2 2 - Gentamicin Resistance (N) 0 11 11 - Number of Surgeries 2.34 ± 1.3 3.91 ± 2.7 2.62 (1-9) 0.043 Teicoplanin Sensitivity and Number of Surgeries 2.46 ± 1.52 5.5 ± 3.53 - 0.005 Number of Single Strain Infection Surgeries 2.24 ± 1.38 4 ±3.36 2.41 ± 1.68 0.37 Number of Polymicrobial Infection Surgeries 2.62 ± 1.04 3.86 ± 2.54 3.05 ± 1.76 0.12 Number of Gram-Negative Infection Surgeries 4 ± 2.23 4.5 ± 2.12 4.14 ± 2.03 0.79 Number of Gram-Positive Infection Surgeries 2.16 ± 1.04 3.78 ± 2.9 2.43 ± 1.61 0.13 Cost ($) 5553.46 ± 4773.31 9581.02 ± 11009.96 6279.74 ± 6422.47 (1254.52-41457.64) 0.26 Table 2: Comparative data based on the gram staining characteristic of the agent. (p: p-value) Variable Gram (-) Gram (+) p Age 66.14 ± 9.58 67.77 ± 9.53 0.67 Number of Comorbidities 1.29 ± 1.49 1.21 ± 1.53 0.9 Number of Surgeries 4.14 ± 2.03 2.43 ± 1.61 0.013 Cost ($) 7024.06 ± 3983.66 6235.24 ± 6747.59 0.76 Table 3: Effects of the presence of single or polymicrobial agents. (p: p-value) Variable Mono-microbial Polymicrobial p Age 66.98 ± 10.73 69.45 ± 6.32 0.26 Number of Comorbidities 1.07 ± 1.4 1.45 ± 1.82 0.37 Number of Surgeries 2.41± 1.68 3.05 ± 1.76 0.17 Cost ($) 5966.03 ± 4985.90 6922.84 ± 8790.59 0.58 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Dec, 2024 Read the published version in European Journal of Orthopaedic Surgery & Traumatology → Version 1 posted Editorial decision: Revision requested 21 Nov, 2024 Reviews received at journal 11 Nov, 2024 Reviewers agreed at journal 03 Nov, 2024 Reviewers invited by journal 31 Oct, 2024 Editor assigned by journal 18 Oct, 2024 Submission checks completed at journal 18 Oct, 2024 First submitted to journal 15 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5270598","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":367766077,"identity":"11b077d2-30a7-401c-ada6-3fd35da20165","order_by":0,"name":"CUMHUR DENIZ DAVULCU","email":"data:image/png;base64,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","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"CUMHUR","middleName":"DENIZ","lastName":"DAVULCU","suffix":""},{"id":367766078,"identity":"1483cd68-50e1-4d40-bc15-6f7ac47a6ce6","order_by":1,"name":"METE OZER","email":"","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"METE","middleName":"","lastName":"OZER","suffix":""},{"id":367766079,"identity":"84dd1e00-95ad-44f9-b770-fe44612ecaf8","order_by":2,"name":"MUHAMMED YUSUF AFACAN","email":"","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"MUHAMMED","middleName":"YUSUF","lastName":"AFACAN","suffix":""},{"id":367766080,"identity":"a934055e-835b-44d1-89f1-6fc7119172ba","order_by":3,"name":"CANSU ELIBOLLAR","email":"","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"CANSU","middleName":"","lastName":"ELIBOLLAR","suffix":""},{"id":367766081,"identity":"53cb8668-cd7d-49ee-ad06-4334b51eceea","order_by":4,"name":"GOKHAN KAYNAK","email":"","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"GOKHAN","middleName":"","lastName":"KAYNAK","suffix":""},{"id":367766082,"identity":"89f99e67-a453-4b6f-a5f0-8d58c198fadd","order_by":5,"name":"MEHMET CAN UNLU","email":"","orcid":"","institution":"Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Orthopaedics and Traumatology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"MEHMET","middleName":"CAN","lastName":"UNLU","suffix":""}],"badges":[],"createdAt":"2024-10-15 17:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5270598/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5270598/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00590-024-04166-4","type":"published","date":"2024-12-21T15:57:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":67355886,"identity":"321c8694-7db7-4d10-966a-a39bdc3ee365","added_by":"auto","created_at":"2024-10-24 05:07:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":557410,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Causative Microorganisms in PJI Cases\u003c/p\u003e\n\u003cp\u003eThis bar chart shows the frequency of various microorganisms isolated from patients with periprosthetic joint infections (PJI). Methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) were the most common pathogens. The chart includes a wide range of bacteria and fungi, illustrating the diversity of infectious agents encountered in PJI cases.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5270598/v1/5941737ee3abbb8b0596f1d9.png"},{"id":67357071,"identity":"09022fec-aff1-4b83-8c5b-d942a4471da5","added_by":"auto","created_at":"2024-10-24 05:23:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":411771,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the Number of Surgeries between Resistant and Sensitive Groups\u003c/p\u003e\n\u003cp\u003eThe figure displays the distribution of the number of surgeries required in patients with periprosthetic joint infections (PJI) following total knee arthroplasty (TKA). The resistant group (left) had an average of 3.91 surgeries (±2.7, n=11), while the sensitive group (right) had an average of 2.34 surgeries (±1.3, n=50). The resistant group experienced a higher number of surgeries due to the complexity of treating antibiotic-resistant infections.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5270598/v1/08b208520c069ac20665fce9.png"},{"id":72202077,"identity":"1b8d43ff-aa59-44d8-bf6c-3101b1f3375c","added_by":"auto","created_at":"2024-12-23 16:14:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1511680,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5270598/v1/50f6c5f9-1ca2-4057-b89d-5ff7f11152b2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Impact of Pathogen Sensitivity to Antibiotics Loaded in Cement on the Number of Revisions and Costs in the Treatment of Periprosthetic Knee Infection","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePrimary total knee arthroplasty (pTKA) has become a highly effective procedure for treating knee osteoarthritis, significantly improving patients' functional capacity and quality of life. With the projected annual volume of pTKA cases expected to rise between 1.3 to 3.5\u0026nbsp;million, the demand for revision total knee arthroplasty (rTKA) is also predicted to surge by approximately 300% by 2030, primarily due to periprosthetic joint infections (PJIs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePeriprosthetic knee infections present significant challenges, often necessitating complex and costly revision surgeries. The standard treatment protocol for late PJIs involves a two-stage revision approach. The initial stage includes removing the infected implant, performing extensive debridement, and placing an antibiotic-loaded cement spacer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This spacer not only helps maintain the joint space but also delivers high local concentrations of antibiotics directly to the infection site, which is crucial for effective infection control [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. According to a study by Lim et al. (2009), the two-stage reimplantation protocol showed a high rate of treatment failure in patients with infections caused by resistant microorganisms, highlighting the importance of selecting effective antibiotic regimens [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although the gold standard method is reported to be two-stage revision surgery, with appropriate patient selection, one-stage revision has also been reported to be associated with successful results comparable to two-stage procedures [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAntibiotic-loaded bone cement (ALBC) has been a pivotal element in orthopedic surgery for both prophylactic and therapeutic purposes. Its introduction by Buchholz and Engelbrecht in the 1970s marked a significant advancement, as it allowed for high local antibiotic concentrations that surpass those achievable through systemic administration alone​​ [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This innovation has proven particularly valuable in the context of PJIs, where high local antibiotic concentrations are essential to combat the infection effectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the widespread use of ALBC, there remains ongoing debate about its optimal application, particularly concerning the selection of appropriate antibiotics and their dosages. Studies have shown varying outcomes regarding the efficacy of ALBC in preventing and treating PJIs. Some research highlights the benefits of using dual or multiple antibiotic-loaded spacers, which can enhance the antimicrobial spectrum and reduce the risk of developing resistant bacterial strains [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, concerns about the potential for antibiotic resistance and the economic implications of ALBC use persist, necessitating further investigation into cost-effective and clinically effective strategies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe objective of this study is to evaluate the impact of the pathogen's sensitivity to antibiotics loaded in cement on infection management, the number of revision surgeries required, and the overall cost analysis in patients undergoing rTKA due to PJIs. By analyzing the outcomes of patients treated with antibiotic-loaded cement spacers, we aim to provide insights into optimizing treatment protocols and improving patient outcomes in the context of periprosthetic knee infections​.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003eIn our clinic, the treatment and follow-up processes of 61 patients who underwent revision total knee arthroplasty due to late periprosthetic joint infection (PJI) after primary total knee arthroplasty were examined. When deciding on the diagnosis of PJI, the diagnostic criteria of the Musculoskeletal Infection Society were used. Criteria include 2 positive cultures with the same microorganism, sinus tract associated with the joint, serum c-reactive protein (CRP), sedimentation, d-dimer values, synovial fluid analysis and peroperative findings [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Synovial fluid samples were repeated at 2-week intervals in cases where the diagnostic criteria were doubtful, due to continued clinical suspicion. In antibiogram studies of the infective agent produced in accordance with the diagnostic criteria, sensitivity to teicoplanin or gentamicin enabled grouping.\u003c/p\u003e \u003cp\u003ePatients were grouped based on the sensivity of their isolated pathogens to antibiotics (teicoplanin and gentamicin) loaded in the cement. We sought resistance to at least one antibiotic. In the resistant group, all pathogens were resistant to gentamicin, and two were additionally resistant to teicoplanin in antibiogram examinitions. Conversely, in the susceptible group, all pathogens were sensitive to both antibiotics. 11 patients were included in the resistant group, and 50 patients were included in the sensitive group. The demographic characteristics and comorbidities of the patients were recorded. It was observed that all patients had dual (by adding teicoplanin to antibiotic cement with gentamicin) antibiotic-loaded cement. Microbiological examinations of the patients were screened. Patients who underwent revision surgeries due to late PJI were included in the study. Patients who underwent surgery due to early PJI or could not complete their follow-up were not included.\u003c/p\u003e \u003cp\u003eAll surgeries performed for infection management, including single-stage or two-stage procedures, implant extraction, and antibiotic-loaded cement spacer application, cement spacer exchange and debridement surgery, revision prostheses (including tumor prostheses) implantations, were individually analyzed, and the number of revision surgeries performed for each patient throughout the process was examined. In our clinic, we generally prefer a two-stage revision procedure for the treatment of PJE. However, single-stage revision surgery may be preferred in selected patients. Single-stage revision is considered in patients with antibiotic-sensitive microorganisms in preoperative cultures, absence of sepsis signs, uninfected neurovascular bundles, good soft tissue condition and no soft tissue infections hindering wound closure [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Whether the causative organism was detected in the joint samples taken before surgery was screened. The total cost amounts recorded in the hospital system during the patients' admissions were examined. Costs were calculated in dollars based on the exchange rate of the period and compared.\u003c/p\u003e \u003cp\u003eSensitive and resistant groups were compared. The relationship between gram staining characteristics, the presence of polymicrobial agents, patient factors, the number of surgeries, and costs were examined.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSTATISTICAL ANALYSIS\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS 26.0 (Armonk, New York: IBM Corp.) software package. The sample size was calculated using G*Power 3.1 software, determining that 11 cases in the antibiotic-resistant group and 40 in the sensitive group were sufficient to achieve 80% power (α\u0026thinsp;=\u0026thinsp;0.05). Descriptive statistics for continuous variables were expressed as mean (Mean), standard deviation (SD), median, while categorical variables were expressed as frequency (n) and percentage (%). Histogram, Kolmogorov-Smirnov, or Shapiro-Wilk tests were used to assess whether continuous variables followed a normal distribution, and Leven\u0026rsquo;s t-test was used to evaluate group homogeneities. T-test was used for quantitative comparisons between groups, and Mann-Whitney U test was used for categorical comparisons. A 5% of Type 1 error (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was used for statistical significance in all analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe follow-up processes of 61 patients were examined. It was observed that the groups were homogeneously distributed. The demographic characteristics of the patients, gram staining characteristics of the isolated causative microorganism, polymicrobial infection rate in the groups, antibiotic resistances, number of surgeries, and total costs are shown in Table 1. Figure 1 depicts the distribution of causative microorganisms in our PJI cases.\u003c/p\u003e\n\u003cp\u003eThe demographic data of the groups were found to be similar. It was observed that factors related to age, gender, and number of comorbidities did not affect the number of surgeries and antibiotic resistance. Polymicrobial agents were more frequently encountered in the resistant group (p:0.017). Resistance to gentamicin was present in all cases in the resistant group. Resistance to teicoplanin was observed in only 2 cases. It was found that the number of surgeries in the resistant group was higher than in the sensitive group (p:0.043) (Figure 2). The presence of teicoplanin resistance doubled the number of revision surgeries required (p:0.005). Antibiotic resistance did not affect the number of surgeries in groups where single strain or polymicrobial agents were detected. Similar total costs were observed in both groups. The average cost in the entire cohort was $6279.74.\u003c/p\u003e\n\u003cp\u003eThe gram staining characteristic of the causative agent was unrelated to age, number of comorbidities, and cost. However, it was found that in patients infected with gram-negative agents, the number of revisions required for infection management was significantly higher (p:0.013) (Table 2).\u003c/p\u003e\n\u003cp\u003eThe presence of polymicrobial agents did not cause a change in age, number of comorbidities, number of surgeries, and cost compared to the group where a single strain was detected. However, the number of surgeries and costs were relatively higher in the polymicrobial group. (Table 3)\u003c/p\u003e\n\u003cp\u003eIn the preoperative sampling, it was observed that the causative agent could not be cultured in only one case in the resistant group.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study highlights the significant challenges posed by antibiotic resistant pathogens in PJIs after TKA. Patients in the resistant group had more and more complex surgeries than those with antibiotic sensitive infections, 3.91 vs 2.34 on average.\u0026nbsp;We believe that the high average of 3.91 surgeries in the resistant group, indicating a higher failure rate, may be attributed to the resistance of the causative microorganisms to the antibiotics loaded in the cement.\u0026nbsp;Presence of polymicrobial infections and gram-negative bacteria increased the number of surgeries. Despite similar demographics and comorbidities between the two groups, the higher revision rates and longer treatment duration for resistant infections shows the need for pathogen specific antibiotic in ALBC. These results highlight the need to optimize treatment protocols to get better infection resolution and reduce the economic burden of resistant PJIs.\u003c/p\u003e\n\u003cp\u003eOur findings are consistent with previous research indicating the complexities of managing PJIs, particularly those caused by resistant organisms\u0026nbsp;[7,11]. Studies have shown that antibiotic-loaded bone cement is effective in reducing infection rates in both primary and revision arthroplasty\u0026nbsp;[1,13]. However, the appropriate selection and concentration of antibiotics are crucial for effective treatment\u0026nbsp;[11,14]. The increased surgical burden associated with resistant infections observed in our study aligns with reports highlighting the challenges and higher complication rates in such cases\u0026nbsp;[11,13].\u0026nbsp;The study\u0026apos;s finding that antibiotic-resistant microorganisms, particularly those resistant to gentamicin and teicoplanin, result in a higher number of revision surgeries is consistent with previous literature. Perry et al.\u0026nbsp;[15]\u0026nbsp;reported that patients referred with an antibiotic knee spacer for PJI have a high rate of positive cultures at the time of re-debridement, with Staphylococcus aureus being the most common organism identified. This aligns with our observation of gentamicin resistance in all cases within the resistant group and the higher number of surgeries required. The presence of polymicrobial infections was significantly higher in the resistant group, and although this did not directly correlate with increased surgical interventions, it did contribute to the complexity of treatment. Shahpari et. al.\u0026nbsp;[16]\u0026nbsp;noted the challenges of using antibiotic-impregnated cement spacers in treating infected joint replacements, emphasizing the need for high local antibiotic concentrations to combat such infections effectively. Thus, the systemic antibiotic adverse effects may also be reduced.\u0026nbsp;Furthermore, the study\u0026apos;s observation that the presence of gram-negative organisms significantly increases the number of required revisions corroborates the findings of Bos et al.\u0026nbsp;[17], who highlighted the impact of pathogen type on the success of revision surgeries using antibiotic-loaded bone cement. The increased number of revisions for gram-negative infections underscores the necessity for targeted antibiotic strategies in these cases.\u003c/p\u003e\n\u003cp\u003eThe study underscores the importance of antibiotic selection based on specific pathogen culture and sensitivity results to enhance the efficacy of local antibiotic delivery. Anagnostakos et. al.\u0026nbsp;[18]\u0026nbsp;discussed the need for optimal antibiotic impregnation in bone cement to achieve high local antibiotic concentrations and improve infection control rates. The effectiveness of dual antibiotic-loaded bone cement in our study aligns with the findings of Sanz-Ruiz et al.\u0026nbsp;[19], who reported that dual antibiotic-loaded bone cement is more effective and cost-efficient in preventing PJI compared to single antibiotic-loaded bone cement. Our findings are consistent with those findings that the optimal dual antibiotic impregnation may show better results. Martos et al.\u0026nbsp;[20]\u0026nbsp;reviewed the principles and limitations of local antibiotic delivery using ALBC, emphasizing that high local antimicrobial concentrations are needed to overcome the recalcitrance of PJIs. Those findings support the necessity for effective antibiotic delivery systems to achieve high local concentrations, reducing the risk of antimicrobial resistance. This aligns with our study\u0026apos;s emphasis on tailoring antibiotic-loaded cements based on specific pathogen sensitivity to improve outcomes. Gandhi et. al.\u0026nbsp;[21]\u0026nbsp;highlighted the controversy surrounding the use of ALBC in primary and revision joint arthroplasty. While the prophylactic use in primary TKA remains debated, its routine use in revision procedures, especially in septic revisions, is well-supported. This supports our approach of using dual antibiotic-loaded cement in rTKA for managing PJIs. The study by Kim et al.\u0026nbsp;[22]\u0026nbsp;highlights the effectiveness of antifungal-impregnated cement spacers in treating chronic fungal PJIs after TKA, with no recurrent infections over a mean follow-up of 66 months. This supports our findings on the necessity of pathogen-specific antimicrobial strategies to manage complex PJIs, reduce revision surgeries, and enhance patient outcomes through targeted antibiotic-loaded bone cement. Another important aspect of Kim\u0026rsquo;s study\u0026nbsp;[22]\u0026nbsp;is Amphotericin B was heat stable and available in powder form, making it preferable to other antifungal agents. Sometimes, very rare organisms can cause PJIs. For instance, a case report documented an infection caused by SDSD in a farmer identified using VITEK MS\u0026nbsp;[3]. In such rare instances, techniques like VITEK MS become especially important to accurately diagnose the microorganism, emphasizing the need for pathogen-specific antibiotic loading and tailored treatment approaches to effectively manage these uncommon infections\u0026nbsp;[23,24].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe economic analysis revealed similar total costs between the resistant and sensitive groups, with an average cost of $6279.74 for the entire cohort. This finding suggests that while antibiotic resistance increases the number of surgical interventions, the overall treatment costs remain comparable. This is in line with the study by Hoskins et al.\u0026nbsp;[25], which found no significant cost difference between ALBC and plain bone cement in preventing infections. Despite the supporting literature for the use of ALBC in PJI, Hao-Qian Li et. al. conducted a meta-analysis on the prophylactic use of ALBC in primary TKA, finding no significant difference in peri-prosthetic infection rates compared to plain cement. However, the analysis noted that ALBC was associated with longer hospital stays and increased risks of acute renal failure and readmission\u0026nbsp;[26]. These findings highlight the need for careful consideration of ALBC\u0026apos;s benefits and potential risks, particularly in the context of prophylaxis versus treatment. Concluding from our study that loading merely the pathogen\u0026rsquo;s susceptible antibiotic to the cement with controlled and appropriate dosage may prevent such negative effects.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations, including its retrospective nature and potential selection bias. The sample size, while adequate according to the power analysis, may not fully represent the broader patient population undergoing TKA revisions. Additionally, despite minimizing the differences in patients, variations in surgical techniques and post-operative care could influence the outcomes. Future research should focus on prospective, randomized controlled trials to validate these findings and explore the long-term benefits of specific antibiotic regimens in ALBC.\u0026nbsp;\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, our study demonstrates that infections caused by antibiotic-resistant microorganisms pose significant challenges in the treatment of PJI following rTKA. The necessity for multiple surgical interventions in resistant cases highlights the importance of selecting appropriate antibiotics based on pathogen sensitivity. The clinical implications of our findings are significant, advocating for the use of pathogen-specific antibiotics in ALBC to improve infection control outcomes and to reduce the economic impact of these infections on healthcare systems. Future research should focus on developing advanced antibiotic delivery systems and exploring alternative antibiotics to enhance treatment outcomes for resistant infections. These findings provide valuable clinical evidence supporting the current treatment methods for PJI and emphasize the need for ongoing improvements in antibiotic-loaded bone cement formulations. There is also a need for studies exploring novel antimicrobials and combination therapies to enhance infection control strategies. Additionally, improving diagnostic tools to identify infections early and accurately will allow for timely and appropriate interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEach author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApplication Date: 26.03.2024\u003c/p\u003e\n\u003cp\u003eApproval Number: E-83045809-604.01-1001730\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical committee approved the study.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. All authors read and approved the final manuscript.Authors' contributions:C.D.D. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.O. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.Y.A. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.C.E. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.G.K. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.M.C.U. contributed to the conception and design of the study, data collection, data analysis, manuscript drafting and critical revision of the manuscript.All authors read and approved the final manuscript.Availability of data and material: The data that support the findings of this study are available from the corresponding author, C.D.D. upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eUpfill-Brown A, Hsiue PP, Sekimura T, et al.: Epidemiology of Revision Total Knee Arthroplasty in the United States, 2012 to 2019. Arthroplast Today. 2022, 15:188-195.e6. 10.1016/j.artd.2022.03.004\u003c/li\u003e\n\u003cli\u003eChang Y, Chen W-C, Hsieh P-H, Chen DW, Lee MS, Shih H-N, Ueng SWN: In Vitro Activities of Daptomycin-, Vancomycin-, and Teicoplanin-Loaded Polymethylmethacrylate against Methicillin-Susceptible, Methicillin-Resistant, and Vancomycin-Intermediate Strains of Staphylococcus aureus. Antimicrob Agents Chemother. 2011, 55:5480\u0026ndash;4. 10.1128/AAC.05312-11\u003c/li\u003e\n\u003cli\u003eAfacan MY, Davulcu CD, Kaynak G, Kılıncarslan AC, Tokuc E, Bahar Tokman H: A Rare Case of Periprosthetic Joint Infection with Streptococcus dysgalactiae subspecies dysgalactiae. Indian J Orthop. 2024, 58:606\u0026ndash;12. 10.1007/s43465-024-01106-6\u003c/li\u003e\n\u003cli\u003eParvizi J, Tan TL, Goswami K, Higuera C, Della Valle C, Chen AF, Shohat N: The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J Arthroplasty. 2018, 33:1309-1314.e2. 10.1016/j.arth.2018.02.078\u003c/li\u003e\n\u003cli\u003ePellegrini A V., Suardi V: Antibiotics and cement: what I need to know? HIP Int. 2020, 30:48\u0026ndash;53. 10.1177/1120700020915463\u003c/li\u003e\n\u003cli\u003eTian MQ, Yang XT, Tian X Bin, Sun YB, Duan YH, Sun L: Short-term Follow-up of Antibiotic-loaded Articulating Cement Spacers in Two-stage Revision of Infected Total Knee Arthroplasty: A Case Series. Orthop Surg. 2018, 10:128\u0026ndash;33. 10.1111/os.12381\u003c/li\u003e\n\u003cli\u003eNettrour JF, Polikandriotis JA, Bernasek TL, Gustke KA, Lyons ST: Articulating spacers for the treatment of infected total knee arthroplasty: Effect of antibiotic combinations and concentrations. Orthopedics. 2013, 36:19\u0026ndash;24. 10.3928/01477447-20121217-13\u003c/li\u003e\n\u003cli\u003eLim SJ, Park JC, Moon YW, Park YS: Treatment of Periprosthetic Hip Infection Caused by Resistant Microorganisms Using 2-Stage Reimplantation Protocol. J Arthroplasty. 2009, 24:1264\u0026ndash;9. 10.1016/j.arth.2009.05.012\u003c/li\u003e\n\u003cli\u003ePradhan TN, Viswanathan VK, Badge R, Pradhan N: Single-stage revision in the management of prosthetic joint infections after total knee arthroplasty \u0026ndash; A review of current concepts. J Clin Orthop Trauma. 2024, 52:102431. 10.1016/j.jcot.2024.102431\u003c/li\u003e\n\u003cli\u003eBini SA, Chan PH, Inacio MCS, Paxton EW, Khatod M: Antibiotic cement was associated with half the risk of re-revision in 1,154 aseptic revision total knee arthroplasties. Acta Orthop. 2016, 87:55\u0026ndash;9. 10.3109/17453674.2015.1103568\u003c/li\u003e\n\u003cli\u003eOrtola DJ, Fenga D, Marcellino S, Rosi M, Centofanti F, Rosa MA: Peri-Prosthetic Knee Infection Management: Spacers Loaded with Two or Three Antibiotic Agents. Surg Infect (Larchmt). 2017, 18:619\u0026ndash;24. 10.1089/sur.2016.260\u003c/li\u003e\n\u003cli\u003eBuyuk AF, Sofu H, Camurcu IY, Ucpunar H, Kaygusuz MA, Sahin V: Can Teicoplanin Be an Effective Choice for Antibiotic-Impregnated Cement Spacer in Two-Stage Revision Total Knee Arthroplasty? J Knee Surg. 2017, 30:283\u0026ndash;8. 10.1055/s-0036-1584535\u003c/li\u003e\n\u003cli\u003eHackett DJ, Rothenberg AC, Chen AF, et al.: The economic significance of orthopaedic infections. J Am Acad Orthop Surg. 2015, 23:S1\u0026ndash;7. 10.5435/JAAOS-D-14-00394\u003c/li\u003e\n\u003cli\u003ePatel A, Pavlou G, M\u0026uacute;jica-Mota RE, Toms AD: The epidemiology of revision total knee and hip arthroplasty in England and Wales: A comparative analysis with projections for the United States. a study using the national joint registry dataset. Bone Jt J. 2015, 97-B:1076\u0026ndash;81. 10.1302/0301-620X.97B8.35170\u003c/li\u003e\n\u003cli\u003ePerry KI, Sproul RC, Sierra RJ, Abdel MP, Fehring TK, Hanssen AD: High Rate of Positive Cultures in Patients Referred With Antibiotic Spacers as Part of 2-Stage Exchange. J Arthroplasty. 2018, 33:2230\u0026ndash;3. 10.1016/j.arth.2018.02.059\u003c/li\u003e\n\u003cli\u003eShahpari O, Mousavian A, Elahpour N, Malahias MA, Ebrahimzadeh MH, Moradi A: The use of antibiotic impregnated cement spacers in the treatment of infected total joint replacement: Challenges and achievements. Arch Bone Jt Surg. 2020, 8:11\u0026ndash;20. 10.22038/abjs.2019.42018.2141\u003c/li\u003e\n\u003cli\u003eBos PK, Spekenbrink-Spooren A, Croughs P, Bierma-Zeinstra SMA, Reijman M, Van Oldenrijk J: Risk for re-revision and type of antibiotic-loaded bone cement in hip or knee arthroplasty revisions: report of the Dutch Arthroplasty Register. Acta Orthop. 2023, 94:471\u0026ndash;6. 10.2340/17453674.2023.18645\u003c/li\u003e\n\u003cli\u003eAnagnostakos K, Sahan I: Are cement spacers and beads loaded with the correct antibiotic(S) at the site of periprosthetic hip and knee joint infections? Antibiotics. 2021, 10:1\u0026ndash;13. 10.3390/antibiotics10020143\u003c/li\u003e\n\u003cli\u003eSanz-Ruiz P, Matas-Diez JA, Villanueva-Mart\u0026iacute;nez M, Santos-Vaquinha Blanco A Dos, Vaquero J: Is Dual Antibiotic-Loaded Bone Cement More Effective and Cost-Efficient Than a Single Antibiotic-Loaded Bone Cement to Reduce the Risk of Prosthetic Joint Infection in Aseptic Revision Knee Arthroplasty? J Arthroplasty. 2020, 35:3724\u0026ndash;9. 10.1016/j.arth.2020.06.045\u003c/li\u003e\n\u003cli\u003eSabater-Martos M, Verdejo MA, Morata L, Mu\u0026ntilde;oz-Mahamud E, Guerra-Farfan E, Martinez-Pastor JC, Soriano A: Antimicrobials in polymethylmethacrylate: from prevention to prosthetic joint infection treatment: basic principles and risk of resistance. Arthroplasty. 2023, 5:. 10.1186/s42836-023-00166-7\u003c/li\u003e\n\u003cli\u003eGandhi R, Backstein D, Zywiel MG: Antibiotic-laden Bone Cement in Primary and Revision Hip and Knee Arthroplasty. J Am Acad Orthop Surg. 2018, 26:727\u0026ndash;34. 10.5435/JAAOS-D-17-00305\u003c/li\u003e\n\u003cli\u003eKim JK, Lee DY, Kang DW, Ro DH, Lee MC, Han HS: Efficacy of antifungal-impregnated cement spacer against chronic fungal periprosthetic joint infections after total knee arthroplasty. Knee. 2018, 25:631\u0026ndash;7. 10.1016/j.knee.2018.04.004\u003c/li\u003e\n\u003cli\u003eSeng P, Drancourt M, Gouriet F, La Scola B, Fournier P, Rolain JM, Raoult D: Ongoing Revolution in Bacteriology: Routine Identification of Bacteria by Matrix‐Assisted Laser Desorption Ionization Time‐of‐Flight Mass Spectrometry. Clin Infect Dis. 2009, 49:543\u0026ndash;51. 10.1086/600885\u003c/li\u003e\n\u003cli\u003eSinghal N, Kumar M, Kanaujia PK, Virdi JS: MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis. Front Microbiol. 2015, 6:. 10.3389/fmicb.2015.00791\u003c/li\u003e\n\u003cli\u003eHoskins T, Shah JK, Patel J, et al.: The cost-effectiveness of antibiotic-loaded bone cement versus plain bone cement following total and partial knee and hip arthroplasty. J Orthop. 2020, 20:217\u0026ndash;20. 10.1016/j.jor.2020.01.029\u003c/li\u003e\n\u003cli\u003eLi HQ, Li PC, Wei XC, Shi JJ: Effectiveness of antibiotics loaded bone cement in primary total knee arthroplasty: A systematic review and meta-analysis. Orthop Traumatol Surg Res. 2022, 108:103295. 10.1016/j.otsr.2022.103295\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Demographic data of the groups and effects of antibiotic resistance. (p: p-value)\u003c/p\u003e\n\u003ctable style=\"border: none;border-collapse: collapse;width: 681px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;background: black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eVariable\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;background: black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eSensitive Group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;background: black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eResistant Group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;background: black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eAll Patients\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;background: black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003ep\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Patients (N)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e50\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eMean Age\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e67.52 \u0026plusmn; 10.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e69 \u0026plusmn; 5.44\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e67.79 (38-87)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.504\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eGender (M/F)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e\u0026nbsp;10 / 40\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e\u0026nbsp;3/8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e13 / 48\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.78\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Comorbidities\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e1.32 \u0026plusmn; 1.58\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.64 \u0026plusmn; 1.28\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e1.2 \u0026plusmn; 1.54\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.18\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eGram Staining (-/+)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e5 / 45\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2 / 11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e7 / 61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.46\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003ePolymicrobial Infection (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e21%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e11%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e32%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;background: rgb(255, 192, 0);padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:black;'\u003e0.017\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eTeicoplanin Resistance (N)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eGentamicin Resistance (N)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.34 \u0026plusmn; 1.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e3.91 \u0026plusmn; 2.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.62 (1-9)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;background: rgb(255, 192, 0);padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:black;'\u003e0.043\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eTeicoplanin Sensitivity and Number of Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.46 \u0026plusmn; 1.52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e5.5 \u0026plusmn; 3.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;background: rgb(255, 192, 0);padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:black;'\u003e0.005\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Single Strain Infection Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.24 \u0026plusmn; 1.38\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e4 \u0026plusmn;3.36\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.41 \u0026plusmn; 1.68\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.37\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Polymicrobial Infection Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.62 \u0026plusmn; 1.04\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e3.86 \u0026plusmn; 2.54\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e3.05 \u0026plusmn; 1.76\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Gram-Negative Infection Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e4 \u0026plusmn; 2.23\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e4.5 \u0026plusmn; 2.12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e4.14 \u0026plusmn; 2.03\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.79\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-left: 1pt solid black;border-bottom: none;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Gram-Positive Infection Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.16 \u0026plusmn; 1.04\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e3.78 \u0026plusmn; 2.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-right: none;border-bottom: none;border-left: none;border-image: initial;border-top: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.43 \u0026plusmn; 1.61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-left: none;border-bottom: none;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.13\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 172.75pt;border-top: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eCost ($)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72.8pt;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e5553.46 \u0026plusmn; 4773.31\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.8pt;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e9581.02 \u0026plusmn; 11009.96\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103.3pt;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e6279.74 \u0026plusmn; 6422.47 (1254.52-41457.64)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81.4pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.26\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2: Comparative data based on the gram staining characteristic of the agent. (p: p-value)\u003c/p\u003e\n\u003ctable style=\"border: none;border-collapse: collapse;width: 693px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 218pt;border-top: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-right: none;background: black;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eVariable\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;background: black;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eGram (-)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: 1pt solid black;border-left: none;border-bottom: 1pt solid black;border-right: none;background: black;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003eGram (+)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;background: black;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:white;'\u003ep\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 218pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eAge\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e66.14 \u0026plusmn; 9.58\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e67.77 \u0026plusmn; 9.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.67\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 218pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Comorbidities\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e1.29 \u0026plusmn; 1.49\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e1.21 \u0026plusmn; 1.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 218pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eNumber of Surgeries\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e4.14 \u0026plusmn; 2.03\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e2.43 \u0026plusmn; 1.61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(255, 192, 0);padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";color:black;'\u003e0.013\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 218pt;border-top: none;border-left: 1pt solid black;border-bottom: 1pt solid black;border-right: none;padding: 0in 5.4pt;height: 16pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003eCost ($)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e7024.06 \u0026plusmn; 3983.66\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e6235.24 \u0026plusmn; 6747.59\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in 5.4pt;height: 16pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-family:\"Times New Roman\";'\u003e0.76\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3: Effects of the presence of single or polymicrobial agents. (p: p-value)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"693\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 41.9308%;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003eMono-microbial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003ePolymicrobial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.8761%;\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 41.9308%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e66.98 \u0026plusmn; 10.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e69.45 \u0026plusmn; 6.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.8761%;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 41.9308%;\"\u003e\n \u003cp\u003eNumber of Comorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e1.07 \u0026plusmn; 1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e1.45 \u0026plusmn; 1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.8761%;\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 41.9308%;\"\u003e\n \u003cp\u003eNumber of Surgeries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e2.41\u0026plusmn; 1.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e3.05 \u0026plusmn; 1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.8761%;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 41.9308%;\"\u003e\n \u003cp\u003eCost ($)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e5966.03 \u0026plusmn; 4985.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 19.5965%;\"\u003e\n \u003cp\u003e6922.84 \u0026plusmn; 8790.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.8761%;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-orthopaedic-surgery-and-traumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejos","sideBox":"Learn more about [European Journal of Orthopaedic Surgery \u0026 Traumatology](http://link.springer.com/journal/590)","snPcode":"590","submissionUrl":"https://submission.springernature.com/new-submission/590/3","title":"European Journal of Orthopaedic Surgery \u0026 Traumatology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pathogen sensitivity, antibiotic-loaded cement, infection resolution, revision total knee arthroplasty, periprosthetic joint infection, antibiotic resistance, polymicrobial infections, Gram-negative infections, surgical revisions, treatment costs, gentamicin resistance, teicoplanin resistance, dual antibiotic-loaded bone cement","lastPublishedDoi":"10.21203/rs.3.rs-5270598/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5270598/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e This study aims to evaluate the impact of the pathogen's sensitivity to the loaded antibiotics on infection resolution, the number of revisions, and the associated costs in patients undergoing revision total knee arthroplasty (rTKA) due to PJI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and Methods:\u003c/strong\u003e We reviewed the treatment and follow-up processes of 61 patients who underwent rTKA for late-stage PJI following primary total knee arthroplasty (pTKA) in our clinic. The study included 11 patients in the resistant group and 50 in the sensitive group in line with the power analysis results. Patients' demographic characteristics and comorbidities were recorded. All patients received dual antibiotic-loaded cement. Microbiological examinations of patients were analyzed, and the number of revision surgeries each patient underwent was determined. We analyzed all surgeries related to infection treatment, including open irrigation, debridement, polyethylene exchange, implant extractions, antibiotic-loaded cement spacer placements, spacer changes, and debridements, and the implantation of revision prostheses, including tumor prostheses. The total number of surgeries each patient underwent was recorded. We also reviewed hospital system records of total protocol costs during patient admissions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of 61 patients undergoing revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI), 11 had antibiotic-resistant infections and 50 had antibiotic-sensitive infections. The groups had similar demographics. Polymicrobial infections were more frequent in the resistant group (p=0.017), with all resistant cases showing gentamicin resistance and two showing teicoplanin resistance. The resistant group required more surgeries (average 3.91±2.7 vs. 2.34±1.3, p=0.043) compared to the sensitive group, with teicoplanin resistance doubling revision surgeries (p=0.005). Costs were similar between groups, averaging $6279.74. Gram-negative infections led to more revisions (p=0.013). Polymicrobial infections did not significantly affect the number of surgeries or costs compared to single-strain infections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our study demonstrates that in rTKA surgeries using dual antibiotic-loaded bone cement, infections caused by antibiotic-resistant microorganisms are more challenging and time-consuming to treat. This underscores the necessity of exploring new methods to enhance local efficacy by loading cement with antibiotics based on specific pathogen culture and sensitivity results, while also providing clinical evidence of the effectiveness of current treatment methods against sensitive microorganisms.\u003c/p\u003e","manuscriptTitle":"The Impact of Pathogen Sensitivity to Antibiotics Loaded in Cement on the Number of Revisions and Costs in the Treatment of Periprosthetic Knee Infection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-24 05:07:06","doi":"10.21203/rs.3.rs-5270598/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-21T16:58:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-11T14:15:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"202501488125757472679085163390355311804","date":"2024-11-03T04:48:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-01T01:10:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-18T15:56:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-18T15:54:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Orthopaedic Surgery \u0026 Traumatology","date":"2024-10-15T17:27:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-orthopaedic-surgery-and-traumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejos","sideBox":"Learn more about [European Journal of Orthopaedic Surgery \u0026 Traumatology](http://link.springer.com/journal/590)","snPcode":"590","submissionUrl":"https://submission.springernature.com/new-submission/590/3","title":"European Journal of Orthopaedic Surgery \u0026 Traumatology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f86005cc-ab2a-474a-a834-bcff816f4b82","owner":[],"postedDate":"October 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:07:48+00:00","versionOfRecord":{"articleIdentity":"rs-5270598","link":"https://doi.org/10.1007/s00590-024-04166-4","journal":{"identity":"european-journal-of-orthopaedic-surgery-and-traumatology","isVorOnly":false,"title":"European Journal of Orthopaedic Surgery \u0026 Traumatology"},"publishedOn":"2024-12-21 15:57:59","publishedOnDateReadable":"December 21st, 2024"},"versionCreatedAt":"2024-10-24 05:07:06","video":"","vorDoi":"10.1007/s00590-024-04166-4","vorDoiUrl":"https://doi.org/10.1007/s00590-024-04166-4","workflowStages":[]},"version":"v1","identity":"rs-5270598","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5270598","identity":"rs-5270598","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}