Optimizing Antibiotic Prophylaxis for Type III Open Fractures in China: A Cost- Effectiveness Analysis

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Recent studies have suggested that narrow-spectrum antibiotics like cefazolin (CEZ) may offer comparable efficacy to broader-spectrum combinations in preventing SSI, with potential cost benefits. However, the cost-effectiveness of different prophylactic regimens in Type III open fractures in China has not been comprehensively evaluated. Methods Six prophylactic antibiotic regimens were compared: cefazolin (CEZ), cefazolin + aminoglycosides (CEZ+AG), piperacillin/tazobactam (PIPC/TAZ), cefotaxime (CTX), ampicillin/sulbactam (ABPC/SBT) and ceftriaxone (CTRX). Transition probabilities and utility values were derived from published clinical studies, while cost data were obtained from the Chinese Volume-Based Procurement (VBP) policy for drug pricing, along with additional expenses incurred due to SSI. Sensitivity analyses were conducted to assess the robustness of the findings against variations in key parameters. Results From the perspective of the Chinese healthcare system, CEZ emerged as the most cost-effective regimen overall, with a total cost of 1272.47 CNY and a total utility of 0.3425 QALYs. In contrast, all other regimens were found to be dominated strategies, offering neither economic nor health utility advantages. Among these, CTRX was the least favorable, incurring the highest cost (3864.94 CNY) while yielding the lowest total utility (0.3262 QALYs). Sensitivity analyses confirmed the robustness of these findings, reinforcing CEZ as the dominant and most cost-effective option. Conclusions This study highlights the cost-effectiveness advantage of CEZ in preventing SSI following Type III open fractures in China. CEZ is the most cost-effective option overall, demonstrating a clear advantage over all other regimens. These findings provide essential insights for guiding antibiotic selection and optimizing healthcare resource allocation in the prevention of surgical infections. cost-effectiveness antibiotic prophylaxis open fractures cefazolin surgical site infection Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Surgical site infections (SSI) remain a significant concern in the management of Gustilo-Anderson type III open fractures, as these severe injuries are associated with a high risk of deep infections and poor clinical outcomes [1-3]. The infection rate for SSI in Type III open fractures can be as high as 50%, which is considerably higher compared to less severe fracture types (Type I and II) [4-6]. Despite advancements in surgical techniques and infection control strategies, SSI can lead to prolonged hospital stays, increased healthcare costs, and adverse long-term outcomes [7]. Early and appropriate antibiotic prophylaxis is universally recommended as a key component of perioperative infection prevention strategies to mitigate these risks and reduce infection-related complications [8]. According to the Chinese guidelines for open fractures, first-generation cephalosporins (e.g., cefazolin, or clindamycin for those allergic to penicillin) are recommended as the base therapy for all open fractures. For Type III fractures, the guidelines advocate the combination of first-generation cephalosporins with aminoglycosides as the primary prophylactic regimen. Alternative regimens include third-generation cephalosporins, such as ceftriaxone, or piperacillin-tazobactam, aimed at providing broader coverage against both Gram-positive and Gram-negative pathogens [9]. These recommendations are consistent with international guidelines, which also emphasize the use of broad-spectrum antibiotics to account for the increased risk of Gram-negative infections in Type III open fractures [8,10]. However, the necessity of broad-spectrum antibiotic coverage has been increasingly questioned. Multiple studies have shown that in Type III open fractures, narrow-spectrum antibiotics (such as cefazolin alone) may offer non-inferior efficacy in preventing SSI compared to broad-spectrum antibiotics, especially when administered early and effectively [4,11-15]. The Chinese Volume-Based Procurement (VBP) policy, implemented in recent years, has significantly altered the landscape of antibiotic pricing and availability, affecting the cost-effectiveness of various therapeutic options [16,17]. While extensive research on the cost-effectiveness of antimicrobial prophylaxis exists in other surgical fields, studies specifically addressing Type III open fractures are limited. To fill this gap, this study aims to perform a comprehensive cost-effectiveness evaluation of various prophylactic antibiotic regimens for Type III open fractures, considering both clinical efficacy and economic feasibility in the Chinese healthcare setting. Methods Overview This study utilized TreeAge Pro 2022 software to construct a decision-tree model assessing the cost-effectiveness of different antibiotic prophylaxis regimens for the prevention of SSI in patients with Gustilo-Anderson Type III open fractures. Efficacy data were derived from a retrospective study conducted in Japan [15]. The economic evaluation adhered to the Chinese Guidelines for Pharmacoeconomic Evaluations (2020), ensuring methodological consistency with national pharmacoeconomic standards [18]. Model Construction A decision-tree model was developed to compare the cost-effectiveness of six prophylactic antibiotic regimens in preventing SSI following Type III open fractures. The evaluated regimens included: cefazolin (CEZ), cefazolin combined with aminoglycosides (CEZ+AG), piperacillin/tazobactam (PIPC/TAZ), cefotaxime (CTX), ampicillin/sulbactam (ABPC/SBT) and ceftriaxone (CTRX). Each regimen was associated with two possible health outcomes: occurrence of SSI and non-occurrence of SSI (Figure 1). (Insert Figure 1 about here) The model simulated patient outcomes over a 90-day postoperative period, consistent with the timeframe utilized in the referenced retrospective study, which defined deep SSI as infections occurring within 90 days post-surgery. Cost-effectiveness was assessed by calculating cumulative costs, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) for each regimen. A regimen was considered dominant if it resulted in lower costs and higher effectiveness compared to alternatives, whereas it was classified as dominated if it incurred higher costs and yielded lower effectiveness. Data and Sources Probability The probabilities of surgical site infection (SSI) in this model were derived from a retrospective study conducted in Japan, which evaluated SSI occurrence within 90 days postoperatively across six different prophylactic antibiotic regimens for Type III open fractures [15]. In this study, the absolute number of SSI was explicitly reported for the CEZ and CEZ+AG regimens, whereas for the other four regimens, the SSI incidence rates were provided as bar chart representations. To accurately extract these values, we utilized Origin software for data point estimation, converting graphically represented incidence rates into numerical values for model input. To account for uncertainty and variability, all SSI probability estimates were assumed to follow a Beta distribution, which is commonly used in probabilistic modeling to represent incidence rates. The specific distribution parameters (α, β) for each regimen were derived from the observed SSI counts and are detailed in Table S1. Since the original study did not provide confidence intervals or explicit upper/lower bounds for SSI rates, we estimated these limits using the subgroup infection rates reported for the CEZ and CEZ+AG regimens, stratified by Type IIIA, IIIB, and IIIC fractures. Given that Type IIIC fractures exhibited the highest infection rates and Type IIIA the lowest, we applied this gradient to extrapolate plausible upper and lower bounds for the other four regimens. The lower bound was estimated as 40% below the base SSI rate, while the upper bound was set at 100% above the base rate, ensuring a conservative range for sensitivity analysis. These values are presented in Table S1. In the decision-tree model, each regimen was associated with two possible health states: occurrence of SSI and non-occurrence of SSI. Given this binary structure, the probability of non-occurrence of SSI was defined as 1 minus the SSI incidence rate for the corresponding antibiotic regimen. Cost All costs in this study are presented in Chinese Yuan (CNY). In our model, we assume that each antibiotic regimen follows a unified treatment plan. The specific antibiotic regimens are detailed in Table S2, while the total costs for each regimen are summarized in Table S3. The drug costs for the various antibiotic regimens were sourced from the 2023 Chinese Drug Bidding Database. Given the nature of China's centralized drug procurement policy, it is common for a single manufacturer to dominate the market for each drug in a given province. Accordingly, we collected price data for each antibiotic regimen across different provinces in China. For AG, the prices for gentamicin and amikacin were considered. Each regimen's cost data includes realistic upper and lower bounds, reflecting the variation across provinces. These cost values were modeled using a gamma distribution with mean values and standard deviations (SD) as detailed in Table S3, to allow for uncertainty analysis in the model. The cost of SSI was defined as the additional direct medical expenses incurred by patients who developed SSI compared to those who did not. This value was derived from a study that reviewed costs associated with SSI for orthopedic surgeries in China. Similar to the antibiotic costs, the SSI costs also have upper and lower bounds, and these costs were modeled using a gamma distribution, with the specific parameters provided in Table S3. Utility In our model, there are two possible health states: occurrence of SSI and non-occurrence of SSI, each with corresponding health utility values for the 90-day postoperative period. These values, derived from a quality-of-life study on open fracture patients, provide quality-adjusted life years (QALYs) for patients with and without SSI at 3 months post-surgery. To account for uncertainty, the mean values and SD from the study were used to define normal distributions for each state, with 95% confidence intervals applied for further robustness. These utility values were incorporated into the decision-tree model to calculate the QALYs associated with SSI, and the distribution parameters (mean, SD, and 95% CI) are detailed in Table S4. Sensitivity Analysis To assess the robustness of our model, both one-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were conducted. In the DSA, we evaluated the impact of varying individual model parameters on cost-effectiveness outcomes. The PSA combined simultaneous variations in model parameters through a Monte Carlo simulation, running 1000 iterations to generate 1000 ICER estimates for the competing treatment options. The specific ranges and distributions for each parameter used in both DSA and PSA are detailed in Tables S1, S3, and S4. Results Base-Case Analysis The results of our model showed that, at 90 days post-surgery for Type III open fractures, CEZ was the dominant regimen for preventing SSI compared to other antibiotic options. Specifically, CEZ resulted in a total cost of 1272.47 CNY and a total utility of 0.3425 QALYs. In contrast, all other regimens incurred higher total costs and provided lower health benefits. CTRX was the least cost-effective option in our analysis, incurring the highest total cost of 3864.94 CNY while yielding the lowest total utility of 0.3262 QALYs. Detailed comparisons of the costs and health outcomes between the different antibiotic regimens are provided in Table 1 and Figure S1. (Insert Table 1 about here) The incremental cost-effectiveness ratio (ICER) was calculated relative to CEZ, the dominant regimen. Since CEZ provides both the lowest cost and highest effectiveness, the ICER values for the other regimens are negative. Specifically, the ICER in this case represents the additional cost per QALY lost relative to cefazolin. It is important to note that, since the goal of medical interventions is to improve effectiveness rather than reduce it, the negative ICER values are for reference purposes only and do not have practical significance in this context. Sensitivity Analysis The results of the DSA are presented in tornado diagram. In this analysis, we evaluated the impact of individual parameter variations on the ICER for each regimen compared to CEZ. Across all five regimens analyzed, the two most influential factors on the ICER were the cost of SSI occurrence and the utility value for non-SSI health states. The price of antibiotics had a modest effect on the ICER. However, other factors had minimal influence on the overall cost-effectiveness outcomes. The tornado diagram comparing CEZ with CTRX-which was found to be the least cost-effective regimen-is shown in Figure 2. The DSA results for the remaining regimens can be found in Figures S2 to S5. (Insert Figure 2 about here) The cost-effectiveness acceptability curve (CEAC) shown in Figure 3 illustrates the probability of each antibiotic regimen being cost-effective relative to CEZ across varying willingness-to-pay (WTP) thresholds. At a WTP of 0 CNY, the probabilities of cost-effectiveness for each regimen are as follows: CEZ at 50.8%, CEZ+AG at 19.9%, PIPC/TAZ at 15.7%, CTX at 11.7%, CTRX at 1.3%, and ABPC/SBT at 0.6%. Although the probability of CEZ being cost-effective decreases as the WTP threshold increases, it remains significantly higher than that of the other regimens. The curves for CEZ+AG, PIPC/TAZ, and CTX exhibit relatively stable patterns, suggesting that these regimens maintain consistent performance across different WTP levels, with minimal variation in cost-effectiveness. In contrast, CTRX and ABPC/SBT start with the lowest probabilities of cost-effectiveness at 0 CNY (1.3% and 0.6%, respectively), but as the WTP threshold increases, their probability of being cost-effective also rises, indicating that these regimens perform better under higher levels of willingness to pay. Scatter plots provide a more intuitive display of the cost-effectiveness outcomes for each antibiotic regimen compared to CEZ, with each pairwise comparison based on the 1000 Monte Carlo simulation iterations. At a WTP of 0 CNY, the probability of CEZ being cost-effective relative to the other regimens was 70.9% for CEZ+AG, 79.3% for PIPC/TAZ, 85.7% for CTX, 99.2% for ABPC/SBT, and 98.1% for CTRX. (Insert Figure 3 about here) Figure 4 presents the scatter plot for the simulation results comparing CEZ to CEZ+AG, showing the variation in cost-effectiveness across the 1000 iterations. Figures S6 to S9 display the scatter plots for the remaining regimens, highlighting superiority of CEZ compared to the other options. (Insert Figure 4 about here) Discussion International guidelines recommend the use of first-generation cephalosporins combined with aminoglycosides for the prevention of SSI in Type III open fractures [ 4 , 8 , 10 , 19 , 20 ]. The inclusion of aminoglycosides aims to cover this broad spectrum of pathogens, providing enhanced protection against Gram-negative infections. In fact, there is mounting evidence suggesting that monotherapy with cephalosporins, such as cefazolin, may provide non-inferior efficacy in preventing SSI compared to the combined use. Several recent studies support this view. For example, a study of 126 type III open fractures found comparable SSI rates between cefazolin monotherapy and combination therapy, though the latter showed higher acute kidney injury risk [ 11 ]. Notably, a study of 138 type III open fractures revealed that cefotetan monotherapy showed no significant differences in SSI or deep infection rates compared to traditional regimens [ 21 ]. These findings are consistent with another multicenter study of 134 patients, which found no significant difference in fracture site infection rates between cefazolin monotherapy and combination therapy [ 14 ]. Furthermore, several systematic reviews and meta-analyses have reached consistent conclusions [ 21 – 23 ]. These findings support a shift towards narrow-spectrum antibiotics, which can provide similar efficacy with lower risk of adverse effects and potentially better cost-effectiveness. In China, the 2019 guidelines for open fractures have not been updated and continue to recommend the use of first-generation cephalosporins combined with aminoglycosides for SSI prevention, in line with international recommendations [ 9 ]. However, the guidelines also mention that ceftriaxone can be used as an alternative. Due to its relatively low cost under the VBP policy, ceftriaxone has become a common choice, particularly in county hospitals and primary healthcare settings, for SSI prevention in Type III open fractures. Despite its affordability, our study found that ceftriaxone was the least cost-effective option, offering the lowest health benefit compared to other regimens, such as cefazolin. This highlights the need for updated guidelines and further cost-effectiveness analysis to ensure optimal treatment decisions in the prevention of SSI. There are several limitations to our study that should be considered. First, the infection rates used in our model are derived from a retrospective study conducted on an Asian population [ 15 ]. While the sample size of this study is large, there may be discrepancies between the infection rates observed in this cohort and the real-world infection rates in the Chinese population, especially considering the high costs associated with SSI, which make the cost-effectiveness results highly sensitive to these infection rate assumptions. Second, the dosing regimens for each antibiotic, though based on product labels and guidelines, may vary across different hospitals and physicians. Additionally, the time between fracture occurrence and completion of surgery can differ among patients, which could impact the antibiotic usage and schedules [ 24 , 25 ]. This variability could lead to differences in costs associated with each regimen. Third, the drug prices used in our model were sourced from VBP policy data, focusing on the prices of market-leading manufacturers in each province. While this approach represents the majority market share, a more accurate representation would require collecting all market prices, which was beyond the scope of this study. Finally, ampicillin/sulbactam and piperacillin/tazobactam, require skin testing before use. Although the cost of skin testing is relatively low, it was not included in our cost estimates. Additionally, these two drugs are categorized as restricted in Chinese public hospitals, which limits their clinical use. Therefore, the model’s results for these regimens should be considered for reference only. Conclusions Within the context of the Chinese healthcare system, our study demonstrates the highly cost-effectiveness of cefazolin over other antibiotic regimens for the prevention of SSI following Type III open fractures. Despite the relatively lower cost of ceftriaxone under the VBP policy, our study finds that it is the least cost-effective choice due to its lower clinical benefit. These insights are crucial for guiding clinical decision-making and optimizing antibiotic selection in the prevention of SSI in Type III fractures in China. Declarations Author contributions ST, LF, ZS, RM: Conceptualization, Methodology, Investigation, Formal analysis, Writing – original draft, Writing – review & editing. YZ, PJ: Data curation, Visualization, Writing – review & editing. HL, YG: Supervision, Funding acquisition, Project administration, Writing – review & editing. Conflict of Interest Statement The author(s) have no conflicts of interest relevant to this article. Funding This work was supported by Beijing Life Oasis Public Service Center and Primary Health Care Foundation of China (Grant numbers BH003159-CT202408020051) and the Key R&D Program of Jining (Grant numbers 2023YXNS205). Consent to Publish declaration This manuscript has not been published or presented elsewhere in part or in entirety, and is not under consideration by another journal. All the authors have approved the manuscript and agree with submission to your esteemed journal. Ethical Review Committee Statement Ethical approval for this study was waived by the Clinical Ethics Committee of Jining No.1 People's Hospital (Approval number 2024-药-快002). Consent to Participate declaration Not applicable. Disclosure instructions During the preparation of this work, we used ChatGPT in order to improve readability and language expression. After using this tool, we reviewed and edited the content as needed and take full responsibility for the content of the publication. 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Base-Case Analysis Results for Antibiotic Regimens Regimen Cost (CNY) Incremental Cost (CNY) Effectiveness (QALY) Incremental Effectiveness (QALY) ICER (CNY/QALY) CEZ 1272.47 - 0.3425 - - CEZ+AG 1450.81 178.34 0.3415 -0.0011 -165835.77 PIPC/TAZ 1742.26 469.80 0.3405 -0.0020 -236009.93 CTX 2199.28 926.81 0.3365 -0.0060 -153327.50 ABPC/SBT 3800.16 2527.69 0.3267 -0.0159 -159330.68 CTRX 3864.94 2592.47 0.3262 -0.0163 -158651.64 Abbreviations: CNY, Chinese Yuan; QALY, quality-adjusted life years; CEZ, cefazolin; CEZ+AG, cefazolin combined with aminoglycosides; PIPC/TAZ, piperacillin/tazobactam; CTX, cefotaxime; ABPC/SBT, ampicillin/sulbactam; CTRX, ceftriaxone. Additional Declarations No competing interests reported. Supplementary Files Supplementary.docx Supplementary Material Supplementary materials have been uploaded separately. Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2026 Read the published version in Health and Quality of Life Outcomes → Version 1 posted Editorial decision: Revision requested 28 Dec, 2025 Reviews received at journal 26 Oct, 2025 Reviews received at journal 19 Oct, 2025 Reviewers agreed at journal 11 Oct, 2025 Reviewers agreed at journal 09 Oct, 2025 Reviewers invited by journal 29 Jul, 2025 Editor assigned by journal 20 Jul, 2025 Submission checks completed at journal 20 Jul, 2025 First submitted to journal 14 Jul, 2025 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 Advisory Board 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-7118629","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":494849466,"identity":"41fbdbf9-48ab-4c46-8c4e-e1be0c3f8f20","order_by":0,"name":"Shuo Tian","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Tian","suffix":""},{"id":494849467,"identity":"efd5d898-39a2-4ab4-824a-cee7698b06e9","order_by":1,"name":"Lei Feng","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Feng","suffix":""},{"id":494849468,"identity":"e6aa5f78-8b17-4ad3-8f3f-7917a087bf72","order_by":2,"name":"Zhen Sun","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Sun","suffix":""},{"id":494849469,"identity":"b02b72a5-486c-40ee-a736-c17cd6640a87","order_by":3,"name":"Ruishuai Miao","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruishuai","middleName":"","lastName":"Miao","suffix":""},{"id":494849470,"identity":"a5b8a53f-e9e6-4b37-a55c-ef7250de02dd","order_by":4,"name":"Yazhou Zhang","email":"","orcid":"","institution":"Tengzhou Central People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yazhou","middleName":"","lastName":"Zhang","suffix":""},{"id":494849471,"identity":"a5e00cae-18b3-4384-9859-ef4b75702950","order_by":5,"name":"Pei Jiang","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Pei","middleName":"","lastName":"Jiang","suffix":""},{"id":494849472,"identity":"7ed3a9ed-09fe-436f-9886-b2346b0a15e2","order_by":6,"name":"Hongqiang Liu","email":"","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongqiang","middleName":"","lastName":"Liu","suffix":""},{"id":494849473,"identity":"81275530-73b2-4144-9983-683ff04fe5f6","order_by":7,"name":"Yujin Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArUlEQVRIiWNgGAWjYHCCxAcfKiTk+EnRkmw444yFsWQDCVrYpHnbKhI3EK1FPiLhmTTvPAnGDQzMDx/dIEaL4Y2EZMu52ySYzRnYjI1ziNIyIyHxxtttEmyWDTxs0sRqSZDgnSPBY3CAWC3yEglJkrwNEhLEazHgeQAM5GMSBpLNxPpFvj0HGJU1dfX97M0PHxNny4WcBAiLmRjlYFv6jx8gVu0oGAWjYBSMVAAAI5wwq/vvW/0AAAAASUVORK5CYII=","orcid":"","institution":"Jining No.1 People's Hospital, Shandong First Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yujin","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2025-07-14 08:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7118629/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7118629/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12955-026-02517-9","type":"published","date":"2026-03-25T16:13:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88231490,"identity":"74a52c85-e759-4867-97d1-92924695b29f","added_by":"auto","created_at":"2025-08-04 09:35:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":190038,"visible":true,"origin":"","legend":"\u003cp\u003eDiagram of decision tree model\u003cbr\u003e\nAbbreviations: SSI, Surgical site infections; CEZ, cefazolin; CEZ+AG, cefazolin combined with aminoglycosides; GM, gentamycin; AMK, amikacin; PIPC/TAZ, piperacillin/tazobactam; CTX, cefotaxime; ABPC/SBT, ampicillin/sulbactam; CTRX, ceftriaxone.\u003c/p\u003e","description":"","filename":"Figure1.Diagramofdecisiontreemodel.png","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/aa250387f53562a70e0f3711.png"},{"id":88231492,"identity":"3414e69f-7bd0-4eb0-bc33-a321b0fee833","added_by":"auto","created_at":"2025-08-04 09:35:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":203061,"visible":true,"origin":"","legend":"\u003cp\u003eTornado Diagram Comparing CEZ with CTRX\u003cbr\u003e\nAbbreviations: SSI, Surgical site infections; CEZ, cefazolin; CEZ+AG, cefazolin combined with aminoglycosides; GM, gentamycin; AMK, amikacin; PIPC/TAZ, piperacillin/tazobactam; CTX, cefotaxime; ABPC/SBT, ampicillin/sulbactam; CTRX, ceftriaxone; CNY, Chinese Yuan; ICER, incremental cost-effectiveness ratio; EV, expected value.\u003c/p\u003e","description":"","filename":"Figure2.TornadoDiagramComparingCEZwithCTRXinDSA.png","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/6484707f394036a8da0707e9.png"},{"id":88232897,"identity":"67d4d72a-ec3a-4e96-a1ab-b10021055a7c","added_by":"auto","created_at":"2025-08-04 09:43:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":403878,"visible":true,"origin":"","legend":"\u003cp\u003eCost-Effectiveness Acceptability Curve\u003cbr\u003e\nAbbreviations: CEZ, cefazolin; CEZ+AG, cefazolin combined with aminoglycosides; PIPC/TAZ, piperacillin/tazobactam; CTX, cefotaxime; ABPC/SBT, ampicillin/sulbactam; CTRX, ceftriaxone.\u003c/p\u003e","description":"","filename":"Figure3.CostEffectivenessAcceptabilityCurve.png","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/f6cbcb110f66710289c43de7.png"},{"id":88231509,"identity":"eddcfddb-ba69-4524-8781-20eb6014ceb4","added_by":"auto","created_at":"2025-08-04 09:35:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":330016,"visible":true,"origin":"","legend":"\u003cp\u003eMonte Carlo Simulation Scatter Plot (comparing CEZ to CEZ+AG)\u003cbr\u003e\nAbbreviations: WTP, Willingness-to-pay.\u003c/p\u003e","description":"","filename":"Figure4.MonteCarloSimulationScatterPlot.png","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/65a7d562123a357842f1ee8e.png"},{"id":105756074,"identity":"c89653ad-6a22-4b31-8ecf-231ea38646df","added_by":"auto","created_at":"2026-03-30 16:35:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1605811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/4aca7b2f-ba19-4ee3-b66e-1342c577ee2e.pdf"},{"id":88232899,"identity":"e195fee0-2c75-4be0-9e70-5804b0db5fd3","added_by":"auto","created_at":"2025-08-04 09:43:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11951238,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary materials have been uploaded separately.\u003c/p\u003e","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7118629/v1/7d2e6c6e5d8a253331fc04ae.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Optimizing Antibiotic Prophylaxis for Type III Open Fractures in China: A Cost- Effectiveness Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSurgical site infections (SSI) remain a significant concern in the management of Gustilo-Anderson type III open fractures, as these severe injuries are associated with a high risk of deep infections and poor clinical outcomes [1-3]. The infection rate for SSI in Type III open fractures can be as high as 50%, which is considerably higher compared to less severe fracture types (Type I and II) [4-6]. Despite advancements in surgical techniques and infection control strategies, SSI can lead to prolonged hospital stays, increased healthcare costs, and adverse long-term outcomes [7]. Early and appropriate antibiotic prophylaxis is universally recommended as a key component of perioperative infection prevention strategies to mitigate these risks and reduce infection-related complications [8]. According to the Chinese guidelines for open fractures, first-generation cephalosporins (e.g., cefazolin, or clindamycin for those allergic to penicillin) are recommended as the base therapy for all open fractures. For Type III fractures, the guidelines advocate the combination of first-generation cephalosporins with aminoglycosides as the primary prophylactic regimen. Alternative regimens include third-generation cephalosporins, such as ceftriaxone, or piperacillin-tazobactam, aimed at providing broader coverage against both Gram-positive and Gram-negative pathogens [9]. These recommendations are consistent with international guidelines, which also emphasize the use of broad-spectrum antibiotics to account for the increased risk of Gram-negative infections in Type III open fractures [8,10]. However, the necessity of broad-spectrum antibiotic coverage has been increasingly questioned. Multiple studies have shown that in Type III open fractures, narrow-spectrum antibiotics (such as cefazolin alone) may offer non-inferior efficacy in preventing SSI compared to broad-spectrum antibiotics, especially when administered early and effectively [4,11-15].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Chinese Volume-Based Procurement (VBP) policy, implemented in recent years, has significantly altered the landscape of antibiotic pricing and availability, affecting the cost-effectiveness of various therapeutic options [16,17]. While extensive research on the cost-effectiveness of antimicrobial prophylaxis exists in other surgical fields, studies specifically addressing Type III open fractures are limited. To fill this gap, this study aims to perform a comprehensive cost-effectiveness evaluation of various prophylactic antibiotic regimens for Type III open fractures, considering both clinical efficacy and economic feasibility in the Chinese healthcare setting.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003e\u003cem\u003eOverview\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized TreeAge Pro 2022 software to construct a decision-tree model assessing the cost-effectiveness of different antibiotic prophylaxis regimens for the prevention of SSI in patients with Gustilo-Anderson Type III open fractures. Efficacy data were derived from a retrospective study conducted in Japan [15]. The economic evaluation adhered to the Chinese Guidelines for Pharmacoeconomic Evaluations (2020), ensuring methodological consistency with national pharmacoeconomic standards [18]. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eModel Construction\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA decision-tree model was developed to compare the cost-effectiveness of six prophylactic antibiotic regimens in preventing SSI following Type III open fractures. The evaluated regimens included: cefazolin (CEZ), cefazolin combined with aminoglycosides (CEZ+AG), piperacillin/tazobactam (PIPC/TAZ), cefotaxime (CTX), ampicillin/sulbactam (ABPC/SBT) and ceftriaxone (CTRX). Each regimen was associated with two possible health outcomes: occurrence of SSI and non-occurrence of SSI (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(Insert Figure 1 about here)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe model simulated patient outcomes over a 90-day postoperative period, consistent with the timeframe utilized in the referenced retrospective study, which defined deep SSI as infections occurring within 90 days post-surgery. Cost-effectiveness was assessed by calculating cumulative costs, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) for each regimen. A regimen was considered dominant if it resulted in lower costs and higher effectiveness compared to alternatives, whereas it was classified as dominated if it incurred higher costs and yielded lower effectiveness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData and Sources\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProbability\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe probabilities of surgical site infection (SSI) in this model were derived from a retrospective study conducted in Japan, which evaluated SSI occurrence within 90 days postoperatively across six different prophylactic antibiotic regimens for Type III open fractures [15]. In this study, the absolute number of SSI was explicitly reported for the CEZ and CEZ+AG regimens, whereas for the other four regimens, the SSI incidence rates were provided as bar chart representations. To accurately extract these values, we utilized Origin software for data point estimation, converting graphically represented incidence rates into numerical values for model input. To account for uncertainty and variability, all SSI probability estimates were assumed to follow a Beta distribution, which is commonly used in probabilistic modeling to represent incidence rates. The specific distribution parameters (α, β) for each regimen were derived from the observed SSI counts and are detailed in Table S1. Since the original study did not provide confidence intervals or explicit upper/lower bounds for SSI rates, we estimated these limits using the subgroup infection rates reported for the CEZ and CEZ+AG regimens, stratified by Type IIIA, IIIB, and IIIC fractures. Given that Type IIIC fractures exhibited the highest infection rates and Type IIIA the lowest, we applied this gradient to extrapolate plausible upper and lower bounds for the other four regimens. The lower bound was estimated as 40% below the base SSI rate, while the upper bound was set at 100% above the base rate, ensuring a conservative range for sensitivity analysis. These values are presented in Table S1. In the decision-tree model, each regimen was associated with two possible health states: occurrence of SSI and non-occurrence of SSI. Given this binary structure, the probability of non-occurrence of SSI was defined as 1 minus the SSI incidence rate for the corresponding antibiotic regimen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCost\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll costs in this study are presented in Chinese Yuan (CNY). In our model, we assume that each antibiotic regimen follows a unified treatment plan. The specific antibiotic regimens are detailed in Table S2, while the total costs for each regimen are summarized in Table S3. The drug costs for the various antibiotic regimens were sourced from the 2023 Chinese Drug Bidding Database. Given the nature of China's centralized drug procurement policy, it is common for a single manufacturer to dominate the market for each drug in a given province. Accordingly, we collected price data for each antibiotic regimen across different provinces in China. For AG, the prices for gentamicin and amikacin were considered. Each regimen's cost data includes realistic upper and lower bounds, reflecting the variation across provinces. These cost values were modeled using a gamma distribution with mean values and standard deviations (SD) as detailed in Table S3, to allow for uncertainty analysis in the model. The cost of SSI was defined as the additional direct medical expenses incurred by patients who developed SSI compared to those who did not. This value was derived from a study that reviewed costs associated with SSI for orthopedic surgeries in China. Similar to the antibiotic costs, the SSI costs also have upper and lower bounds, and these costs were modeled using a gamma distribution, with the specific parameters provided in Table S3. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUtility\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn our model, there are two possible health states: occurrence of SSI and non-occurrence of SSI, each with corresponding health utility values for the 90-day postoperative period. These values, derived from a quality-of-life study on open fracture patients, provide quality-adjusted life years (QALYs) for patients with and without SSI at 3 months post-surgery. To account for uncertainty, the mean values and SD from the study were used to define normal distributions for each state, with 95% confidence intervals applied for further robustness. These utility values were incorporated into the decision-tree model to calculate the QALYs associated with SSI, and the distribution parameters (mean, SD, and 95% CI) are detailed in Table S4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;To assess the robustness of our model, both one-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were conducted. In the DSA, we evaluated the impact of varying individual model parameters on cost-effectiveness outcomes. The PSA combined simultaneous variations in model parameters through a Monte Carlo simulation, running 1000 iterations to generate 1000 ICER estimates for the competing treatment options. The specific ranges and distributions for each parameter used in both DSA and PSA are detailed in Tables S1, S3, and S4.\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003e\u003cem\u003eBase-Case Analysis\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe results of our model showed that, at 90 days post-surgery for Type III open fractures, CEZ was the dominant regimen for preventing SSI compared to other antibiotic options. Specifically, CEZ resulted in a total cost of 1272.47 CNY and a total utility of 0.3425 QALYs. In contrast, all other regimens incurred higher total costs and provided lower health benefits. CTRX was the least cost-effective option in our analysis, incurring the highest total cost of 3864.94 CNY while yielding the lowest total utility of 0.3262 QALYs. Detailed comparisons of the costs and health outcomes between the different antibiotic regimens are provided in Table 1 and Figure S1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(Insert Table 1 about here)\u003c/p\u003e\n\u003cp\u003eThe incremental cost-effectiveness ratio (ICER) was calculated relative to CEZ, the dominant regimen. Since CEZ provides both the lowest cost and highest effectiveness, the ICER values for the other regimens are negative. Specifically, the ICER in this case represents the additional cost per QALY lost relative to cefazolin. It is important to note that, since the goal of medical interventions is to improve effectiveness rather than reduce it, the negative ICER values are for reference purposes only and do not have practical significance in this context.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity Analysis\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the DSA are presented in tornado diagram. In this analysis, we evaluated the impact of individual parameter variations on the ICER for each regimen compared to CEZ. Across all five regimens analyzed, the two most influential factors on the ICER were the cost of SSI occurrence and the utility value for non-SSI health states. The price of antibiotics had a modest effect on the ICER. However, other factors had minimal influence on the overall cost-effectiveness outcomes. The tornado diagram comparing CEZ with CTRX-which was found to be the least cost-effective regimen-is shown in Figure 2. The DSA results for the remaining regimens can be found in Figures S2 to S5.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(Insert Figure 2 about here)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe cost-effectiveness acceptability curve (CEAC) shown in Figure 3 illustrates the probability of each antibiotic regimen being cost-effective relative to CEZ across varying willingness-to-pay (WTP) thresholds. At a WTP of 0 CNY, the probabilities of cost-effectiveness for each regimen are as follows: CEZ at 50.8%, CEZ+AG at 19.9%, PIPC/TAZ at 15.7%, CTX at 11.7%, CTRX at 1.3%, and ABPC/SBT at 0.6%. Although the probability of CEZ being cost-effective decreases as the WTP threshold increases, it remains significantly higher than that of the other regimens. The curves for CEZ+AG, PIPC/TAZ, and CTX exhibit relatively stable patterns, suggesting that these regimens maintain consistent performance across different WTP levels, with minimal variation in cost-effectiveness. In contrast, CTRX and ABPC/SBT start with the lowest probabilities of cost-effectiveness at 0 CNY (1.3% and 0.6%, respectively), but as the WTP threshold increases, their probability of being cost-effective also rises, indicating that these regimens perform better under higher levels of willingness to pay. Scatter plots provide a more intuitive display of the cost-effectiveness outcomes for each antibiotic regimen compared to CEZ, with each pairwise comparison based on the 1000 Monte Carlo simulation iterations. At a WTP of 0 CNY, the probability of CEZ being cost-effective relative to the other regimens was 70.9% for CEZ+AG, 79.3% for PIPC/TAZ, 85.7% for CTX, 99.2% for ABPC/SBT, and 98.1% for CTRX.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(Insert Figure 3 about here)\u003c/p\u003e\n\u003cp\u003eFigure 4 presents the scatter plot for the simulation results comparing CEZ to CEZ+AG, showing the variation in cost-effectiveness across the 1000 iterations. Figures S6 to S9 display the scatter plots for the remaining regimens, highlighting superiority of CEZ compared to the other options.\u003c/p\u003e\n\u003cp\u003e(Insert Figure 4 about here)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eInternational guidelines recommend the use of first-generation cephalosporins combined with aminoglycosides for the prevention of SSI in Type III open fractures [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The inclusion of aminoglycosides aims to cover this broad spectrum of pathogens, providing enhanced protection against Gram-negative infections. In fact, there is mounting evidence suggesting that monotherapy with cephalosporins, such as cefazolin, may provide non-inferior efficacy in preventing SSI compared to the combined use. Several recent studies support this view. For example, a study of 126 type III open fractures found comparable SSI rates between cefazolin monotherapy and combination therapy, though the latter showed higher acute kidney injury risk [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Notably, a study of 138 type III open fractures revealed that cefotetan monotherapy showed no significant differences in SSI or deep infection rates compared to traditional regimens [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These findings are consistent with another multicenter study of 134 patients, which found no significant difference in fracture site infection rates between cefazolin monotherapy and combination therapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, several systematic reviews and meta-analyses have reached consistent conclusions [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. These findings support a shift towards narrow-spectrum antibiotics, which can provide similar efficacy with lower risk of adverse effects and potentially better cost-effectiveness. In China, the 2019 guidelines for open fractures have not been updated and continue to recommend the use of first-generation cephalosporins combined with aminoglycosides for SSI prevention, in line with international recommendations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the guidelines also mention that ceftriaxone can be used as an alternative. Due to its relatively low cost under the VBP policy, ceftriaxone has become a common choice, particularly in county hospitals and primary healthcare settings, for SSI prevention in Type III open fractures. Despite its affordability, our study found that ceftriaxone was the least cost-effective option, offering the lowest health benefit compared to other regimens, such as cefazolin. This highlights the need for updated guidelines and further cost-effectiveness analysis to ensure optimal treatment decisions in the prevention of SSI.\u003c/p\u003e\u003cp\u003eThere are several limitations to our study that should be considered. First, the infection rates used in our model are derived from a retrospective study conducted on an Asian population [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. While the sample size of this study is large, there may be discrepancies between the infection rates observed in this cohort and the real-world infection rates in the Chinese population, especially considering the high costs associated with SSI, which make the cost-effectiveness results highly sensitive to these infection rate assumptions. Second, the dosing regimens for each antibiotic, though based on product labels and guidelines, may vary across different hospitals and physicians. Additionally, the time between fracture occurrence and completion of surgery can differ among patients, which could impact the antibiotic usage and schedules [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This variability could lead to differences in costs associated with each regimen. Third, the drug prices used in our model were sourced from VBP policy data, focusing on the prices of market-leading manufacturers in each province. While this approach represents the majority market share, a more accurate representation would require collecting all market prices, which was beyond the scope of this study. Finally, ampicillin/sulbactam and piperacillin/tazobactam, require skin testing before use. Although the cost of skin testing is relatively low, it was not included in our cost estimates. Additionally, these two drugs are categorized as restricted in Chinese public hospitals, which limits their clinical use. Therefore, the model\u0026rsquo;s results for these regimens should be considered for reference only.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWithin the context of the Chinese healthcare system, our study demonstrates the highly cost-effectiveness of cefazolin over other antibiotic regimens for the prevention of SSI following Type III open fractures. Despite the relatively lower cost of ceftriaxone under the VBP policy, our study finds that it is the least cost-effective choice due to its lower clinical benefit. These insights are crucial for guiding clinical decision-making and optimizing antibiotic selection in the prevention of SSI in Type III fractures in China.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eST, LF, ZS, RM: Conceptualization, Methodology, Investigation, Formal analysis, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing. YZ, PJ: Data curation, Visualization, Writing \u0026ndash; review \u0026amp; editing. HL, YG: Supervision, Funding acquisition, Project administration, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) have no conflicts of interest relevant to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Beijing Life Oasis Public Service Center and Primary Health Care Foundation of China (Grant numbers BH003159-CT202408020051) and the Key R\u0026amp;D Program of Jining (Grant numbers 2023YXNS205).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript has not been published or presented elsewhere in part or in entirety, and is not under consideration by another journal. All the authors have approved the manuscript and agree with submission to your esteemed journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Review Committee Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was waived by the Clinical Ethics Committee of Jining No.1 People\u0026apos;s Hospital (Approval number 2024-药-快002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure instructions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, we used ChatGPT in order to improve readability and language expression. After using this tool, we reviewed and edited the content as needed and take full responsibility for the content of the publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eO\u0026apos;Connor O, Thahir A, Krkovic M. How Much Does an Infected Fracture Cost? The archives of bone and joint surgery 2022;10(2):135-40.\u003c/li\u003e\n\u003cli\u003eRupp M, Popp D, Alt V. Prevention of infection in open fractures: Where are the pendulums now? Injury 2020;51:S57-S63.\u003c/li\u003e\n\u003cli\u003eSiebler J, Ogden B, Deans C, McCarthy M, Lyden E, Hewlett A, et al. A Performance Improvement Project in Antibiotic Administration for Open Fractures. Journal of the American Academy of Orthopaedic Surgeons 2020;28(1):e34-e40.\u003c/li\u003e\n\u003cli\u003eRodriguez L, Jung HS, Goulet JA, Cicalo A, Machado-Aranda DA, Napolitano LM. Evidence-based protocol for prophylactic antibiotics in open fractures: Improved antibiotic stewardship with no increase in infection rates. Journal of Trauma and Acute Care Surgery 2014;77(3):400-08.\u003c/li\u003e\n\u003cli\u003eSaveli CC, Morgan SJ, Belknap RW, Ross E, Stahel PF, Chaus GW, et al. Prophylactic antibiotics in open fractures: a pilot randomized clinical safety study. Journal of orthopaedic trauma 2013;27(10):552-7.\u003c/li\u003e\n\u003cli\u003eTakahara S, Tokura T, Nishida R, Uefuji A, Ichimura K, Nishihara H, et al. Ampicillin/sulbactam versus cefazolin plus aminoglycosides for antimicrobial prophylaxis in management of Gustilo type IIIA open fractures: A retrospective cohort study. Injury 2022;53(4):1517-22.\u003c/li\u003e\n\u003cli\u003eParker B, Petrou S, Masters JPM, Achana F, Costa ML. Economic outcomes associated with deep surgical site infection in patients with an open fracture of the lower limb. Bone Joint J 2018;100-b(11):1506-10.\u003c/li\u003e\n\u003cli\u003eHoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: Update to Practice Management Guidelines for Prophylactic Antibiotic Use in Open Fractures. J Trauma 2011;2011(70).\u003c/li\u003e\n\u003cli\u003eTraumatic Orthopedics Group Society of Orthopedics Chinese Medical Association, Group of External Fixation and Limb Reconstruction Society of Orthopedics Chinese Medical Association, Professional Committee of Traumatic Infection Society of Traumatic Surgeons Association of Chinese Doctors, Trauma Experts Working Committee Society of Orthopaedists Association of Chinese Doctors. Guidelines on diagnosis and treatment of open fractures in China(2019). Chinese Journal of Orthopaedic Trauma 2019;21(11):921-28. [In Chinese].\u003c/li\u003e\n\u003cli\u003eHauser CJ, Adams CA, Jr., Eachempati SR. Surgical Infection Society guideline: prophylactic antibiotic use in open fractures: an evidence-based guideline. Surg Infect (Larchmt) 2006;7(4):379-405.\u003c/li\u003e\n\u003cli\u003eBankhead-Kendall B, Gutierrez T, Murry J, Holland D, Agrawal V, Almahmoud K, et al. Antibiotics and open fractures of the lower extremity: less is more. European Journal of Trauma and Emergency Surgery 2017;45(1):125-29.\u003c/li\u003e\n\u003cli\u003eHand TL, Hand EO, Welborn A, Zelle BA. Gram-Negative Antibiotic Coverage in Gustilo-Anderson Type-III Open Fractures. Journal of Bone and Joint Surgery 2020;102(16):1468-74.\u003c/li\u003e\n\u003cli\u003eLloyd BA, Murray CK, Shaikh F, Carson ML, Blyth DM, Schnaubelt ER, et al. Early infectious outcomes after addition of fluoroquinolone or aminoglycoside to posttrauma antibiotic prophylaxis in combat-related open fracture injuries. Journal of Trauma and Acute Care Surgery 2017;83(5):854-61.\u003c/li\u003e\n\u003cli\u003ePatanwala AE, Radosevich JJ, Meshay I, Naderi M, Culver MA, Lee YG, et al. Cefazolin Monotherapy Versus Cefazolin Plus Aminoglycosides for Antimicrobial Prophylaxis of Type III Open Fractures. American journal of therapeutics 2019;28(3):e284-e91.\u003c/li\u003e\n\u003cli\u003eSuzuki T, Inui T, Sakai M, Ishii K, Kurozumi T, Watanabe Y. Type III Gustilo\u0026ndash;Anderson open fracture does not justify routine prophylactic Gram-negative antibiotic coverage. Scientific Reports 2023;13(1).\u003c/li\u003e\n\u003cli\u003eTong R, Zhao J, Wang M, Li X, Cui X, Liang S, et al. Expert Consensus on the Management of Centralized Volume-based Procurement of Antibacterial Drugs in Medical Institutions. Herald of Medicine 2023;42(01):1-5. [In Chinese].\u003c/li\u003e\n\u003cli\u003eXie Y, Luo Y, Tian Y, Ao B. Research on the Evaluation of the Implementation Effect of the Centralized Volume-based Procurement of Drugs in Public Hospitals. Chinese Hospitals 2025;29(02):6-10. [In Chinese].\u003c/li\u003e\n\u003cli\u003eYue X, Li Y, Wu J, Guo JJ. Current Development and Practice of Pharmacoeconomic Evaluation Guidelines for Universal Health Coverage in China. Value Health Reg Issues 2021;24:1-5.\u003c/li\u003e\n\u003cli\u003eBuckman SA, Forrester JD, Bessoff KE, Parli SE, Evans HL, Huston JM. Surgical Infection Society Guidelines: 2022 Updated Guidelines for Antibiotic Use in Open Extremity Fractures. Surg Infect (Larchmt) 2022;23(9):817-28.\u003c/li\u003e\n\u003cli\u003eHalawi MJ, Morwood MP. Acute Management of Open Fractures: An Evidence-Based Review. Orthopedics 2015;38(11).\u003c/li\u003e\n\u003cli\u003eVia GG, Brueggeman DA, Murray VA, Froehle AW, Burdette SD, Prayson MJ. Use of single agent Cefotetan for Gustilo-Anderson type III open fracture prophylaxis. Injury 2023;54(8):110914.\u003c/li\u003e\n\u003cli\u003eLin CA, O\u0026apos;Hara NN, Sprague S, O\u0026apos;Toole RV, Joshi M, Harris AD, et al. Low Adherence to Recommended Guidelines for Open Fracture Antibiotic Prophylaxis. J Bone Joint Surg Am 2021;103(7):609-17. [eng].\u003c/li\u003e\n\u003cli\u003eSamai K, Vilella A. Update in Therapeutics: Prophylactic Antibiotics in Open Fractures. Journal of Trauma Nursing 2018;25(2):83-86.\u003c/li\u003e\n\u003cli\u003eUkai T, Hamahashi K, Uchiyama Y, Kobayashi Y, Watanabe M. Retrospective analysis of risk factors for deep infection in lower limb Gustilo\u0026ndash;Anderson type III fractures. Journal of Orthopaedics and Traumatology 2020;21(1).\u003c/li\u003e\n\u003cli\u003eZuelzer DA, Hayes CB, Hautala GS, Akbar A, Mayer RR, Jacobs CA, et al. Early Antibiotic Administration Is Associated with a Reduced Infection Risk When Combined with Primary Wound Closure in Patients with Open Tibia Fractures. Clinical Orthopaedics \u0026amp; Related Research 2021;479(3):613-19.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Base-Case Analysis Results for Antibiotic Regimens\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCost\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(CNY)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003eIncremental Cost\u003c/p\u003e\n \u003cp\u003e(CNY)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eEffectiveness\u003c/p\u003e\n \u003cp\u003e(QALY)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eIncremental Effectiveness\u003c/p\u003e\n \u003cp\u003e(QALY)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eICER\u003c/p\u003e\n \u003cp\u003e(CNY/QALY)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCEZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1272.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCEZ+AG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1450.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e178.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.0011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-165835.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003ePIPC/TAZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e1742.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e469.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.0020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-236009.93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e2199.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e926.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.0060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-153327.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eABPC/SBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e3800.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e2527.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3267\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.0159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-159330.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCTRX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e3864.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e2592.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0.3262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.0163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e-158651.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: CNY, Chinese Yuan; QALY, quality-adjusted life years; CEZ, cefazolin; CEZ+AG, cefazolin combined with aminoglycosides; PIPC/TAZ, piperacillin/tazobactam; CTX, cefotaxime; ABPC/SBT, ampicillin/sulbactam; CTRX, ceftriaxone.\u003c/p\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":"health-and-quality-of-life-outcomes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hqlo","sideBox":"Learn more about [Health and Quality of Life Outcomes](http://hqlo.biomedcentral.com)","snPcode":"12955","submissionUrl":"https://submission.nature.com/new-submission/12955/3","title":"Health and Quality of Life Outcomes","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cost-effectiveness, antibiotic prophylaxis, open fractures, cefazolin, surgical site infection","lastPublishedDoi":"10.21203/rs.3.rs-7118629/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7118629/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSurgical site infections (SSI) remain a significant concern following Type III open fractures. Recent studies have suggested that narrow-spectrum antibiotics like cefazolin (CEZ) may offer comparable efficacy to broader-spectrum combinations in preventing SSI, with potential cost benefits. However, the cost-effectiveness of different prophylactic regimens in Type III open fractures in China has not been comprehensively evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSix prophylactic antibiotic regimens were compared: cefazolin (CEZ), cefazolin + aminoglycosides (CEZ+AG), piperacillin/tazobactam (PIPC/TAZ), cefotaxime (CTX), ampicillin/sulbactam (ABPC/SBT) and ceftriaxone (CTRX). Transition probabilities and utility values were derived from published clinical studies, while cost data were obtained from the Chinese Volume-Based Procurement (VBP) policy for drug pricing, along with additional expenses incurred due to SSI. Sensitivity analyses were conducted to assess the robustness of the findings against variations in key parameters.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrom the perspective of the Chinese healthcare system, CEZ emerged as the most cost-effective regimen overall, with a total cost of 1272.47 CNY and a total utility of 0.3425 QALYs. In contrast, all other regimens were found to be dominated strategies, offering neither economic nor health utility advantages. Among these, CTRX was the least favorable, incurring the highest cost (3864.94 CNY) while yielding the lowest total utility (0.3262 QALYs). Sensitivity analyses confirmed the robustness of these findings, reinforcing CEZ as the dominant and most cost-effective option.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study highlights the cost-effectiveness advantage of CEZ in preventing SSI following Type III open fractures in China. CEZ is the most cost-effective option overall, demonstrating a clear advantage over all other regimens. These findings provide essential insights for guiding antibiotic selection and optimizing healthcare resource allocation in the prevention of surgical infections.\u003c/p\u003e","manuscriptTitle":"Optimizing Antibiotic Prophylaxis for Type III Open Fractures in China: A Cost- Effectiveness Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-04 09:35:28","doi":"10.21203/rs.3.rs-7118629/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-29T00:53:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-26T04:42:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-19T15:33:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"338555348761150252542380574688788827751","date":"2025-10-11T15:17:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277184634481763427687874139490593604025","date":"2025-10-09T08:20:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-30T01:30:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-21T02:27:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-21T02:27:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Health and Quality of Life Outcomes","date":"2025-07-14T08:07:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"health-and-quality-of-life-outcomes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hqlo","sideBox":"Learn more about [Health and Quality of Life Outcomes](http://hqlo.biomedcentral.com)","snPcode":"12955","submissionUrl":"https://submission.nature.com/new-submission/12955/3","title":"Health and Quality of Life Outcomes","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c938ede-bed3-47ea-a9d0-e0a328a5572f","owner":[],"postedDate":"August 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:33:21+00:00","versionOfRecord":{"articleIdentity":"rs-7118629","link":"https://doi.org/10.1186/s12955-026-02517-9","journal":{"identity":"health-and-quality-of-life-outcomes","isVorOnly":false,"title":"Health and Quality of Life Outcomes"},"publishedOn":"2026-03-25 16:13:19","publishedOnDateReadable":"March 25th, 2026"},"versionCreatedAt":"2025-08-04 09:35:28","video":"","vorDoi":"10.1186/s12955-026-02517-9","vorDoiUrl":"https://doi.org/10.1186/s12955-026-02517-9","workflowStages":[]},"version":"v1","identity":"rs-7118629","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7118629","identity":"rs-7118629","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}