Predictive value of AFR and UCR for the Methicillin-resistant Staphylococcus aureus infection in children with bone and joint infections

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Therefore, this study aimed to evaluate the predictive value of the albumin-to-fibrinogen ratio (AFR) and the urea-to-creatinine ratio (UCR) at admission for MRSA infections in pediatric patients with BJIs. Methods: Patients were retrospectively categorized into MRSA ( n = 23) and methicillin-susceptible Staphylococcus aureus (MSSA, n = 54) groups based on microbiological culture results (MSSA group = 0, MRSA group = 1). Clinical data and laboratory parameters, including serum albumin, fibrinogen, urea, creatinine, white blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were collected. Receiver operating characteristic (ROC) curves were employed to assess the predictive accuracy of AFR and UCR for MRSA infection. Logistic regression analyses were conducted to identify independent predictors of MRSA infection. Results: Compared to the MSSA group, the MRSA group demonstrated significantly lower values for both AFR and UCR values (both P < 0.05). ROC analysis indicated moderate diagnostic accuracy for AFR (AUC = 0.696) and UCR (AUC = 0.655) in predicting MRSA infections. Multivariate logistic regression analysis confirmed that higher levels of AFR > 6.73 and UCR > 23.91 served as independent protective factors against MRSA infection ( P = 0.016 and P = 0.024, respectively). Traditional inflammatory markers (WBC, CRP, and ESR) showed no significant differences between groups ( P > 0.05). Conclusions: In pediatric patients admitted with BJIs, AFR ≤ 6.73 and UCR ≤ 23.91 at admission may indicate an increased likelihood of MRSA infection. Both AFR and UCR exhibit moderate predictive value for early identification of MRSA-associated pediatric BJIs, thus they may facilitate optimization of empirical antimicrobial therapy. Bone and joint infections Pediatrics Methicillin-resistant Staphylococcus aureus Albumin to fibrinogen ratio Urea to creatinine ratio Predictive biomarkers Background Bone and joint infections (BJIs), primarily acute osteomyelitis and septic arthritis, represent significant pediatric conditions often arise from the hematogenous spread of pathogenic microorganisms [ 1 , 2 ]. Staphylococcus aureus remains the predominant pathogen, however, local epidemiological variations can influence microbial profiles [ 1 , 3 , 4 ]. While early empirical antibiotic therapy generally yields favorable outcomes, infections caused by methicillin-resistant Staphylococcus aureus (MRSA) present considerable clinical challenges. The propensity of MRSA to form biofilms complicates treatment and significantly heightens the risk of severe complications [ 5 , 6 ]. Current guidelines recommend initial empiric antibiotic regimens targeting methicillin-susceptible Staphylococcus aureus (MSSA) in regions with low prevalence of MRSA. However, when MRSA constitutes more than 10–20% of local S. aureus isolates or when patient conditions are severe, empirical anti-MRSA therapy, typically involving vancomycin, is advised [ 7 , 8 ]. Nonetheless, the use of vancomycin is limited by concerns regarding nephrotoxicity and the lack of clearly defined pediatric dosing and therapeutic monitoring guidelines. This limitation hinders its universal adoption as first-line empiric therapy [ 6 ]. For BJIs without suspected MRSA or complications, initial oral regimens (e.g., amoxicillin-clavulanate or dicloxacillin) may be comparably effective to intravenous therapy [ 9 ]. However, the rising incidence of MRSA and its associated adverse outcomes highlight the necessity for rapid and accurate identification [ 5 ]. Traditional diagnostic methods, including blood or pus cultures, typically require three to five days to produce results, which can delay appropriate management. Although advanced diagnostic technologies such as polymerase chain reaction (PCR) and metagenomic next-generation sequencing (mNGS) have significantly reduced pathogen detection times and enhanced diagnostic accuracy, their higher cost and technical complexity limit widespread adoption, particularly in primary care settings [ 10 ]. Furthermore, while elevated levels of C-reactive protein (CRP) (> 73.23 µg/mL) may indicate a potential MRSA infection, this biomarker lacks sufficient specificity due to its susceptibility to various clinical influences [ 11 ]. Therefore, there is an urgent need for simple yet reliable biomarkers that can facilitate early clinical decision-making. The albumin to fibrinogen ratio (AFR) and the urea to creatinine ratio (UCR) are readily accessible in clinical practice and have garnered increasing attention for their potential predictive value across various diseases. Li et al. identified AFR as an independent protective factor against 28-day mortality in patients with sepsis [ 12 ]. Similarly, Shang et al. reported that a decreased preoperative AFR significantly increases the risk of postoperative complications, indicating its utility for both nutritional assessment and wound prognosis following primary total joint arthroplasty [ 13 ]. Additionally, Moreira et al. found that UCR is predictive of clinical events in patients with chronic heart failure, likely due to persistent neuroendocrine activation during low-volume states [ 14 ]. Furthermore, Jiang et al. observed that fluctuations in UCR may facilitate the early identification of critically ill septic patients at risk of rapid muscle wasting [ 15 ]. However, evidence regarding the specific predictive value of AFR and UCR for MRSA infection in pediatric BJIs remains limited. Therefore, this study aims to assess the clinical utility of AFR and UCR in predicting MRSA infections among pediatric patients diagnosed with BJIs. Materials and methods Patients This study was approved by the Ethics Committees of our hospital (approval number 2021KS024). The requirement for informed consent was waived by both ethics committees due to the retrospective nature of the study. We retrospectively enrolled 77 pediatric patients diagnosed with BJIs, admitted to the Departments of Orthopedics at Shanghai Children’s Hospital or the Affiliated Children’s Hospital of Soochow University between January 2015 and August 2024. The study population included 47 males and 30 females. Patient data were retrieved through electronic medical record reviews. The inclusion criteria were as follows: (1) confirmed diagnosis of BJIs; (2) positive microbiological cultures (blood, pus, or synovial fluid) identifying either Methicillin-resistant Staphylococcus aureus (MRSA) or Methicillin-sensitive Staphylococcus aureus (MSSA); (3) symptom onset within 14 days prior to hospitalization and no antibiotic therapy prior to initial blood sampling; and (4) patient age ranging from 1 month to 18 years. Exclusion criteria included: (1) underlying chronic or systemic conditions such as hematological disorders, rheumatic diseases, cardiovascular diseases, malignancies, or other chronic illnesses; (2) cases involving open fractures or postoperative infections; and (3) incomplete or unavailable medical records. Treatment and indicators Patient demographics and clinical characteristics collected included sex, age, infection site, body temperature upon admission, and culture results. Laboratory tests conducted within 24 hours of admission included white blood cell count (WBC), CRP, erythrocyte sedimentation rate (ESR), serum albumin, fibrinogen, urea, and creatinine levels. The AFR and UCR were subsequently calculated. AFR was defined as serum albumin (g/L) divided by fibrinogen (g/L), and UCR as serum urea (mg/dL) divided by serum creatinine (mg/dL). Fever at admission was defined as a body temperature exceeding 38.5°C. All pediatric patients with suspected BJIs underwent bilateral blood cultures and were initially treated empirically with intravenous first- or second-generation cephalosporins. Based on clinical progression and imaging findings, invasive procedures such as ultrasound-guided aspiration or surgical interventions were performed to collect pus specimens for further bacterial cultures and antibiotic susceptibility testing. Patients were classified into MSSA and MRSA groups according to culture outcomes, and antibiotic regimens were adjusted accordingly based on susceptibility profiles.. The diagnostic criteria for BJIs were categorized as follows [16, 17]: (1) Widely accepted criteria: Positive cultures from blood, pus, or synovial fluid, providing direct microbiological confirmation. (2) Comprehensive diagnostic criteria: Clinical symptoms, imaging findings, laboratory indicators, and surgical or aspiration evidence. Clinical manifestations typically included systemic symptoms (e.g., fever) and localized signs (joint redness, swelling, heat, pain, and limited mobility or weight-bearing reluctance). Imaging modalities used for diagnosis included radiographs (joint space widening), ultrasound (effusions or purulent collections), and magnetic resonance imaging (typical infection-related findings). Laboratory parameters such as elevated WBC, ESR, and CRP further supported the diagnosis. Intraoperative or aspiration findings provided additional direct evidence of infection. In this study, BJIs diagnoses were based exclusively on the widely accepted microbiological criteria outlined above. Statistical analysis Data were analyzed using IBM SPSS Statistics Version 26.0 (IBM Corporation, Armonk, NY). Quantitative data, adhering to a normal distribution, were expressed as mean ± standard deviation, while those not conforming to normal distribution were presented as median (P25, P75). Categorical data were represented by frequency and proportion. Independent sample t-tests were employed for normally distributed quantitative data, whereas non-parametric tests were utilized for data not following a normal distribution. Chi-square tests were applied for categorical data. Receiver operator curves (ROC) were constructed to identify cut points with optimal sensitivity and specificity for the variables found to remain significant in multivariate analysis. Sensitivity and specificity were calculated based on the suggested ROC cut points. Univariate and multivariate logistic regression analyses were subsequently performed. A p -value of <0.05 was considered statistically significant. Results General information A total of 77 pediatric patients diagnosed with BJIs were included in this study, consisting of 47 males and 30 females. The femur was the most frequently affected site, accounting for 16 cases (20.8%), followed by the tibia with 12 cases (15.6%), calcaneus with 8 cases (10.4%), fibula with 7 cases (9.1%), humerus with 3 cases (3.9%), patella with 3 cases (3.9%), pelvis with 3 cases (3.9%), ulna with 2 cases (2.6%), radius with 1 case (1.3%), and phalanx also with 1 case (1.3%). Among joint infections, the hip joint was most commonly involved, presenting in 9 cases (11.7%), this was followed by the knee joint in 6 cases (7.8%), ankle joint in 3 cases (3.9%), shoulder joint in 2 cases (2.6%), and elbow joint in 1 case (1.3%). Pathogen detection was conducted through blood, pus, or synovial fluid cultures across all 77 cases included in the study. Based on culture results, patients were classified into two groups: MSSA comprising n = 54 and MRSA comprising n = 23. Single factor analysis of MRSA-related factors The Chi-square and non-parametric tests indicated no significant differences in sex, age, or presence of fever upon admission between MSSA and MRSA groups ( P > 0.05). However, serum albumin, AFR, and UCR levels were significantly lower in the MRSA group compared to the MSSA group ( P 0.05). Although the MRSA group demonstrated a notably higher median ESR of 77 mm/L compared to 51 mm/L in the MSSA group, this difference approached but did not achieve statistical significance ( P = 0.059) (Table 1). ROC Curve Analysis The ROC curve analysis showed that albumin, AFR, and UCR yielded moderate predictive values for MRSA infection, with areas under the curve (AUC) of 0.662, 0.696, and 0.655, respectively (Table 2). The optimal cutoff values were determined as follows: albumin at 39.32 g/L (sensitivity: 69.6%, specificity: 63.0%), AFR at 6.73 (highest sensitivity: 82.6%, specificity: 55.6%), and UCR at 23.91 (highest specificity: 70.3%, sensitivity: 60.9%). Univariate Logistic Regression Analysis Binary variables were created established based on the optimal cutoff values of albumin, AFR, and UCR for logistic regression analysis purposes. Univariate logistic regression demonstrated significant associations between MRSA infection and albumin levels (OR: 0.314, 95% CI: 0.113-0.870, P = 0.026), AFR levels (OR: 0.222, 95% CI: 0.072-0.686, P = 0.009), and UCR levels (OR: 0.271, 95% CI: 0.098-0.751, P = 0.012) (Table 3). Multivariate Logistic Regression Analysis In multivariate logistic regression analysis employing stepwise backward elimination of variables identified as significant in univariate analysis, both AFR ( P = 0.016) and UCR ( P = 0.024) as independent protective factors against MRSA infection in pediatric BJIs. Conversely, albumin was not determined to be an independently predictive in the final multivariate model (Table 4). Patients presenting with an AFR ≤ 6.73 and a UCR ≤ 23.91 upon admission demonstrated a significantly higher likelihood of developing MRSA-related BJIs. Discussion In this study, we investigated the predictive value of AFR and UCR for MRSA infection in children with BJIs. The results showed that serum albumin, AFR, and UCR levels were significantly lower in the MRSA group compared to the MSSA group. In contrast, no statistically significant differences were observed in traditional inflammatory markers such as WBC, CRP and ESR. These findings are partially consistent with previous studies suggesting that WBC, CRP, and ESR may not consistently differ at admission between pediatric patients with MRSA and MSSA musculoskeletal infections [ 18 ]. Nonetheless, it is important to note that studies have shown that MRSA infections are generally more severe, often associated with higher WBC counts, CRP levels, and prolonged disease courses [ 19 ]. For instance, Wen et al. found that, compared with MSSA, MRSA-induced osteomyelitis in children more frequently leads to high-grade fever and significantly elevated WBC counts. This is often accompanied by pyogenic infections in adjacent joints as well as metastatic abscesses-conditions which necessitated additional surgical interventions and extended hospitalization [ 5 ]. Similarly, Wang et al. found that in children presenting with acute osteomyelitis, an admission CRP level exceeding73.23 µg/mL substantially heightened the likelihood of MRSA infection [ 11 ]. The lack of significant differences in WBC counts, CRP levels, and ESR between the MRSA and MSSA groups observed in our study may be attributable to the a limited sample size or variations in clinical presentation timing. This observation underscores the potential inadequacy of relying solely on these conventional markers to distinguishing between MRSA infections, thus highlighting the necessity for alternative indicators. Due to economic and technical limitaions, PCR and mNGS were not employed for pathogen detection within this study framework. Against this backdrop, our study represents a pioneering effort to explore AFR and UCR as differentiators for MRSA infections specifically within pediatric BJIs. The findings indicate that both AFR and UCR possess moderate utility in predicting MRSA infection risk, with AUC valus of 0.70 and 0.66 respectively, thereby providing new insights into early identification strategies. Notably, logistic regression analysis revealed that elevated values of AFR and UCR values serve as independent protective factors against MRSA infection, suggesting that increased levels of these parameters are associated with a diminished risk of MRSA. AFR provides a comprehensive assessment of a patient’s nutritional status, inflammatory response, and coagulation function [ 12 , 20 , 21 ]. Albumin is recognized as a typical negative acute-phase reactant that decreases during severe infections due to reduced synthesis and increased catabolism, resulting in lower serum albumin levels [ 22 ]. In contrast, fibrinogen is a positive acute-phase reactant that rises rapidly under the influence of inflammatory mediators [ 23 ]. Consequently, a decreased AFR often signifies an exacerbated inflammatory response or malnutrition. Previous studies have confirmed strong correlations between hypoalbuminemia or hyperfibrinogenemia and adverse outcomes in infectious diseases. For instance, Campbell et al. reported that low albumin levels were a significant risk factors for Staphylococcus aureus (including MRSA) infections in patients with deep musculoskeletal infections following orthopedic surgery. Similarly, Nugroho et al. conducted a meta-analysis revealing that elevated fibrinogen levels at admission were associated with an increased risk of poor prognosis in COVID-19 patients [ 24 , 25 ]. Moreover, because MRSA strains frequently harbor virulence factors such as Panton-Valentine leukocidin, which can lead to more extensive tissue damage and inflammatory responses. This results in a significant decrease in albumin and increase levels and an increase in fibrinogen-manifesting as a significantly reduced AFR [ 26 ]. Given that AFR is highly sensitive to the severity of inflammation, its decline has been linked to poorer clinical outcomes in patients suffering from sepsis. For example, Tai et al. demonstrated that among patients with sepsis secondary to abdominal infections, those exhibiting an AFR ≤ 8.85 had notably higher 28-day mortality rates [ 20 ]. Another multicenter study similarly identified AFR as an independent protective factor for 28-day mortality in sepsis cases, indicating that lower AFR correlates with an increased risk of death [ 12 ]. Collectively, these findings reinforce the notion that a reduced AFR signifies to a more severe infection. In the present study, we observed that lower AFR levels suggest MRSA may be the causative pathogen in pediatric bone and joint infections, consistent with AFR’s capacity to reflect the extent of the inflammatory response. Therefore, clinicians should remain regarding the potential presenceof resistant pathogens in pediatric patients presenting with markedly reduced AFR. UCR is routinely applied as an indicator of fluid balance and renal perfusion in clinical settings. In adults under normal conditions, the typical ratio of UCR ranges from approximately 10 to 20; ratios exceeding 20 often indicate prerenal azotemia, which can be caused by dehydration or hypovolemia. However, this benchmark has yet to be fully validated in pediatric populations [ 27 ]. Unlike most studies that focus on the association between UCR and infection-related outcomes, our investigation centers on its relationship with the specific causative pathogens. The results showed that the UCR in the MRSA group was lower than in the MSSA group (median 23 vs. 27). One plausible explanation this finding is that MRSA infection typically present more acutely and elicit a more intense inflammatory response, potentially leading to early renal parenchymal injury. This injury may raise creatinine levels relative to urea, whose reabsorption is often reduced, thereby resulting in a lower UCR. Alternatively, children with MRSA may experience a prolonged disease course coupled with poor nutritional status, which could reduce protein catabolism and subsequently decrease urea levels [ 28 , 29 ]. In critically ill patients, early fluid resuscitation and anti-shock therapy might also dilute urea concentrations. In contrast, children with milder MSSA infections may only exhibit mild dehydration presenting as prerenal azotemia, which would consequently elevate their UCR [ 27 ]. Consequently, the observed difference in UCR suggests that MRSA infections may influence fluid balance and organ function differently from MSSA. As an independent protective factor, a lower UCR appears more indicative of MRSA infections, conversely, a markedly elevated UCR aligns more closely with MSSA infection. Given the limited literature addressing this phenomenon, further large-scale research is warranted to validate these findings. Timely identification of the causative pathogen in bone and joint infections is critical for ensuring targeted therapy. In clinical practice, MRSA is typically confirmed through culture, but this process requires time and introduces uncertainty into early empirical treatment. Our findings indicate a significant association between low AFR and low UCR and MRSA infection. Specifically, when patients demonstrate markedly reduced albumin levels (AFR ≤ 6.73) alongside a UCR ≤ 23.91, clinicians should be highly vigilant for MRSA and consider initiating anti-MRSA therapies at an early stage. Where feasible, confirmatory tests such as PCR and mNGS are recommended, particularly if other high-risk factors (e.g., epidemiological history of community-acquired MRSA) are present. This study provides a novel perspective for pediatric clinical practice by suggesting that AFR and UCR may be integrated with traditional indicators (such as high fever, elevated WBC, and increased CRP) to enhance the accuracy of early MRSA prediction. Moreover, changes in AFR and UCR may partially reflect the overall inflammatory burden and organ function, implying that children with MRSA infection often experience more severe disease requiring more aggressive intervention. Nevertheless, it is important to note that AFR and UCR currently serve only as adjunctive markers and cannot replace bacterial culture or drug susceptibility testing. In routine clinical application, these measures should be interpreted in conjunction with clinical signs and symptoms, imaging studies, and other laboratory data. This study presents several limitations. First, it was a retrospective analysis conducted at two centers, focusing exclusively on pediatric patients with BJIs in China. The relatively small sample size (particularly in the MRSA group, with only 23 cases) may limit the generalizability of our findings. Second, potential confounders such as nutritional status and fluid management were not fully controlled for, which may have influenced levels of AFR and UCR levels. Moreover, our analysis relied solely on baseline data obtained at admission without longitudinal follow-up; thus, the temporal patterns of AFR and UCR throughout the disease course and treatment remain unclear. In future research, large-scale multicenter prospective studies are necessary to further validate the clinical utility of AFR and UCR in predicting pathogens associated with BJIs and to evaluate the cost-effectiveness of incorporating these markers into standard diagnostic and therapeutic protocols. Conclusion In conclusion, an AFR of ≤ 6.73 and a UCR of ≤ 23.91 at admission may serve as potential predictive biomarkers for MRSA infection in pediatric patients with BJIs. While these parameters demonstrate moderate predictive accuracy, they are best utilized as adjunctive rather than standalone diagnostic measures. Further prospective studies are warranted to validate the clinical applicability of AFR and UCR, enhance diagnostic precision, and facilitate optimized treatment strategies for pediatric BJIs. Abbreviations MRSA Methicillin-resistant Staphylococcus aureus MSSA Methicillin-susceptible Staphylococcus aureus BJIs Bone and joint infections AFR Albumin to fibrinogen ratio UCR Urea to creatinine ratio WBC White blood cell CRP C-reactive protein ESR Erythrocyte sedimentation rate PCR Polymerase chain reaction mNGS Metagenomic Next-Generation Sequencing AUC Area under the curve Declarations Acknowledgements The authors gratefully acknowledge all individuals who participated in this study. Author Contributions Conception and design of the research: CZ, CK, LD, Acquisition of data: CZ, ZG, QJ, Analysis and interpretation of the data: CZ, ZG, QJ, Statistical analysis: CZ, CK, Writing of the manuscript: CZ, CK, Critical revision of the manuscript for intellectual content: DY, LD. All authors contributed to the article and approved the submitted version. Funding The author(s) declare financial support was received for there search, authorship, and/or publication of this article. This work was supported by Medical and industrial cross research Fund of “Star of Jiaotong University” program of Shanghai Jiao Tong University (No. YG2022QN098). Availability of data and materials The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author. Ethics approval and consent for publications The studies involving humans were approved by the Ethics Committees of Shanghai Children’s Hospital and the Children’s Hospital of Soochow University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Consent for publication Not applicable. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . References Hunter S, Chan H, Baker J F. Global epidemiology of childhood bone and joint infection: a systematic review. Infection. 2022; 50(2):329-341. https://doi.org/10.1007/s15010-021-01741-3 Alvares P A, Mimica M J. Osteoarticular infections in pediatrics. 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Clin Hemorheol Microcirc. 2021; 77(2):221-231. https://doi.org/10.3233/ch-200978 Bocchini C E, Hulten K G, Mason E O, Jr., Gonzalez B E, Hammerman W A, Kaplan S L. Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics. 2006; 117(2):433-440. https://doi.org/10.1542/peds.2005-0566 Uchino S, Bellomo R, Goldsmith D. The meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury. Clin Kidney J. 2012; 5(2):187-191. https://doi.org/10.1093/ckj/sfs013 Keenswijk W, Vanmassenhove J, Raes A, Dhont E, Vande Walle J. Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome, a preliminary study. Eur J Pediatr. 2017; 176(3):355-360. https://doi.org/10.1007/s00431-016-2846-z Balestracci A, Meni Battaglia L, Toledo I, Martin S M, Alvarado C. Blood urea nitrogen to serum creatinine ratio as a prognostic factor in diarrhea-associated hemolytic uremic syndrome: a validation study. Eur J Pediatr. 2018; 177(1):63-68. https://doi.org/10.1007/s00431-017-2999-4 Tables Tables 1 to 4 are available in the Supplementary Files section Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6232542","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434330827,"identity":"0d993664-46e0-4cd5-abd4-ff3cf9bb352e","order_by":0,"name":"Chaochen Zhao","email":"","orcid":"","institution":"Shanghai Children's Hospital: Children's Hospital of Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Chaochen","middleName":"","lastName":"Zhao","suffix":""},{"id":434330828,"identity":"daffda68-018f-4557-bbbc-227832e56092","order_by":1,"name":"Chenghui Ke","email":"","orcid":"","institution":"Shanghai Children's Hospital: Children's Hospital of Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Chenghui","middleName":"","lastName":"Ke","suffix":""},{"id":434330829,"identity":"374e3699-2806-41c3-bbd8-219078455511","order_by":2,"name":"Dan Yang","email":"","orcid":"","institution":"Shanghai Children's Hospital: Children's Hospital of Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Yang","suffix":""},{"id":434330830,"identity":"484a0606-e2fb-4a2d-a729-187a3e0008a6","order_by":3,"name":"Zhiye Guan","email":"","orcid":"","institution":"Shanghai Children's Hospital: Children's Hospital of Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Zhiye","middleName":"","lastName":"Guan","suffix":""},{"id":434330831,"identity":"ee0cf406-4883-48fc-bdfc-6d0c6513c097","order_by":4,"name":"Qizhi Jiang","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Qizhi","middleName":"","lastName":"Jiang","suffix":""},{"id":434330832,"identity":"00fb4859-8b7f-47d7-9d59-07fa5cafe708","order_by":5,"name":"Liangchao Dong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYDACdigtz9988MEHAxs7wlqYgfgAEBvOOJZsOKMgLZl4LQwHcsykeT4cYmwgpIO/mfmY9Me2O3aNDWfMpG0MDjAzsB8+ugGfFonDbMkGB9ueJbcztxVb5xjc4WPgSUu7gdeawzyGDw62HU5mbDi88XaOwTNmBgkeM7xa5A/zfzgA0sJwIMFA2sLgMGMDIS0Gh3kYQbbYMRxIMZJmIEaL4WE2Y4Mz5w4ngAO5xyAtmY2QX+SONz+TqCg7bA+Oyh9/bOz42Q8fw+99KEhsgLHYiFEOAvbEKhwFo2AUjIIRCAAGcVFKFuXeuAAAAABJRU5ErkJggg==","orcid":"","institution":"Shanghai Children's Hospital: Children's Hospital of Shanghai","correspondingAuthor":true,"prefix":"","firstName":"Liangchao","middleName":"","lastName":"Dong","suffix":""}],"badges":[],"createdAt":"2025-03-15 11:37:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6232542/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6232542/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82465393,"identity":"f12e2a54-80d7-4a4d-9ed7-39e0ebc5eac6","added_by":"auto","created_at":"2025-05-11 16:09:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":406987,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6232542/v1/bd23c2d4-d546-42e9-a711-754a2050f1e9.pdf"},{"id":80366042,"identity":"43388532-e5b3-41fd-bae4-bcc7266ffa10","added_by":"auto","created_at":"2025-04-11 05:29:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26599,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6232542/v1/bb5482f8ed270478d9b616b5.docx"}],"financialInterests":"","formattedTitle":"Predictive value of AFR and UCR for the Methicillin-resistant Staphylococcus aureus infection in children with bone and joint infections","fulltext":[{"header":"Background","content":"\u003cp\u003eBone and joint infections (BJIs), primarily acute osteomyelitis and septic arthritis, represent significant pediatric conditions often arise from the hematogenous spread of pathogenic microorganisms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. \u003cem\u003eStaphylococcus aureus\u003c/em\u003e remains the predominant pathogen, however, local epidemiological variations can influence microbial profiles [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. While early empirical antibiotic therapy generally yields favorable outcomes, infections caused by methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MRSA) present considerable clinical challenges. The propensity of MRSA to form biofilms complicates treatment and significantly heightens the risk of severe complications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Current guidelines recommend initial empiric antibiotic regimens targeting methicillin-susceptible \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MSSA) in regions with low prevalence of MRSA. However, when MRSA constitutes more than 10\u0026ndash;20% of local S. aureus isolates or when patient conditions are severe, empirical anti-MRSA therapy, typically involving vancomycin, is advised [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nonetheless, the use of vancomycin is limited by concerns regarding nephrotoxicity and the lack of clearly defined pediatric dosing and therapeutic monitoring guidelines. This limitation hinders its universal adoption as first-line empiric therapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor BJIs without suspected MRSA or complications, initial oral regimens (e.g., amoxicillin-clavulanate or dicloxacillin) may be comparably effective to intravenous therapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the rising incidence of MRSA and its associated adverse outcomes highlight the necessity for rapid and accurate identification [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Traditional diagnostic methods, including blood or pus cultures, typically require three to five days to produce results, which can delay appropriate management. Although advanced diagnostic technologies such as polymerase chain reaction (PCR) and metagenomic next-generation sequencing (mNGS) have significantly reduced pathogen detection times and enhanced diagnostic accuracy, their higher cost and technical complexity limit widespread adoption, particularly in primary care settings [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, while elevated levels of C-reactive protein (CRP) (\u0026gt;\u0026thinsp;73.23 \u0026micro;g/mL) may indicate a potential MRSA infection, this biomarker lacks sufficient specificity due to its susceptibility to various clinical influences [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, there is an urgent need for simple yet reliable biomarkers that can facilitate early clinical decision-making.\u003c/p\u003e \u003cp\u003eThe albumin to fibrinogen ratio (AFR) and the urea to creatinine ratio (UCR) are readily accessible in clinical practice and have garnered increasing attention for their potential predictive value across various diseases. Li et al. identified AFR as an independent protective factor against 28-day mortality in patients with sepsis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, Shang et al. reported that a decreased preoperative AFR significantly increases the risk of postoperative complications, indicating its utility for both nutritional assessment and wound prognosis following primary total joint arthroplasty [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, Moreira et al. found that UCR is predictive of clinical events in patients with chronic heart failure, likely due to persistent neuroendocrine activation during low-volume states [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, Jiang et al. observed that fluctuations in UCR may facilitate the early identification of critically ill septic patients at risk of rapid muscle wasting [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, evidence regarding the specific predictive value of AFR and UCR for MRSA infection in pediatric BJIs remains limited.\u003c/p\u003e \u003cp\u003eTherefore, this study aims to assess the clinical utility of AFR and UCR in predicting MRSA infections among pediatric patients diagnosed with BJIs.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003ch2\u003ePatients\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethics Committees of our hospital (approval number 2021KS024). The requirement for informed consent was waived by both ethics committees due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003eWe retrospectively enrolled 77 pediatric patients diagnosed with BJIs, admitted to the Departments of Orthopedics at Shanghai Children\u0026rsquo;s Hospital or the Affiliated Children\u0026rsquo;s Hospital of Soochow University between January 2015 and August 2024. The study population included 47 males and 30 females. Patient data were retrieved through electronic medical record reviews.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were as follows: (1) confirmed diagnosis of BJIs; (2) positive microbiological cultures (blood, pus, or synovial fluid) identifying either Methicillin-resistant Staphylococcus aureus (MRSA) or Methicillin-sensitive Staphylococcus aureus (MSSA); (3) symptom onset within 14 days prior to hospitalization and no antibiotic therapy prior to initial blood sampling; and (4) patient age ranging from 1 month to 18 years.\u003c/p\u003e\n\u003cp\u003eExclusion criteria included: (1) underlying chronic or systemic conditions such as hematological disorders, rheumatic diseases, cardiovascular diseases, malignancies, or other chronic illnesses; (2) cases involving open fractures or postoperative infections; and (3) incomplete or unavailable medical records.\u003c/p\u003e\n\u003ch2\u003eTreatment and indicators\u003c/h2\u003e\n\u003cp\u003ePatient demographics and clinical characteristics collected included sex, age, infection site, body temperature upon admission, and culture results. Laboratory tests conducted within 24 hours of admission included white blood cell count (WBC), CRP, erythrocyte sedimentation rate (ESR), serum albumin, fibrinogen, urea, and creatinine levels. The AFR and UCR were subsequently calculated. AFR was defined as serum albumin (g/L) divided by fibrinogen (g/L), and UCR as serum urea (mg/dL) divided by serum creatinine (mg/dL). Fever at admission was defined as a body temperature exceeding 38.5\u0026deg;C.\u003c/p\u003e\n\u003cp\u003eAll pediatric patients with suspected BJIs underwent bilateral blood cultures and were initially treated empirically with intravenous first- or second-generation cephalosporins. Based on clinical progression and imaging findings, invasive procedures such as ultrasound-guided aspiration or surgical interventions were performed to collect pus specimens for further bacterial cultures and antibiotic susceptibility testing. Patients were classified into MSSA and MRSA groups according to culture outcomes, and antibiotic regimens were adjusted accordingly based on susceptibility profiles..\u003c/p\u003e\n\u003cp\u003eThe diagnostic criteria for BJIs were categorized as follows [16, 17]:\u003c/p\u003e\n\u003cp\u003e(1) Widely accepted criteria: Positive cultures from blood, pus, or synovial fluid, providing direct microbiological confirmation.\u003c/p\u003e\n\u003cp\u003e(2) Comprehensive diagnostic criteria: Clinical symptoms, imaging findings, laboratory indicators, and surgical or aspiration evidence. Clinical manifestations typically included systemic symptoms (e.g., fever) and localized signs (joint redness, swelling, heat, pain, and limited mobility or weight-bearing reluctance). Imaging modalities used for diagnosis included radiographs (joint space widening), ultrasound (effusions or purulent collections), and magnetic resonance imaging (typical infection-related findings). Laboratory parameters such as elevated WBC, ESR, and CRP further supported the diagnosis. Intraoperative or aspiration findings provided additional direct evidence of infection.\u003c/p\u003e\n\u003cp\u003eIn this study, BJIs diagnoses were based exclusively on the widely accepted microbiological criteria outlined above.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eData were analyzed using IBM SPSS Statistics Version 26.0 (IBM Corporation, Armonk, NY). Quantitative data, adhering to a normal distribution, were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, while those not conforming to normal distribution were presented as median (P25, P75). Categorical data were represented by frequency and proportion. Independent sample t-tests were employed for normally distributed quantitative data, whereas non-parametric tests were utilized for data not following a normal distribution. Chi-square tests were applied for categorical data. Receiver operator curves (ROC) were constructed to identify cut points with optimal sensitivity and specificity for the variables found to remain significant in multivariate analysis. Sensitivity and specificity were calculated based on the suggested ROC cut points. Univariate and multivariate logistic regression analyses were subsequently performed. A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eGeneral information\u003c/p\u003e\n\u003cp\u003eA total of 77 pediatric patients diagnosed with BJIs were included in this study, consisting of 47 males and 30 females. The femur was the most frequently affected site, accounting for 16 cases (20.8%), followed by the tibia with 12 cases (15.6%), calcaneus with 8 cases (10.4%), fibula with 7 cases (9.1%), humerus with 3 cases (3.9%), patella with 3 cases (3.9%), pelvis with 3 cases (3.9%), ulna with 2 cases (2.6%), radius with 1 case (1.3%), and phalanx also with 1 case (1.3%). Among joint infections, the hip joint was most commonly involved, presenting in 9 cases (11.7%), this was followed by the knee joint in 6 cases (7.8%), ankle joint in 3 cases (3.9%), shoulder joint in 2 cases (2.6%), and elbow joint in 1 case (1.3%).\u003c/p\u003e\n\u003cp\u003ePathogen detection was conducted through blood, pus, or synovial fluid cultures across all 77 cases included in the study. Based on culture results, patients were classified into two groups: MSSA comprising\u0026nbsp;\u003cem\u003en\u003c/em\u003e = 54 and MRSA comprising\u0026nbsp;\u003cem\u003en\u003c/em\u003e = 23.\u003c/p\u003e\n\u003cp\u003eSingle factor analysis of MRSA-related factors\u003c/p\u003e\n\u003cp\u003eThe Chi-square and non-parametric tests indicated no significant differences in sex, age, or presence of fever upon admission between MSSA and MRSA groups (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). However, serum albumin, AFR, and UCR levels were significantly lower in the MRSA group compared to the MSSA group (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). No significant differences were observed in WBC, CRP, ESR, fibrinogen, urea, or creatinine levels between the two groups (all \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt; 0.05). Although the MRSA group demonstrated a notably higher median ESR of 77 mm/L compared to 51 mm/L in the MSSA group, this difference approached but did not achieve statistical significance (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.059) (Table 1).\u003c/p\u003e\n\u003cp\u003eROC Curve Analysis\u003c/p\u003e\n\u003cp\u003eThe ROC curve analysis showed that albumin, AFR, and UCR yielded moderate predictive values for MRSA infection, with areas under the curve (AUC) of 0.662, 0.696, and 0.655, respectively (Table 2). The optimal cutoff values were determined as follows: albumin at 39.32 g/L (sensitivity: 69.6%, specificity: 63.0%), AFR at 6.73 (highest sensitivity: 82.6%, specificity: 55.6%), and UCR at 23.91 (highest specificity: 70.3%, sensitivity: 60.9%).\u003c/p\u003e\n\u003cp\u003eUnivariate Logistic Regression Analysis\u003c/p\u003e\n\u003cp\u003eBinary variables were created established based on the optimal cutoff values of albumin, AFR, and UCR for logistic regression analysis purposes. Univariate logistic regression demonstrated significant associations between MRSA infection and albumin levels (OR: 0.314, 95% CI: 0.113-0.870, \u003cem\u003eP\u003c/em\u003e = 0.026), AFR levels (OR: 0.222, 95% CI: 0.072-0.686, \u003cem\u003eP\u003c/em\u003e = 0.009), and UCR levels (OR: 0.271, 95% CI: 0.098-0.751, \u003cem\u003eP\u003c/em\u003e = 0.012) (Table 3).\u003c/p\u003e\n\u003cp\u003eMultivariate Logistic Regression Analysis\u003c/p\u003e\n\u003cp\u003eIn multivariate logistic regression analysis employing stepwise backward elimination of variables identified as significant in univariate analysis, both AFR (\u003cem\u003eP\u003c/em\u003e = 0.016) and UCR (\u003cem\u003eP\u003c/em\u003e = 0.024) as independent protective factors against MRSA infection in pediatric BJIs. Conversely, albumin was not determined to be an independently predictive in the final multivariate model (Table 4). Patients presenting with an AFR \u0026le; 6.73 and a UCR \u0026le; 23.91 upon admission demonstrated a significantly higher likelihood of developing MRSA-related BJIs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we investigated the predictive value of AFR and UCR for MRSA infection in children with BJIs. The results showed that serum albumin, AFR, and UCR levels were significantly lower in the MRSA group compared to the MSSA group. In contrast, no statistically significant differences were observed in traditional inflammatory markers such as WBC, CRP and ESR. These findings are partially consistent with previous studies suggesting that WBC, CRP, and ESR may not consistently differ at admission between pediatric patients with MRSA and MSSA musculoskeletal infections [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nonetheless, it is important to note that studies have shown that MRSA infections are generally more severe, often associated with higher WBC counts, CRP levels, and prolonged disease courses [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For instance, Wen et al. found that, compared with MSSA, MRSA-induced osteomyelitis in children more frequently leads to high-grade fever and significantly elevated WBC counts. This is often accompanied by pyogenic infections in adjacent joints as well as metastatic abscesses-conditions which necessitated additional surgical interventions and extended hospitalization [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Similarly, Wang et al. found that in children presenting with acute osteomyelitis, an admission CRP level exceeding73.23 \u0026micro;g/mL substantially heightened the likelihood of MRSA infection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The lack of significant differences in WBC counts, CRP levels, and ESR between the MRSA and MSSA groups observed in our study may be attributable to the a limited sample size or variations in clinical presentation timing. This observation underscores the potential inadequacy of relying solely on these conventional markers to distinguishing between MRSA infections, thus highlighting the necessity for alternative indicators. Due to economic and technical limitaions, PCR and mNGS were not employed for pathogen detection within this study framework. Against this backdrop, our study represents a pioneering effort to explore AFR and UCR as differentiators for MRSA infections specifically within pediatric BJIs. The findings indicate that both AFR and UCR possess moderate utility in predicting MRSA infection risk, with AUC valus of 0.70 and 0.66 respectively, thereby providing new insights into early identification strategies. Notably, logistic regression analysis revealed that elevated values of AFR and UCR values serve as independent protective factors against MRSA infection, suggesting that increased levels of these parameters are associated with a diminished risk of MRSA.\u003c/p\u003e \u003cp\u003eAFR provides a comprehensive assessment of a patient\u0026rsquo;s nutritional status, inflammatory response, and coagulation function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Albumin is recognized as a typical negative acute-phase reactant that decreases during severe infections due to reduced synthesis and increased catabolism, resulting in lower serum albumin levels [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In contrast, fibrinogen is a positive acute-phase reactant that rises rapidly under the influence of inflammatory mediators [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Consequently, a decreased AFR often signifies an exacerbated inflammatory response or malnutrition. Previous studies have confirmed strong correlations between hypoalbuminemia or hyperfibrinogenemia and adverse outcomes in infectious diseases. For instance, Campbell et al. reported that low albumin levels were a significant risk factors for Staphylococcus aureus (including MRSA) infections in patients with deep musculoskeletal infections following orthopedic surgery. Similarly, Nugroho et al. conducted a meta-analysis revealing that elevated fibrinogen levels at admission were associated with an increased risk of poor prognosis in COVID-19 patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Moreover, because MRSA strains frequently harbor virulence factors such as Panton-Valentine leukocidin, which can lead to more extensive tissue damage and inflammatory responses. This results in a significant decrease in albumin and increase levels and an increase in fibrinogen-manifesting as a significantly reduced AFR [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Given that AFR is highly sensitive to the severity of inflammation, its decline has been linked to poorer clinical outcomes in patients suffering from sepsis. For example, Tai et al. demonstrated that among patients with sepsis secondary to abdominal infections, those exhibiting an AFR\u0026thinsp;\u0026le;\u0026thinsp;8.85 had notably higher 28-day mortality rates [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Another multicenter study similarly identified AFR as an independent protective factor for 28-day mortality in sepsis cases, indicating that lower AFR correlates with an increased risk of death [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Collectively, these findings reinforce the notion that a reduced AFR signifies to a more severe infection. In the present study, we observed that lower AFR levels suggest MRSA may be the causative pathogen in pediatric bone and joint infections, consistent with AFR\u0026rsquo;s capacity to reflect the extent of the inflammatory response. Therefore, clinicians should remain regarding the potential presenceof resistant pathogens in pediatric patients presenting with markedly reduced AFR.\u003c/p\u003e \u003cp\u003eUCR is routinely applied as an indicator of fluid balance and renal perfusion in clinical settings. In adults under normal conditions, the typical ratio of UCR ranges from approximately 10 to 20; ratios exceeding 20 often indicate prerenal azotemia, which can be caused by dehydration or hypovolemia. However, this benchmark has yet to be fully validated in pediatric populations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Unlike most studies that focus on the association between UCR and infection-related outcomes, our investigation centers on its relationship with the specific causative pathogens. The results showed that the UCR in the MRSA group was lower than in the MSSA group (median 23 vs. 27). One plausible explanation this finding is that MRSA infection typically present more acutely and elicit a more intense inflammatory response, potentially leading to early renal parenchymal injury. This injury may raise creatinine levels relative to urea, whose reabsorption is often reduced, thereby resulting in a lower UCR. Alternatively, children with MRSA may experience a prolonged disease course coupled with poor nutritional status, which could reduce protein catabolism and subsequently decrease urea levels [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In critically ill patients, early fluid resuscitation and anti-shock therapy might also dilute urea concentrations. In contrast, children with milder MSSA infections may only exhibit mild dehydration presenting as prerenal azotemia, which would consequently elevate their UCR [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Consequently, the observed difference in UCR suggests that MRSA infections may influence fluid balance and organ function differently from MSSA. As an independent protective factor, a lower UCR appears more indicative of MRSA infections, conversely, a markedly elevated UCR aligns more closely with MSSA infection. Given the limited literature addressing this phenomenon, further large-scale research is warranted to validate these findings.\u003c/p\u003e \u003cp\u003eTimely identification of the causative pathogen in bone and joint infections is critical for ensuring targeted therapy. In clinical practice, MRSA is typically confirmed through culture, but this process requires time and introduces uncertainty into early empirical treatment. Our findings indicate a significant association between low AFR and low UCR and MRSA infection. Specifically, when patients demonstrate markedly reduced albumin levels (AFR\u0026thinsp;\u0026le;\u0026thinsp;6.73) alongside a UCR\u0026thinsp;\u0026le;\u0026thinsp;23.91, clinicians should be highly vigilant for MRSA and consider initiating anti-MRSA therapies at an early stage. Where feasible, confirmatory tests such as PCR and mNGS are recommended, particularly if other high-risk factors (e.g., epidemiological history of community-acquired MRSA) are present. This study provides a novel perspective for pediatric clinical practice by suggesting that AFR and UCR may be integrated with traditional indicators (such as high fever, elevated WBC, and increased CRP) to enhance the accuracy of early MRSA prediction. Moreover, changes in AFR and UCR may partially reflect the overall inflammatory burden and organ function, implying that children with MRSA infection often experience more severe disease requiring more aggressive intervention. Nevertheless, it is important to note that AFR and UCR currently serve only as adjunctive markers and cannot replace bacterial culture or drug susceptibility testing. In routine clinical application, these measures should be interpreted in conjunction with clinical signs and symptoms, imaging studies, and other laboratory data.\u003c/p\u003e \u003cp\u003eThis study presents several limitations. First, it was a retrospective analysis conducted at two centers, focusing exclusively on pediatric patients with BJIs in China. The relatively small sample size (particularly in the MRSA group, with only 23 cases) may limit the generalizability of our findings. Second, potential confounders such as nutritional status and fluid management were not fully controlled for, which may have influenced levels of AFR and UCR levels. Moreover, our analysis relied solely on baseline data obtained at admission without longitudinal follow-up; thus, the temporal patterns of AFR and UCR throughout the disease course and treatment remain unclear. In future research, large-scale multicenter prospective studies are necessary to further validate the clinical utility of AFR and UCR in predicting pathogens associated with BJIs and to evaluate the cost-effectiveness of incorporating these markers into standard diagnostic and therapeutic protocols.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, an AFR of \u0026le;\u0026thinsp;6.73 and a UCR of \u0026le;\u0026thinsp;23.91 at admission may serve as potential predictive biomarkers for MRSA infection in pediatric patients with BJIs. While these parameters demonstrate moderate predictive accuracy, they are best utilized as adjunctive rather than standalone diagnostic measures. Further prospective studies are warranted to validate the clinical applicability of AFR and UCR, enhance diagnostic precision, and facilitate optimized treatment strategies for pediatric BJIs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMRSA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMSSA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Methicillin-susceptible \u003cem\u003eStaphylococcus aureus\u003c/em\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBJIs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Bone and joint infections\u003c/p\u003e\n\u003cp\u003eAFR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Albumin to fibrinogen ratio \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUCR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Urea to creatinine ratio \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWBC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;White blood cell \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;C-reactive protein \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eESR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Erythrocyte sedimentation rate \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Polymerase chain reaction \u0026nbsp;\u003c/p\u003e\n\u003cp\u003emNGS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Metagenomic Next-Generation Sequencing \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAUC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Area under the curve \u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge all individuals who participated in this\u0026nbsp;study.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eConception and design of the research: CZ, CK, LD, Acquisition of data: CZ, ZG, QJ, Analysis and interpretation of the data: CZ, ZG, QJ, Statistical analysis: CZ, CK, Writing of the manuscript: CZ, CK, Critical revision of the manuscript for intellectual content: DY, LD. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe author(s) declare financial support was received for there search, authorship, and/or publication of this article. This work was supported by Medical and industrial cross research Fund of \u0026ldquo;Star of Jiaotong University\u0026rdquo; program of Shanghai Jiao Tong University (No. YG2022QN098).\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent for publications\u003c/p\u003e\n\u003cp\u003eThe studies involving humans were approved by the\u0026nbsp;Ethics Committees of Shanghai Children\u0026rsquo;s Hospital and the Children\u0026rsquo;s Hospital of Soochow University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants\u0026rsquo; legal guardians/next of kin.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\u003c/em\u003e.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHunter S, Chan H, Baker J F. Global epidemiology of childhood bone and joint infection: a systematic review. Infection. 2022; 50(2):329-341. https://doi.org/10.1007/s15010-021-01741-3\u003c/li\u003e\n \u003cli\u003eAlvares P A, Mimica M J. Osteoarticular infections in pediatrics. 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Epidemiology of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children. Pediatrics. 2017; 139(6). https://doi.org/10.1542/peds.2017-0183\u003c/li\u003e\n \u003cli\u003eWoods C R, Bradley J S, Chatterjee A, Copley L A, Robinson J, Kronman M P, et al. Clinical Practice Guideline by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America: 2021 Guideline on Diagnosis and Management of Acute Hematogenous Osteomyelitis in Pediatrics. J Pediatric Infect Dis Soc. 2021; 10(8):801-844. https://doi.org/10.1093/jpids/piab027\u003c/li\u003e\n \u003cli\u003eWoods C R, Bradley J S, Chatterjee A, Kronman M P, Arnold S R, Robinson J, et al. Clinical Practice Guideline by the Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA): 2023 Guideline on Diagnosis and Management of Acute Bacterial Arthritis in Pediatrics. 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European Heart Journal. 2024; 45(Supplement_1). https://doi.org/10.1093/eurheartj/ehae666.980\u003c/li\u003e\n \u003cli\u003eJiang J, Chen H, Meng S S, Pan C, Xie J F, Guo F M. Early urea-to-creatinine ratio to predict rapid muscle loss in critically ill patients with sepsis: a single-center retrospective observational study. BMC Anesthesiol. 2025; 25(1):26. https://doi.org/10.1186/s12871-025-02892-8\u003c/li\u003e\n \u003cli\u003eAutore G, Bernardi L, Esposito S. Update on Acute Bone and Joint Infections in Paediatrics: A Narrative Review on the Most Recent Evidence-Based Recommendations and Appropriate Antinfective Therapy. Antibiotics (Basel). 2020; 9(8). https://doi.org/10.3390/antibiotics9080486\u003c/li\u003e\n \u003cli\u003eHamilton E C, Villani M C, Klosterman M M, Jo C, Liu J, Copley L a B. Children with Primary Septic Arthritis Have a Markedly Lower Risk of Adverse Outcomes Than Those with Contiguous Osteomyelitis. J Bone Joint Surg Am. 2021; 103(13):1229-1237. https://doi.org/10.2106/jbjs.20.01685\u003c/li\u003e\n \u003cli\u003eAn T J, Benvenuti M A, Mignemi M E, Martus J, Wood J B, Thomsen I P, et al. Similar Clinical Severity and Outcomes for Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Pediatric Musculoskeletal Infections. Open Forum Infect Dis. 2017; 4(1):ofx013. https://doi.org/10.1093/ofid/ofx013\u003c/li\u003e\n \u003cli\u003eHawkshead J J, 3rd, Patel N B, Steele R W, Heinrich S D. Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin-sensitive Staphylococcus aureus. J Pediatr Orthop. 2009; 29(1):85-90. https://doi.org/10.1097/BPO.0b013e3181901c3a\u003c/li\u003e\n \u003cli\u003eTai H, Zhu Z, Mei H, Sun W, Zhang W. Albumin-to-Fibrinogen Ratio Independently Predicts 28-Day Mortality in Patients with Peritonitis-Induced Sepsis. Mediators Inflamm. 2020; 2020:7280708. https://doi.org/10.1155/2020/7280708\u003c/li\u003e\n \u003cli\u003eYang W M, Zhang W H, Ying H Q, Xu Y M, Zhang J, Min Q H, et al. Two new inflammatory markers associated with disease activity score-28 in patients with rheumatoid arthritis: Albumin to fibrinogen ratio and C-reactive protein to albumin ratio. Int Immunopharmacol. 2018; 62:293-298. https://doi.org/10.1016/j.intimp.2018.07.007\u003c/li\u003e\n \u003cli\u003eDelaney A P, Dan A, Mccaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011; 39(2):386-391. https://doi.org/10.1097/CCM.0b013e3181ffe217\u003c/li\u003e\n \u003cli\u003eXu H, Xie J, Yang J, Chen G, Huang Q, Pei F. Plasma Fibrinogen and Platelet Count Are Referable Tools for Diagnosing Periprosthetic Joint Infection: A Single-Center Retrospective Cohort Study. J Arthroplasty. 2020; 35(5):1361-1367. https://doi.org/10.1016/j.arth.2019.12.015\u003c/li\u003e\n \u003cli\u003eCampbell M P, Mott M D, Owen J R, Reznicek J E, Beck C A, Muthukrishnan G, et al. Low albumin level is more strongly associated with adverse outcomes and Staphylococcus aureus infection than hemoglobin A1C or smoking tobacco. J Orthop Res. 2022; 40(11):2670-2677. https://doi.org/10.1002/jor.25282\u003c/li\u003e\n \u003cli\u003eNugroho J, Wardhana A, Mulia E P, Maghfirah I, Rachmi D A, A\u0026apos;yun M Q, et al. Elevated fibrinogen and fibrin degradation product are associated with poor outcome in COVID-19 patients: A meta-analysis. Clin Hemorheol Microcirc. 2021; 77(2):221-231. https://doi.org/10.3233/ch-200978\u003c/li\u003e\n \u003cli\u003eBocchini C E, Hulten K G, Mason E O, Jr., Gonzalez B E, Hammerman W A, Kaplan S L. Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics. 2006; 117(2):433-440. https://doi.org/10.1542/peds.2005-0566\u003c/li\u003e\n \u003cli\u003eUchino S, Bellomo R, Goldsmith D. The meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury. Clin Kidney J. 2012; 5(2):187-191. https://doi.org/10.1093/ckj/sfs013\u003c/li\u003e\n \u003cli\u003eKeenswijk W, Vanmassenhove J, Raes A, Dhont E, Vande Walle J. Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome, a preliminary study. Eur J Pediatr. 2017; 176(3):355-360. https://doi.org/10.1007/s00431-016-2846-z\u003c/li\u003e\n \u003cli\u003eBalestracci A, Meni Battaglia L, Toledo I, Martin S M, Alvarado C. 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Eur J Pediatr. 2018; 177(1):63-68. https://doi.org/10.1007/s00431-017-2999-4\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Bone and joint infections, Pediatrics, Methicillin-resistant Staphylococcus aureus, Albumin to fibrinogen ratio, Urea to creatinine ratio, Predictive biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-6232542/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6232542/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e (MRSA) infections present significant diagnostic and therapeutic challenges in pediatric bone and joint infections (BJIs). Therefore, this study aimed to evaluate the predictive value of the albumin-to-fibrinogen ratio (AFR) and the urea-to-creatinine ratio (UCR) at admission for MRSA infections in pediatric patients with BJIs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePatients were retrospectively categorized into MRSA (\u003cem\u003en\u003c/em\u003e = 23) and methicillin-susceptible Staphylococcus aureus (MSSA, \u003cem\u003en\u003c/em\u003e = 54) groups based on microbiological culture results (MSSA group = 0, MRSA group = 1). Clinical data and laboratory parameters, including serum albumin, fibrinogen, urea, creatinine, white blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were collected. Receiver operating characteristic (ROC) curves were employed to assess the predictive accuracy of AFR and UCR for MRSA infection. Logistic regression analyses were conducted to identify independent predictors of MRSA infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Compared to the MSSA group, the MRSA group demonstrated significantly lower values for both AFR and UCR values (both \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.05). ROC analysis indicated moderate diagnostic accuracy for AFR (AUC = 0.696) and UCR (AUC = 0.655) in predicting MRSA infections. Multivariate logistic regression analysis confirmed that higher levels of AFR \u0026gt; 6.73 and UCR \u0026gt; 23.91 served as independent protective factors against MRSA infection (\u003cem\u003eP\u003c/em\u003e= 0.016 and \u003cem\u003eP\u003c/em\u003e = 0.024, respectively). Traditional inflammatory markers (WBC, CRP, and ESR) showed no significant differences between groups (\u003cem\u003eP \u003c/em\u003e\u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In pediatric patients admitted with BJIs, AFR ≤ 6.73 and UCR ≤ 23.91 at admission may indicate an increased likelihood of MRSA infection. Both AFR and UCR exhibit moderate predictive value for early identification of MRSA-associated pediatric BJIs, thus they may facilitate optimization of empirical antimicrobial therapy.\u003c/p\u003e","manuscriptTitle":"Predictive value of AFR and UCR for the Methicillin-resistant Staphylococcus aureus infection in children with bone and joint infections","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-11 05:20:52","doi":"10.21203/rs.3.rs-6232542/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1a0d89d5-18b6-4ec6-9a42-b901fb672317","owner":[],"postedDate":"April 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-11T16:01:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-11 05:20:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6232542","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6232542","identity":"rs-6232542","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}