Impact of intervertebral disc degeneration and endplate changes on cefazolin penetration into the intervertebral disc

Impact of intervertebral disc degeneration and endplate changes on cefazolin penetration into the intervertebral disc | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of intervertebral disc degeneration and endplate changes on cefazolin penetration into the intervertebral disc Aleksejs Repnikovs, Kalvis Briuks, Artūrs Paulausks, Peteris Studers, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6965320/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose. Preoperative cefazolin is the standard of care for intervertebral disc surgery as it reduces the incidence of iatrogenic spondylodiscitis. The aim of this study was to determine the impact of intervertebral disc degeneration and endplate changes on the penetration of prophylactic cefazolin into the intervertebral disc during spinal surgery. Methods. Adult patients undergoing single-level microdiscectomy for lumbar disc herniation received prophylaxis with 2 g of cefazolin. Venous blood and intervertebral disc samples were collected and analyzed using high-performance liquid chromatography to determine cefazolin concentrations. The severity of intervertebral disc and endplate changes was assessed on magnetic resonance images using the Pfirrmann and Modic grading systems. Results. Cefazolin concentrations were significantly higher in cases with Modic type II changes compared to type 0/I (14.6 ± 9.2 µg g − 1 vs. 10.2 ± 4.5 µg g − 1 and 9.2 ± 4.1 µg g − 1 ; P = 0.01). 35.4% of patients with Modic type II changes had concentrations > 16 µg g − 1 , compared to 10% and 25% for patients with Modic type 0/I (p = 0.008). For Pfirrmann grading, 34.6% of grade V discs reached > 16 µg g⁻¹ versus 16.7% and 20.3% for grades III and IV (p = 0.26). Patient age, weight, and timing showed no significant correlations with intradisc concentrations. Conclusion. Disc degeneration and endplate changes significantly impact cefazolin penetration, with higher concentrations in Modic type II changes and advanced Pfirrmann grades, potentially affecting antibiotic efficacy for surgical prophylaxis. Cefazolin antibiotic prophylaxis degenerative disc disease spine surgery Figures Figure 1 Introduction Intervertebral disc (IVD) infections occur when bacteria spread into the disc space due to bacteremia or as a consequence of spinal surgery. After discectomy, surgical site infections (SSI) rank third among the most frequent complications, with cerebrospinal fluid leak and recurrent herniation being the two most common [ 1 ]. The European Centre for Disease Prevention and Control reported a pooled incidence rate of SSI after laminectomy and discectomy at 0.8 [0.2–2.7] % among 23,950 patients, with spondylodiscitis accounting for 54% of cases [ 2 ]. Although the incidence is low, SSI usually causes severe pain and can result in major disability. The current standard of care for IVD surgery involves prophylactic antibiotics, which have been demonstrated to reduce iatrogenic discitis [ 3 , 4 ]. First or second generation cephalosporins are the first-line choice for perioperative prophylaxis [ 5 ]. The detection period and concentration of cefazolin after prophylactic dosing vary among individuals [ 6 – 9 ]. As IVDs are avascular, antibiotics must be transported by diffusion from blood vessels through the endplates and then through the extracellular matrix of the disc [ 10 ]. It has been suggested that optimal antibiotic regimens may vary depending on disc and endplate health [ 11 ]. Magnetic resonance imaging (MRI) is a useful tool for investigating IVD degeneration and structural endplate changes. Disc morphology and hydration can be graded on MRI T2 spin-echo weighted images using Pfirrmann’s grading system (grade 1–5) [ 12 ]. According to Modic et al. [ 13 ], three types of lumbar vertebral body marrow and endplate lesions can be identified on MRI [ 14 ]. From histological studies of surgical material, these lesions represent endplate fissuring, with subsequent subchondral sclerosis formation which can increase or reduce substance penetration depending on the stage of degeneration. The relationship between antibiotic penetration and MRI changes in IVDs and endplates has not been investigated, despite potential clinical implications. We hypothesized that IVD degeneration severity and endplate changes, as quantified by MRI, affect prophylactic cefazolin penetration into the IVD during spinal surgery. Methods After approval by the Hospital Ethics Committee, adult patients scheduled for single level microdiscectomy for symptomatic lumbar disc herniation receiving 2 g of cefazolin as part of their perioperative antibiotic regimen were consecutively enrolled after providing written informed consent. Patients were excluded if they had received any antibiotic treatment within the previous 2 weeks. All patients underwent an MRI at baseline. Demographic and clinical data were collected, including sex, age, weight, and the affected intervertebral segment. Sample collection To obtain IVD material for measurement of cefazolin concentration, a rectangular window was created in both the posterior longitudinal ligament and anulus fibrosus during the surgical procedure, and a portion of the nucleus pulposus was excised while ensuring that there was no contamination of the tissue by blood. The disc specimen was collected immediately after excision, placed into a sterile container, and the collection time was recorded. The specimen was stored at -80°C until analysis. Blood sampling to measure the plasma concentration of cefazolin was performed at two different time points. The baseline sample was taken at the time of peripheral venous catheterization prior to anesthesia. The second blood sample was taken 30 minutes after the administration of cefazolin. Blood samples were collected in EDTA tubes (5 mL). Within 15 minutes after sampling, the EDTA tubes were centrifuged at 3500 × g for 10 min to obtain plasma. Plasma was stored at -80° C until analysis. All three time points, including the baseline blood sample, the second sample, and the time of cefazolin administration, were recorded. MRI Two experienced orthopedic surgeons independently graded the severity of IVD and endplate changes using MRI images. Grading of intervertebral disc degeneration was performed on sagittal T2WI images, and the Pfirrmann criteria [ 12 ] were used to assess the involved intervertebral discs. The Pfirrmann grading system evaluates degenerated intervertebral discs by MRI for asymmetry in disc structure, distinction of the nucleus and annulus, signal intensity of IVDs, and height of IVDs, and assigns a grade from I to V for disc degeneration. The upper and lower endplate of the involved disc were graded according to Modic classification: type 0, indicating normal endplate; type I, indicating endplate neovascularity that was hyperintense on T2-weighted images and hypointense on T1-weighted images; type II, indicating endplate fatty replacement that was hyperintense on T1-weighted images and isointense or hypointense on T2-weighted images; and type III, indicating endplate bony sclerosis that was hypointense on both T1- and T2-weighted images [ 13 ]. Follow up To monitor for postoperative discitis, patients underwent follow-up appointments at 2 and 4 months. Sample analysis IVD samples were thawed, cut, and 50–400 mg portions were weighed into 2 mL Eppendorf tubes. After adding 1 mL grinding buffer (25 mM NaH₂PO₄, pH 3), samples were homogenized with a glass rod, sonicated for 10 minutes in an ultrasonic bath filled with ice, and centrifuged (9000×g, 10 min). The supernatant was filtered through PVDF Ultrafree-MC filters and transferred to high-performance liquid chromatography (HPLC) vials with inserts. External calibration was used. Plasma samples were thawed at room temperature. Proteins were precipitated by adding 50 µL water and 600 µL cold acetonitrile to 200 µL plasma, followed by centrifugation (9000×g, 10 min). The supernatant was then mixed with 600 µL trichloromethane, vortexed, and centrifuged (14,000×g, 2 min). The upper aqueous layer was transferred to HPLC vials with inserts. Matrix-matched calibration was performed using cefazolin-spiked blank plasma. Cefazolin concentrations were determined by HPLC using a ThermoScientific Ultimate 3000 system. Separation was performed using an Ascentis Express C18 column (2.7 µm, 100 × 4.6 mm) with a guard column. The column was thermostated at 40°C, and a 2 µL sample was injected into a mobile phase of acetonitrile (A) and 25 mM phosphate buffer pH 3 at 1.4 mL min − 1 . Gradient conditions were such that A was increased linearly from 12–70% over a period of 5.5 minutes and was kept at 70% for another 3 minutes. Total analysis run time was 11 minutes, and the UV detector was set at 272 nm. The lower limit of quantitation for cefazolin concentration was 1.62 µg mL − 1 (linear range 1.62–245 µg mL − 1 ), with interday and intraday coefficients of variation < 5%. Statistical analysis Data were analyzed using statistical software R (version 4.0.5). Baseline characteristics are presented for the entire cohort. Continuous variables are presented as mean (standard deviation), categorical data as number and percentage. Categorical variables were compared using the Fisher's exact test. A heteroscedastic ANOVA model was used to compare cefazolin concentrations between different disc degeneration grades and endplate change types, with Pfirrmann grade V and Modic type 0 as reference groups for comparisons. P-values and 95% confidence intervals were adjusted for multiple testing using the max-t test method, as implemented in the multcomp package. Effects of patient age, weight, and time from cefazolin administration to IVD sampling on plasma and IVD cefazolin concentrations were analyzed using general linear regression modeling. A two-sided P value < 0.05 indicated statistical significance. Results Between November 2021 and June 2023, 106 patients were enrolled in the study, resulting in 102 valid IVD sample measurements. The characteristics of the study population are summarized in Table 1 . Most participants (62.5%) had moderate intervertebral disc degeneration (Pfirrmann grade IV), and none had discs classified as normal (Pfirrmann grade ≤ II). Modic changes were present in 49.6% of patients, with type I changes observed in 4.7% and type II in 44.9%. Two patients developed surgical site infections; their IVD cefazolin concentrations were 4.6 and 13.3 µg g − 1 . Table 1 Summary of participant characteristics. BMI, body mass index. Variable Overall (N = 106) Age (years) 45.9 (12.6) Sex (male, n(%)) 54 (50.9%) Height (m) 176 (9.40) Weight (kg) 84.2 (17.8) BMI (kg/m2) 27.0 (4.77) Intervertebral disc level L2 - L3 5 (4.7%) L3 - L4 8 (7.5%) L4 - L5 52 (49.1%) L5 - S1 41 (38.7%) Data are presented as mean ± SD. Cefazolin was undetectable in serum prior to antibiotic administration. Thirty minutes after administration, the plasma concentration of cefazolin was 110.9 ± 31.2 mg L − 1 . The mean time to collection of IVD samples was 73 ± 42 minutes after antibiotic administration. The mean concentration of cefazolin in IVDs was 12.1 ± 7.2 µg g − 1 , with a range of 2.0–43.3 µg g − 1 . Plasma cefazolin concentrations correlated with weight (r 2 = 0.14, p < 0.001). No correlations were found between the IVD concentration of cefazolin and patient age (r 2 = 0.01), weight (r 2 = 0.01), or time from cefazolin administration to IVD sampling (r 2 = 0.03). Effects of disc degeneration and Modic changes on antibiotic transport into IVD Table 2 demonstrates the mean serum and IVD concentrations of cefazolin in samples obtained from patients with different disc degeneration grades. The mean IVD cefazolin concentrations were 11.3 ± 8.7 µg g − 1 for Pfirrmann III, 11.7 ± 7.1 µg g − 1 for Pfirrmann IV, and 14.9 ± 6.0 µg g − 1 for Pfirrmann V (p = 0.29). There were no differences in patient weight (r 2 = 0.01) or time from cefazolin administration to IVD sampling (r 2 = 0.02) between different disc degeneration grades. Table 2 Plasma and Intervertebral Disc Concentrations of Cefazolin by Degree of Disc Degeneration. Degree of disc degeneration Outcome Pfirrmann III (N = 22) Pfirrmann IV (N = 60) Pfirrmann V (N = 14) P a Serum (micrograms/mL) 104.4 (35.6) 115.0 (30.1) 101.2 (24.7) 0.24 Disc concentration (micrograms/g) 11.3 (8.7) 11.6 (7.1) 14.9 (6.0) 0.29 Disc-to-plasma concentration ratio 0.11 (0.08) 0.11 (0.07) 0.15 (0.12) 0.37 Patients with disc concentrations less than 4 micrograms/g 1/22 5/60 0/14 0.43 Data are presented as mean (standard deviation) or n. a Compared with Pfirrmann V group. The effect of Modic change type on IVD concentrations of cefazolin is shown in Table 3 . The IVD concentrations were significantly higher in cases with Modic type II changes compared to those without or type I changes (14.6 ± 9.2 µg g − 1 vs. 10.2 ± 4.5 µg g − 1 and 9.2 ± 4.1 µg g − 1 ; P = 0.01). There were no differences in patient weight (r 2 = 0.02) or time from cefazolin administration to IVD sampling (r 2 = 0.01) between different endplate change types. Table 3 Plasma and Intervertebral Disc Concentrations of Cefazolin by Degree of Endplate Changes Degree of endplate changes Outcome Absent (N = 45) MODIC I (N = 8) MODIC II (N = 43) P a Serum (micrograms/mL) 111.0 (39.4) 107.2 (24) 111.5 (20.9) 0.94 Disc concentration (micrograms/g) 10.1 (4.5) 9.2 (4.1) 14.6 (9.2) 0.01 Disc-to-plasma concentration ratio 0.11 (0.08) 0.11 (0.07) 0.15 (0.12) 0.37 Patients with disc concentrations less than 4 micrograms/g 2/45 1/8 3/43 0.54 Data are mean ± standard deviation or n. a Compared with No MODIC group. Ninety-four percent of the participants exhibited cefazolin concentrations in IVD of > 4 µg g − 1 . However, this percentage decreased for concentrations > 8 and > 16 µg g − 1 . The distribution of samples above and below thresholds of 4, 8 and 16 µg cefazolin/g tissue in each degeneration grade and endplate type is shown in Fig. 1. For patients with Modic type 0 or type I changes, only 10% and 25% had concentrations > 16 µg g − 1 , compared to 35.4% for type II (p = 0.008). Similarly, only 16.7% and 20.3% of Pfirrmann grade III and IV discs had concentrations > 16 µg g − 1 , compared to 34.6% for Pfirrmann grade V discs (p = 0.26). Discussion Our results indicate that mean IVD cefazolin concentrations in patients undergoing single level discectomy were higher in those with more advanced disc degeneration (Pfirrmann grade V) and Modic type II endplate changes. Using 4 µg g − 1 as a target, six percent of patients did not achieve cefazolin concentrations above the proposed thresholds for effective antimicrobial activity. Previous studies have investigated the penetration of cefazolin into cervical and lumbar IVDs and reported varying penetration rates. Cefazolin concentrations in these studies have been expressed in both µg g − 1 and mg L − 1 . Given that the nucleus pulposus comprises approximately 83% water by tissue weight and has a density is close to 1.0, the results can be compared directly across studies [ 15 ]. In the current study, the mean IVD cefazolin concentration was 12.1 ± 7.2 µg g − 1 with a range of 2.7–43.1 µg g − 1 . These values fall between lower concentrations of 0.2–0.8 mg L − 1 [ 11 ] and 2.33 ± 0.45 µg g − 1 [ 16 ], and higher concentrations of 59.91 ± 25.79 µg mL − 1 [ 17 ] reported in prior studies. While one study reported that only 50% of tissue samples achieved the minimum inhibitory concentration for Staphylococcus aureus following administration of 1 g cefazolin prophylaxis[ 11 ], our results show that 94% of patients reached this threshold using the 2 g dosage. Although Walters et al. have suggested that variability of IVD cefazolin concentrations could be explained by factors such as disc degeneration and disc size, previous studies have not addressed this issue [ 11 ]. Our study extends previous observations by supporting an association between IVD and endplate degeneration and better IVD cefazolin penetration. The cartilaginous endplate, which interfaces the disc and bone, influences diffusion of nutrients and therapeutic agents into IVD [ 18 , 19 ]. Degeneration of this interface, seen as Modic changes on MRI, could impact delivery of antibiotics to affected discs. In this study, the observed variation in cefazolin IVD concentrations across different types of Modic changes may be attributed to altered endplate morphology. Some studies also indicate that charge plays a significant role in the kinetics of antibiotic penetration into the IVD [ 21 ]. As IVD degeneration progresses, reduction in proteoglycan content leads to a decrease in the disc's negative charge. The less negative charge environment in IVDs with higher Pfirrmann grades may improve the penetration of negatively charged antibiotics, such as cefazolin, into degenerated disc tissue. However, our findings only partially support this hypothesis, higher cefazolin concentrations were observed in discs with advanced degeneration, but the difference was not statistically significant. An animal study by Walters et al. found no difference in cefazolin penetration between normal and artificially degenerated sheep discs [ 22 ]. Therefore, the effect of IVD degeneration on cefazolin penetration remains inconclusive. As the primary objective of perioperative antibacterial prophylaxis is to prevent iatrogenic spondylodiscitis, IVD cefazolin concentrations can only serve as a surrogate outcome. However, establishing a causal relationship between IVD cefazolin concentrations and iatrogenic spondylodiscitis would require a prospective cohort study involving 3000 patients. The most common cause of postoperative IVD infections is Staphylococcus aureaus (60%), and less commonly Escherichia coli . According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the minimum inhibitory concentration of cefazolin required to inhibit growth susceptible strains of these bacteria is 1 µg mL − 1 (European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website, last accessed 4 January, 2025). Four to five times higher values (4 µg mL − 1 ) are required for clinical efficacy [ 23 ]. Our study found no significant difference in attainment of concentration needed to cover standard microorganisms across all degrees of IVD degeneration and Modic types. Yet, Modic type II changes significantly increased attainment of higher cefazolin concentrations (> 16 µg mL − 1 ) needed to cover Gram-negative organisms. However, the relatively small sample size of patients with Modic type I changes compared to other Modic groups limits our ability to draw definitive conclusions about antibiotic penetration in this population. We acknowledge several limitations to our study. One limitation of our methodology is analysis of total as opposed to free cefazolin concentrations. However, our method provided a comprehensive assessment of cefazolin penetration into IVDs and total cefazolin concentrations are clinically relevant as they correlate with microbiological outcomes in patients [ 24 ]. Another limitation is measurement of tissue cefazolin concentrations via homogenized samples which may underestimate interstitial fluid concentration as intracellular fluid, lacking cefazolin, is included in the homogenate. Our study also focused on degenerated discs, which is a clinically relevant population, and we acknowledge that investigating normal discs would have provided valuable additional information. While antibiotic tissue concentrations have been linked to efficacy, the clinical relevance of the differential cefazolin penetration observed in patients with various Modic changes warrants further investigation in future studies. Conclusion This study shows that a fixed preoperative cefazolin regimen results in significant variability in intervertebral disc concentrations, potentially increasing the risk of therapeutic failure in some patients and unintended high exposure in others. In discectomy cases, endplate degeneration grade is a source of variability that should be considered. Declarations Funding: This study was funded by the Fundamental and Applied Research Programme of the Latvian Council of Science, Optimization of prophylactic antibacterial therapy in spinal surgery through mechanical PKPD modelling to reduce the emergence of antibiotic-resistant bacteria (OPATS-PKPD). No. lzp-2024/1/0303 Institutional Review Board: Hospital of Traumatology and Orthopaedics Ethics Committee, 22 Duntes Street, LV-1013 Riga, Latvia. Approval Number: 13/2021/1. Conflict of Interest Statement : The Authors declare no other conflict of interest. Author Contribution All authors contributed to the study conception and design. P.S., B.M., K.L. collected the data and performed literature research. Data collection and analysis were performed by A.R., S.K., A.P., K.B. and J.K.The first draft of the manuscript was written by A.R., P.S., D.B., A.P. and S.K. and all authors commented on prior versions of the manuscript. All authors read and approved the final manuscript. Acknowledgement The authors acknowledge access to the infrastructure and expertise of the BBCE, Baltic Biomaterials Centre of Excellence (European Union’s Horizon 2020 research and innovation program under grant agreement No. 857287). 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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-6965320","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":479492594,"identity":"4b1b2fae-ad68-4363-b7ac-8b744f90097c","order_by":0,"name":"Aleksejs Repnikovs","email":"","orcid":"","institution":"Riga Stradiņš University","correspondingAuthor":false,"prefix":"","firstName":"Aleksejs","middleName":"","lastName":"Repnikovs","suffix":""},{"id":479492595,"identity":"8aa91119-a5b1-4291-862c-3e1c7fc5b536","order_by":1,"name":"Kalvis Briuks","email":"","orcid":"","institution":"Hospital of Traumatology and 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University","correspondingAuthor":false,"prefix":"","firstName":"Janis","middleName":"","lastName":"Kurlovics","suffix":""},{"id":479492603,"identity":"8e1a7ac3-58e4-4b95-b2e3-d8c49f301022","order_by":8,"name":"Sigita Kazune","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYDACZgaGA0DKAMKrAAs1ENZyAK7lDIhgJKAFBOBaGNuI0CLfzn7x8IcaBmP+/jNmDz7Ou2dvcICxTQKfFoPDPAUHDhxjMJM4cMbccOa24sQNBLUw8yQcOMDGYMNwsMdMmndbQgLQlmYDvA5rBmn5x2Ajf5jHTPrvnAR7gloYDrMfOHCwjcHM4BhQC2NDAiPQYY0PCPiF4cDZPgljwzNsZZI9xxISZx4moEW+//jjDxXfbAznnT+8TeJHTYI93/FmUEThAzwghyMHETN+9UDAjtcVo2AUjIJRMAoYGAA5E0yU6xEM0wAAAABJRU5ErkJggg==","orcid":"","institution":"Riga Stradiņš University","correspondingAuthor":true,"prefix":"","firstName":"Sigita","middleName":"","lastName":"Kazune","suffix":""}],"badges":[],"createdAt":"2025-06-24 11:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6965320/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6965320/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86214457,"identity":"3722adb9-d493-4573-b64a-0008202a1154","added_by":"auto","created_at":"2025-07-08 05:48:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5692,"visible":true,"origin":"","legend":"\u003cp\u003eThis image is not available with this version.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6965320/v1/85157c4f49f0340861bd8c29.png"},{"id":87581684,"identity":"3c829696-a923-48d3-abf7-57663e36f860","added_by":"auto","created_at":"2025-07-25 13:02:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":567318,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6965320/v1/492c8972-3963-4d8e-9b42-5f833102c816.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of intervertebral disc degeneration and endplate changes on cefazolin penetration into the intervertebral disc","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntervertebral disc (IVD) infections occur when bacteria spread into the disc space due to bacteremia or as a consequence of spinal surgery. After discectomy, surgical site infections (SSI) rank third among the most frequent complications, with cerebrospinal fluid leak and recurrent herniation being the two most common [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The European Centre for Disease Prevention and Control reported a pooled incidence rate of SSI after laminectomy and discectomy at 0.8 [0.2\u0026ndash;2.7] % among 23,950 patients, with spondylodiscitis accounting for 54% of cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although the incidence is low, SSI usually causes severe pain and can result in major disability.\u003c/p\u003e \u003cp\u003eThe current standard of care for IVD surgery involves prophylactic antibiotics, which have been demonstrated to reduce iatrogenic discitis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. First or second generation cephalosporins are the first-line choice for perioperative prophylaxis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The detection period and concentration of cefazolin after prophylactic dosing vary among individuals [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As IVDs are avascular, antibiotics must be transported by diffusion from blood vessels through the endplates and then through the extracellular matrix of the disc [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It has been suggested that optimal antibiotic regimens may vary depending on disc and endplate health [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMagnetic resonance imaging (MRI) is a useful tool for investigating IVD degeneration and structural endplate changes. Disc morphology and hydration can be graded on MRI T2 spin-echo weighted images using Pfirrmann\u0026rsquo;s grading system (grade 1\u0026ndash;5) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. According to Modic et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], three types of lumbar vertebral body marrow and endplate lesions can be identified on MRI [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. From histological studies of surgical material, these lesions represent endplate fissuring, with subsequent subchondral sclerosis formation which can increase or reduce substance penetration depending on the stage of degeneration. The relationship between antibiotic penetration and MRI changes in IVDs and endplates has not been investigated, despite potential clinical implications.\u003c/p\u003e \u003cp\u003eWe hypothesized that IVD degeneration severity and endplate changes, as quantified by MRI, affect prophylactic cefazolin penetration into the IVD during spinal surgery.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAfter approval by the Hospital Ethics Committee, adult patients scheduled for single level microdiscectomy for symptomatic lumbar disc herniation receiving 2 g of cefazolin as part of their perioperative antibiotic regimen were consecutively enrolled after providing written informed consent. Patients were excluded if they had received any antibiotic treatment within the previous 2 weeks. All patients underwent an MRI at baseline. Demographic and clinical data were collected, including sex, age, weight, and the affected intervertebral segment.\u003c/p\u003e \u003cp\u003eSample collection\u003c/p\u003e \u003cp\u003eTo obtain IVD material for measurement of cefazolin concentration, a rectangular window was created in both the posterior longitudinal ligament and anulus fibrosus during the surgical procedure, and a portion of the nucleus pulposus was excised while ensuring that there was no contamination of the tissue by blood. The disc specimen was collected immediately after excision, placed into a sterile container, and the collection time was recorded. The specimen was stored at -80\u0026deg;C until analysis.\u003c/p\u003e \u003cp\u003eBlood sampling to measure the plasma concentration of cefazolin was performed at two different time points. The baseline sample was taken at the time of peripheral venous catheterization prior to anesthesia. The second blood sample was taken 30 minutes after the administration of cefazolin. Blood samples were collected in EDTA tubes (5 mL). Within 15 minutes after sampling, the EDTA tubes were centrifuged at 3500 \u0026times; g for 10 min to obtain plasma. Plasma was stored at -80\u0026deg; C until analysis. All three time points, including the baseline blood sample, the second sample, and the time of cefazolin administration, were recorded.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMRI\u003c/h2\u003e \u003cp\u003eTwo experienced orthopedic surgeons independently graded the severity of IVD and endplate changes using MRI images. Grading of intervertebral disc degeneration was performed on sagittal T2WI images, and the Pfirrmann criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] were used to assess the involved intervertebral discs. The Pfirrmann grading system evaluates degenerated intervertebral discs by MRI for asymmetry in disc structure, distinction of the nucleus and annulus, signal intensity of IVDs, and height of IVDs, and assigns a grade from I to V for disc degeneration. The upper and lower endplate of the involved disc were graded according to Modic classification: type 0, indicating normal endplate; type I, indicating endplate neovascularity that was hyperintense on T2-weighted images and hypointense on T1-weighted images; type II, indicating endplate fatty replacement that was hyperintense on T1-weighted images and isointense or hypointense on T2-weighted images; and type III, indicating endplate bony sclerosis that was hypointense on both T1- and T2-weighted images [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollow up\u003c/p\u003e \u003cp\u003eTo monitor for postoperative discitis, patients underwent follow-up appointments at 2 and 4 months.\u003c/p\u003e \u003cp\u003eSample analysis\u003c/p\u003e \u003cp\u003eIVD samples were thawed, cut, and 50\u0026ndash;400 mg portions were weighed into 2 mL Eppendorf tubes. After adding 1 mL grinding buffer (25 mM NaH₂PO₄, pH 3), samples were homogenized with a glass rod, sonicated for 10 minutes in an ultrasonic bath filled with ice, and centrifuged (9000\u0026times;g, 10 min). The supernatant was filtered through PVDF Ultrafree-MC filters and transferred to high-performance liquid chromatography (HPLC) vials with inserts. External calibration was used.\u003c/p\u003e \u003cp\u003ePlasma samples were thawed at room temperature. Proteins were precipitated by adding 50 \u0026micro;L water and 600 \u0026micro;L cold acetonitrile to 200 \u0026micro;L plasma, followed by centrifugation (9000\u0026times;g, 10 min). The supernatant was then mixed with 600 \u0026micro;L trichloromethane, vortexed, and centrifuged (14,000\u0026times;g, 2 min). The upper aqueous layer was transferred to HPLC vials with inserts. Matrix-matched calibration was performed using cefazolin-spiked blank plasma.\u003c/p\u003e \u003cp\u003eCefazolin concentrations were determined by HPLC using a ThermoScientific Ultimate 3000 system. Separation was performed using an Ascentis Express C18 column (2.7 \u0026micro;m, 100 \u0026times; 4.6 mm) with a guard column. The column was thermostated at 40\u0026deg;C, and a 2 \u0026micro;L sample was injected into a mobile phase of acetonitrile (A) and 25 mM phosphate buffer pH 3 at 1.4 mL min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Gradient conditions were such that A was increased linearly from 12\u0026ndash;70% over a period of 5.5 minutes and was kept at 70% for another 3 minutes. Total analysis run time was 11 minutes, and the UV detector was set at 272 nm.\u003c/p\u003e \u003cp\u003eThe lower limit of quantitation for cefazolin concentration was 1.62 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (linear range 1.62\u0026ndash;245 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), with interday and intraday coefficients of variation\u0026thinsp;\u0026lt;\u0026thinsp;5%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using statistical software R (version 4.0.5). Baseline characteristics are presented for the entire cohort. Continuous variables are presented as mean (standard deviation), categorical data as number and percentage.\u003c/p\u003e \u003cp\u003eCategorical variables were compared using the Fisher's exact test. A heteroscedastic ANOVA model was used to compare cefazolin concentrations between different disc degeneration grades and endplate change types, with Pfirrmann grade V and Modic type 0 as reference groups for comparisons. P-values and 95% confidence intervals were adjusted for multiple testing using the max-t test method, as implemented in the multcomp package.\u003c/p\u003e \u003cp\u003eEffects of patient age, weight, and time from cefazolin administration to IVD sampling on plasma and IVD cefazolin concentrations were analyzed using general linear regression modeling.\u003c/p\u003e \u003cp\u003eA two-sided P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween November 2021 and June 2023, 106 patients were enrolled in the study, resulting in 102 valid IVD sample measurements. The characteristics of the study population are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Most participants (62.5%) had moderate intervertebral disc degeneration (Pfirrmann grade IV), and none had discs classified as normal (Pfirrmann grade\u0026thinsp;\u0026le;\u0026thinsp;II). Modic changes were present in 49.6% of patients, with type I changes observed in 4.7% and type II in 44.9%. Two patients developed surgical site infections; their IVD cefazolin concentrations were 4.6 and 13.3 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of participant characteristics. BMI, body mass index.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;106)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.9 (12.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex (male, n(%))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (50.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight (m)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176 (9.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.2 (17.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.0 (4.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntervertebral disc level\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL2 - L3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL3 - L4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL4 - L5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (49.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL5 - S1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (38.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD.\u003c/p\u003e \u003cp\u003eCefazolin was undetectable in serum prior to antibiotic administration. Thirty minutes after administration, the plasma concentration of cefazolin was 110.9\u0026thinsp;\u0026plusmn;\u0026thinsp;31.2 mg L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The mean time to collection of IVD samples was 73\u0026thinsp;\u0026plusmn;\u0026thinsp;42 minutes after antibiotic administration. The mean concentration of cefazolin in IVDs was 12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, with a range of 2.0\u0026ndash;43.3 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePlasma cefazolin concentrations correlated with weight (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.14, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No correlations were found between the IVD concentration of cefazolin and patient age (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.01), weight (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.01), or time from cefazolin administration to IVD sampling (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eEffects of disc degeneration and Modic changes on antibiotic transport into IVD\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates the mean serum and IVD concentrations of cefazolin in samples obtained from patients with different disc degeneration grades. The mean IVD cefazolin concentrations were 11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for Pfirrmann III, 11.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for Pfirrmann IV, and 14.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for Pfirrmann V (p\u0026thinsp;=\u0026thinsp;0.29). There were no differences in patient weight (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.01) or time from cefazolin administration to IVD sampling (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02) between different disc degeneration grades.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma and Intervertebral Disc Concentrations of Cefazolin by Degree of Disc Degeneration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eDegree of disc degeneration\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePfirrmann III (N\u0026thinsp;=\u0026thinsp;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePfirrmann IV (N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePfirrmann V (N\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum (micrograms/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104.4 (35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e115.0 (30.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e101.2 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisc concentration (micrograms/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.3 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.6 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.9 (6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisc-to-plasma concentration ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.11 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with disc concentrations less than 4 micrograms/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eData are presented as mean (standard deviation) or n.\u003c/p\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Compared with Pfirrmann V group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe effect of Modic change type on IVD concentrations of cefazolin is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The IVD concentrations were significantly higher in cases with Modic type II changes compared to those without or type I changes (14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e vs. 10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; P\u0026thinsp;=\u0026thinsp;0.01). There were no differences in patient weight (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.02) or time from cefazolin administration to IVD sampling (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.01) between different endplate change types.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlasma and Intervertebral Disc Concentrations of Cefazolin by Degree of Endplate Changes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eDegree of endplate changes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMODIC I\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMODIC II (N\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum (micrograms/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111.0 (39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107.2 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e111.5 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisc concentration (micrograms/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.1 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.2 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.6 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisc-to-plasma concentration ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.11 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients with disc concentrations less than 4 micrograms/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eData are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or n.\u003c/p\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Compared with No MODIC group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNinety-four percent of the participants exhibited cefazolin concentrations in IVD of \u0026gt;\u0026thinsp;4 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. However, this percentage decreased for concentrations\u0026thinsp;\u0026gt;\u0026thinsp;8 and \u0026gt;\u0026thinsp;16 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The distribution of samples above and below thresholds of 4, 8 and 16 \u0026micro;g cefazolin/g tissue in each degeneration grade and endplate type is shown in Fig.\u0026nbsp;1. For patients with Modic type 0 or type I changes, only 10% and 25% had concentrations\u0026thinsp;\u0026gt;\u0026thinsp;16 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, compared to 35.4% for type II (p\u0026thinsp;=\u0026thinsp;0.008). Similarly, only 16.7% and 20.3% of Pfirrmann grade III and IV discs had concentrations\u0026thinsp;\u0026gt;\u0026thinsp;16 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, compared to 34.6% for Pfirrmann grade V discs (p\u0026thinsp;=\u0026thinsp;0.26).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results indicate that mean IVD cefazolin concentrations in patients undergoing single level discectomy were higher in those with more advanced disc degeneration (Pfirrmann grade V) and Modic type II endplate changes. Using 4 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e as a target, six percent of patients did not achieve cefazolin concentrations above the proposed thresholds for effective antimicrobial activity.\u003c/p\u003e \u003cp\u003ePrevious studies have investigated the penetration of cefazolin into cervical and lumbar IVDs and reported varying penetration rates. Cefazolin concentrations in these studies have been expressed in both \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and mg L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Given that the nucleus pulposus comprises approximately 83% water by tissue weight and has a density is close to 1.0, the results can be compared directly across studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the current study, the mean IVD cefazolin concentration was 12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e with a range of 2.7\u0026ndash;43.1 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. These values fall between lower concentrations of 0.2\u0026ndash;0.8 mg L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and 2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and higher concentrations of 59.91\u0026thinsp;\u0026plusmn;\u0026thinsp;25.79 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] reported in prior studies. While one study reported that only 50% of tissue samples achieved the minimum inhibitory concentration for Staphylococcus aureus following administration of 1 g cefazolin prophylaxis[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], our results show that 94% of patients reached this threshold using the 2 g dosage. Although Walters et al. have suggested that variability of IVD cefazolin concentrations could be explained by factors such as disc degeneration and disc size, previous studies have not addressed this issue [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Our study extends previous observations by supporting an association between IVD and endplate degeneration and better IVD cefazolin penetration.\u003c/p\u003e \u003cp\u003eThe cartilaginous endplate, which interfaces the disc and bone, influences diffusion of nutrients and therapeutic agents into IVD [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Degeneration of this interface, seen as Modic changes on MRI, could impact delivery of antibiotics to affected discs. In this study, the observed variation in cefazolin IVD concentrations across different types of Modic changes may be attributed to altered endplate morphology. Some studies also indicate that charge plays a significant role in the kinetics of antibiotic penetration into the IVD [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. As IVD degeneration progresses, reduction in proteoglycan content leads to a decrease in the disc's negative charge. The less negative charge environment in IVDs with higher Pfirrmann grades may improve the penetration of negatively charged antibiotics, such as cefazolin, into degenerated disc tissue. However, our findings only partially support this hypothesis, higher cefazolin concentrations were observed in discs with advanced degeneration, but the difference was not statistically significant. An animal study by Walters et al. found no difference in cefazolin penetration between normal and artificially degenerated sheep discs [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, the effect of IVD degeneration on cefazolin penetration remains inconclusive.\u003c/p\u003e \u003cp\u003eAs the primary objective of perioperative antibacterial prophylaxis is to prevent iatrogenic spondylodiscitis, IVD cefazolin concentrations can only serve as a surrogate outcome. However, establishing a causal relationship between IVD cefazolin concentrations and iatrogenic spondylodiscitis would require a prospective cohort study involving 3000 patients.\u003c/p\u003e \u003cp\u003eThe most common cause of postoperative IVD infections is \u003cem\u003eStaphylococcus aureaus\u003c/em\u003e (60%), and less commonly \u003cem\u003eEscherichia coli\u003c/em\u003e. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the minimum inhibitory concentration of cefazolin required to inhibit growth susceptible strains of these bacteria is 1 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website, last accessed 4 January, 2025). Four to five times higher values (4 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) are required for clinical efficacy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our study found no significant difference in attainment of concentration needed to cover standard microorganisms across all degrees of IVD degeneration and Modic types. Yet, Modic type II changes significantly increased attainment of higher cefazolin concentrations (\u0026gt;\u0026thinsp;16 \u0026micro;g mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) needed to cover Gram-negative organisms. However, the relatively small sample size of patients with Modic type I changes compared to other Modic groups limits our ability to draw definitive conclusions about antibiotic penetration in this population.\u003c/p\u003e \u003cp\u003eWe acknowledge several limitations to our study. One limitation of our methodology is analysis of total as opposed to free cefazolin concentrations. However, our method provided a comprehensive assessment of cefazolin penetration into IVDs and total cefazolin concentrations are clinically relevant as they correlate with microbiological outcomes in patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Another limitation is measurement of tissue cefazolin concentrations via homogenized samples which may underestimate interstitial fluid concentration as intracellular fluid, lacking cefazolin, is included in the homogenate. Our study also focused on degenerated discs, which is a clinically relevant population, and we acknowledge that investigating normal discs would have provided valuable additional information.\u003c/p\u003e \u003cp\u003eWhile antibiotic tissue concentrations have been linked to efficacy, the clinical relevance of the differential cefazolin penetration observed in patients with various Modic changes warrants further investigation in future studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study shows that a fixed preoperative cefazolin regimen results in significant variability in intervertebral disc concentrations, potentially increasing the risk of therapeutic failure in some patients and unintended high exposure in others. In discectomy cases, endplate degeneration grade is a source of variability that should be considered.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis study was funded by the Fundamental and Applied Research Programme of the Latvian Council of Science, Optimization of prophylactic antibacterial therapy in spinal surgery through mechanical PKPD modelling to reduce the emergence of antibiotic-resistant bacteria (OPATS-PKPD). No. lzp-2024/1/0303\u003c/p\u003e \u003cp\u003eInstitutional Review Board: Hospital of Traumatology and Orthopaedics Ethics Committee, 22 Duntes Street, LV-1013 Riga, Latvia. Approval Number: 13/2021/1.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003e \u003cb\u003eConflict of Interest Statement\u003c/b\u003e:\u003c/strong\u003e \u003cp\u003eThe Authors declare no other conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. P.S., B.M., K.L. collected the data and performed literature research. Data collection and analysis were performed by A.R., S.K., A.P., K.B. and J.K.The first draft of the manuscript was written by A.R., P.S., D.B., A.P. and S.K. and all authors commented on prior versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors acknowledge access to the infrastructure and expertise of the BBCE, Baltic Biomaterials Centre of Excellence (European Union\u0026rsquo;s Horizon 2020 research and innovation program under grant agreement No. 857287).\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShriver MF, Xie JJ, Tye EY et al (2015) Lumbar microdiscectomy complication rates: a systematic review and meta-analysis. 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J Biomech 49:3079\u0026ndash;3084. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jbiomech.2016.07.012\u003c/span\u003e\u003cspan address=\"10.1016/j.jbiomech.2016.07.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalters R, Rahmat R, Fraser R, Moore R (2006) Preventing and treating discitis: cephazolin penetration in ovine lumbar intervertebral disc. Eur Spine J 15:1397\u0026ndash;1403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00586-006-0144-6\u003c/span\u003e\u003cspan address=\"10.1007/s00586-006-0144-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdul-Aziz MH, Lipman J, Mouton JW et al (2015) Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. 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Int J Antimicrob Agents 51:443\u0026ndash;449. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijantimicag.2017.11.013\u003c/span\u003e\u003cspan address=\"10.1016/j.ijantimicag.2017.11.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Cefazolin, antibiotic prophylaxis, degenerative disc disease, spine surgery","lastPublishedDoi":"10.21203/rs.3.rs-6965320/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6965320/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose.\u003c/h2\u003e \u003cp\u003ePreoperative cefazolin is the standard of care for intervertebral disc surgery as it reduces the incidence of iatrogenic spondylodiscitis. The aim of this study was to determine the impact of intervertebral disc degeneration and endplate changes on the penetration of prophylactic cefazolin into the intervertebral disc during spinal surgery.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eAdult patients undergoing single-level microdiscectomy for lumbar disc herniation received prophylaxis with 2 g of cefazolin. Venous blood and intervertebral disc samples were collected and analyzed using high-performance liquid chromatography to determine cefazolin concentrations. The severity of intervertebral disc and endplate changes was assessed on magnetic resonance images using the Pfirrmann and Modic grading systems.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e \u003cp\u003eCefazolin concentrations were significantly higher in cases with Modic type II changes compared to type 0/I (14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e vs. 10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; P\u0026thinsp;=\u0026thinsp;0.01). 35.4% of patients with Modic type II changes had concentrations\u0026thinsp;\u0026gt;\u0026thinsp;16 \u0026micro;g g\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, compared to 10% and 25% for patients with Modic type 0/I (p\u0026thinsp;=\u0026thinsp;0.008). For Pfirrmann grading, 34.6% of grade V discs reached\u0026thinsp;\u0026gt;\u0026thinsp;16 \u0026micro;g g⁻\u0026sup1; versus 16.7% and 20.3% for grades III and IV (p\u0026thinsp;=\u0026thinsp;0.26). Patient age, weight, and timing showed no significant correlations with intradisc concentrations.\u003c/p\u003e\u003ch2\u003eConclusion.\u003c/h2\u003e \u003cp\u003eDisc degeneration and endplate changes significantly impact cefazolin penetration, with higher concentrations in Modic type II changes and advanced Pfirrmann grades, potentially affecting antibiotic efficacy for surgical prophylaxis.\u003c/p\u003e","manuscriptTitle":"Impact of intervertebral disc degeneration and endplate changes on cefazolin penetration into the intervertebral disc","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-08 05:48:02","doi":"10.21203/rs.3.rs-6965320/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":"b7a661ad-1fab-4ec4-a1dd-05c2610c3438","owner":[],"postedDate":"July 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-25T12:53:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-08 05:48:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6965320","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6965320","identity":"rs-6965320","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}