Insufficient diffusion of tedizolid in cerebrospinal fluid: about a case report and mini-review of literature

Insufficient diffusion of tedizolid in cerebrospinal fluid: about a case report and mini-review of literature | 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 Case Report Insufficient diffusion of tedizolid in cerebrospinal fluid: about a case report and mini-review of literature Xavier BROUSSE, Minh P LÊ, Marin LAHOUATI, Paul PETITGAS This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4378400/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 Background : Tedizolid, a recent oxazolidinone developed for skin and soft tissues infection with bacteriostatic activity, is believed to have identical pharmacokinetic parameters to linezolid with less myelosuppression and neurotoxicity. However, its neuro-meningeal diffusion seems different than linezolid. This case report and this review aim to investigate the diffusion of this molecule. Case presentation: We report a clinical case of meningitis secondary to skull base osteomyelitis and we present a rapid review of literature. Liquid chromatography coupled with mass tandem spectrometry was used to measure tedizolid concentration. The trough concentration in CSF was under the limit of quantification while serum concentration was appropriate. A short review of the literature seems to confirm that meningeal diffusion is weaker than linezolid. Conclusion : It is therefore important to be cautious when prescribing tedizolid in neuro-meningeal infections, especially if targeted pathogens have high MICs. case report tedizolid pharmacokinetics diffusion neuromeningeal infections Figures Figure 1 Introduction Tedizolid phosphate (TDZ) is the second oxazolidinone currently available. Its daily administration due to a prolonged half-life of around 11 hours [ 1 ] simplifies its prescription compared to linezolid [ 2 ]. Although recommended for skin and soft tissue infections [ 3 ], its prescription is extending to other infections, such as osteoarticular infections [ 4 ] and seems promising in certain infections such as nocardiosis [ 5 ] or VABP (ventilator-associated bacterial pneumonia) [ 6 ]. Moreover, TDZ is alleged to have a lower rate of myelotoxicity and neurotoxicity than linezolid [ 7 , 8 ] However, clinical studies found a limited neuro-meningeal diffusion of TDZ in the cerebrospinal fluid (CSF) [ 9 ]. Also, animal model suggested that the diffusion of TDZ seemed moderate with a penetration ratio (AUC CSF /AUC plasma ) between 1.45% and 3.84% [ 10 ]. These values appear insufficient in relation to the MICs of the target microorganisms. In this context, we report the case of a 68-year-old patient treated for skull base osteomyelitis with acute aseptic meningitis, as well as a mini review of the literature. Case presentation A 68-year-old female patient with dyslipidemia, genotype 4 hepatitis C treated with glecaprevir/pibrentasvir without chronic liver disease, and a cholesteatoma of the left ear for which she underwent an external auditory canal plasty in 2015 as her medical history. She was hospitalized in the University hospital of Reunion Island in the emergency department in a context of fever associated with headache and diplopia. She reported vertigo evolving for several months with an MRI of the petrous bone finding an aspect of labyrinthitis and a cone beam CT of the left petrous bone in favor of an osteitis of the mastoid for which a specialized ENT management was in progress. She had neck stiffness, without altered level of consciousness neither focal deficit. Diplopia was not accompanied by objective oculomotor paralysis, so the brain scan was carried before lumbar puncture (LP). The LP revealed a hypercellularity with 860 leukocytes/mm 3 including 42% of neutrophiles and 47% of lymphocytes. There was a hyperproteinorachia at 1.05 g/L (N = 0.15–0.4 g/L). Lactatorachia was slightly elevated at 3.9 mmol/L (N = 1.1–2.4 mmol/L) and glycorachia was normal at 0.45 g/L (glycemia was 0.92 g/L). Direct examination was negative. Then, she was treated with cefotaxime 300 mg/kg/d associated with amoxicillin 200 mg/kg/d and dexamethasone 10 mg x 4/day in the hypothesis of a bacterial meningitis. Her BMI was 20,41. Her renal function was normal with an eGFR of 97 mL/min (MDRD). She was subsequently admitted to the infectious diseases ward (day 0). The MRI of the brain and petrous bone showed osteitis with a meso-tympanic osteo-dural collection on a possible remnant of cholesteatoma with a perilymphatic fistulization and a sub-arachnoid fistulization behind the acoustic-facial bundle with an empyema of 5 x 4 x 4 mm and a suspicious appearance of leptomeningitis. Amoxicillin was rapidly stopped due to the lack of arguments for a neurolisteriosis. The culture of the CSF was negative imposing the realization of a 16S PCR which was also negative. In this context (Fig. 1 ), antibiotic therapy was modified with ceftazidime 3 g thrice-daily and TDZ 200 mg once-daily (day 2) in the hypothesis of skull base osteomyelitis with aseptic meningitis. In the absence of possibility of emergency surgical management, we repeated the lumbar puncture on day 6 to check cellularity and measure TDZ in the CSF, i.e., 4 days after the start of treatment. The latter showed a decrease in cellularity (730 leukocytes/mm 3 ) with a proteinorachia of 0.55 g/L and a lactatorachia of 1.8 mmol/L. Plasma and CSF samples were drawn simultaneously, 24 hours after administration, to determine residual TDZ concentrations in both compartments. The samples were analyzed 3 days later at Bichat Hospital in Paris. TDZ concentrations were determined using liquid chromatography coupled with mass tandem spectrometry (LC-MSMS, Waters Xevo TQD, TDZ limit of quantification (LOQ) = 0.1 mg/L) [ 11 ]. Trough TDZ plasma and CSF concentrations were 0.3 mg/L (expected range of concentrations: 0.1–0.8 mg/L, [ 11 ]) and < LOQ, respectively. In this context, due to a favorable evolution, the patient's treatment was not modified. The prescription of TDZ was justified by a prolonged duration of treatment (6 weeks) and a clinical condition allowing a return at home. After a wash-out period of antibiotics, the patient finally underwent ENT surgery for milling the petrous bone and filling the labyrinthine fistula. Bone samples were sterile. At the medical check-up 3 months after the medical and surgical treatment, the patient was cured. Discussion Linezolid has become a first-line antibiotic in gram-positive cocci neuromeningeal infections given its excellent bioavailability [12] and neuromeningeal diffusion [13]. The question therefore arose for this new oxazolidinone, TDZ. TDZ had an excellent bioavailability too, with peak and steady-state plasma concentrations reached within approximately 3 hours and 3 days, respectively, of oral administration [14]. C max was an average of 2.0 mg/L and AUC was 23.4 µg.h/mL after oral administration of 200 mg of TDZ in healthy subjects [14], with a linear increase with doses from 200 to 600 mg. C max were measured between 1.86 and 3.89 mg/L after infusion of 200 mg of TDZ in healthy subjects [12], globally similar to oral administration. It distributed well into skin and soft tissue [13]. However, CSF diffusion of TDZ is still poorly known. In an animal study, penetration ratio was low, between 1.45% to 3.84%. Clinical studies are lacking and limited to a few case reports (Table 1). In a case report [15], authors reported a CSF concentration of 0.204 mg/L, with a penetration ratio of approximately 50% of the plasma concentration. However, this CSF sample was performed 8.5 hours after the last intravenous administration of 200 mg of TDZ, which is not a residual, and plasma concentration was not measured but extrapolated from its pharmacokinetic characteristics. This ratio was much higher than suggested by other authors [9], where it was around 20%. In this publication, TDZ was increased to 200 mg x 2/day in an attempt to compensate for this lack of neuro-meningeal diffusion but diffusion ratio remained weak (16-27%), however, outcome was favorable [9]. Considering our case report, the CSF concentrations of TDZ measured between 5 and 10 hours after administrations were less than 0.2 mg/L, and the residual concentration at 24 hours after administration was undetectable. However, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) consider most gram-positive cocci sensitive to TDZ with a MIC < 1 mg/L. So the risk of not reaching the MIC during a large part of the exposure to TDZ is significant. This is why it does not appear to be a good candidate for the treatment of neuromeningeal infections. Table 1. Summary of the different studies on the subject. Micro-organisms Other treatments Doses CSF concentrations (time since last dose) Plasma concentrations (time since last dose) Diffusion ratios (mean) Outcome Bouet et al [8] (patient 1) N. farcinica (MIC TZD 0.75 mg/L) SXT / IMI / AMK 200mg/jday (oral) 0.11 mg/L (H5) 1.494 mg/L (H5) 20 % Unfavorable Bouet et al [8] (patient 2) N. farcinica (MIC TZD 0.75 mg/L) SXT 200mg x2/day (oral) 0.21 mg/L (H10) 1mg/L (H10) 16 – 27% Favorable Wenzler et al [11] E. faecium (VRE) Oritavancin 200mg x2/day (IV) 0.204 mg/L 0.30 – 0.49 mg/L (estimated) 50% Unfavorable Matin et al [12] N. farcinica SXT 200mg/day (oral) Not realized Not realized Not realized Favorable Our work Not documented Ceftazidime 200mg/day (oral) <0.1 mg/L (H24) 0.3 mg/L (H24) 0 % Favorable Abbreviations : AMK : amikacin, MIC : minimum inhibitory concentration. CSF : Cerebrospinal fluid. SXT : sulfamethoxazole/trimethoprim. IMI : imipenem. TZD : tedizolid. VRE : vancomycin resistant enterococcus. The pathophysiological rationale for the major difference with linezolid may be that TDZ has a higher protein binding, 80% versus 30% for linezolid [1], which might limit its diffusion across the blood-brain barrier. Furthermore, TDZ is the substrate of efflux pumps such as Pgp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein) and inhibition of these proteins slightly increases the concentration of TDZ in the CSF in vitro [9]. Affinity to these efflux pumps can be different between the two drugs, and between individuals which can explain differences during sampling. Finally, impact of the meningeal inflammation has not been studied for TDZ. One limit of our case report is the LOQ of our dosage. TDZ trough concentration may not be detectable due to the lack of sensitivity. Nevertheless, if we consider the most optimistic scenario (CSF concentration around 0,09 mg/L), the ratio is still around 30% of the serum concentration. In addition, only one sample of TDZ was available, whereas AUC CSF /AUC plasma is the best parameter to evaluate CSF diffusion, but this requires repeated sampling incompatible in practice. Data concerning TDZ pharmacokinetic, and neuromeningeal diffusion notably, are scarce and heterogenous. That’s why more robust studies are needed to definite if neuromeningeal infections should be treated with TDZ or not. Increased dosages strategies should be evaluated. Conclusion Overall, TDZ may not be fully adequate for the treatment of neuromeningeal infections due to poor diffusion into the CSF at regular dosing. The use of linezolid in this setting should probably be preferred until more robust data are available. Abbreviations CSF Cerebrospinal fluid VABP Ventilator Associated Bacterial Pneumonia TDZ Tedizolid BMI Body Mass Index LOQ Limit of quantification Declarations Funding: No funding received. Conflicts of interest: Authors declare no conflict of interest according to ICMJE recommendations. Ethics approval and consent to participate: Patient’s written consent was obtained. This study complied with the ethical and legal requirements of French law (15 April 2019) and the Declaration of Helsinki. Availability of data and material: Some de-identified data will be shared with other researchers upon reasonable request to the corresponding authors ( [email protected] ). The sharing will require a detailed proposal to the study investigators, and a data transfer agreement must be signed. Consent for publication: Written consent to publish was obtained. Author contributions: Conceptualization : X.B; PP. Data curation : X.B; P.P. Investigation : X.B; P.P. Methodology : X.B; P.P;M.L; M.L. Validation : X.B; P.P; M.L; M.L. Roles/Writing - original draft, review & editing : X.B; P.P; M.L; M.L. Each author has approved the submitted version. References Iqbal K, Milioudi A, Wicha SG. Pharmacokinetics and Pharmacodynamics of Tedizolid. Clin Pharmacokinet. 2022;61:489–503. Burdette SD, Trotman R. Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. Clin Infect Dis. 2015;61:1315–21. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections: The ESTABLISH-1 Randomized Trial. JAMA. 2013;309:559. Ferry T, Conrad A, Senneville E, et al. Safety of Tedizolid as Suppressive Antimicrobial Therapy for Patients With Complex Implant-Associated Bone and Joint Infection due to Multidrug-Resistant Gram-Positive Pathogens: Results From the TediSAT Cohort Study. Open Forum Infect Dis. 2021;8:ofab351. Matin A, Sharma S, Mathur P, Apewokin SK. Myelosuppression-sparing treatment of central nervous system nocardiosis in a multiple myeloma patient utilizing a tedizolid-based regimen: a case report. Int J Antimicrob Agents. 2017;49:488–92. Wunderink RG, Roquilly A, Croce M, et al. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia. Clin Infect Dis. 2021;73:e710–8. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17:760–72. Schlosser MJ, Hosako H, Radovsky A, et al. Lack of Neuropathological Changes in Rats Administered Tedizolid Phosphate for Nine Months. Antimicrob Agents Chemother. 2015;59:475–81. Bouet M. Diffusion insuffisante du tédizolide dans le liquide cérébro-spinal: 2 cas de nocardiose cérébrale (Abstract). MMIFMC. 2022;1:S103. Gu L, Ma M, Zhang Y, et al. Comparative pharmacokinetics of tedizolid in rat plasma and cerebrospinal fluid. Regul Toxicol Pharmacol. 2019;107:104420. Tanaka R, Kai M, Goto K, et al. High-throughput and wide-range simultaneous determination of linezolid, daptomycin and tedizolid in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal. 2021;194:113764. Chen R, Shen K, Chang X, Tanaka T, Li L, Hu P. Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects. Clin Ther. 2016;38:1869–79. Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis*. Clin Infect Dis. 2017;64:e34–65. Flanagan SD, Bien PA, Muñoz KA, Minassian SL, Prokocimer PG. Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug. Pharmacotherapy. 2014;34:240–50. Wenzler E, Adeel A, Wu T, et al. Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia. Infect Disease Rep. 2021;13:843–54. Additional Declarations No competing interests reported. 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-4378400","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":304921020,"identity":"2a329ce7-a700-4134-ac02-21f9ee9a5a83","order_by":0,"name":"Xavier BROUSSE","email":"data:image/png;base64,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","orcid":"","institution":"Centre Hospitalier Universitaire de La Réunion","correspondingAuthor":true,"prefix":"","firstName":"Xavier","middleName":"","lastName":"BROUSSE","suffix":""},{"id":304921021,"identity":"57133882-2489-4f34-b727-79341eb7b24d","order_by":1,"name":"Minh P LÊ","email":"","orcid":"","institution":"Hôpital Bichat-Claude-Bernard","correspondingAuthor":false,"prefix":"","firstName":"Minh","middleName":"P","lastName":"LÊ","suffix":""},{"id":304921022,"identity":"b907262c-6fc5-4ad9-84ce-d77708bfbe0f","order_by":2,"name":"Marin LAHOUATI","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Marin","middleName":"","lastName":"LAHOUATI","suffix":""},{"id":304921023,"identity":"ab9afbea-e8f9-4fc5-beb4-795e439b94a0","order_by":3,"name":"Paul PETITGAS","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de La Réunion","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"PETITGAS","suffix":""}],"badges":[],"createdAt":"2024-05-06 17:10:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4378400/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4378400/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57518784,"identity":"eee58a24-39d8-4b68-9910-4c889ac77569","added_by":"auto","created_at":"2024-05-31 20:37:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56635,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of our patient.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4378400/v1/b2375078f4ee09594bf9ec87.png"},{"id":61511959,"identity":"4ba5b1d9-2886-41c4-8ac0-b9a87d327196","added_by":"auto","created_at":"2024-07-31 14:59:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":396771,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4378400/v1/32373964-c2a9-4b9b-8cd6-7ca464452cb2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Insufficient diffusion of tedizolid in cerebrospinal fluid: about a case report and mini-review of literature","fulltext":[{"header":"Introduction ","content":"\u003cp\u003eTedizolid phosphate (TDZ) is the second oxazolidinone currently available. Its daily administration due to a prolonged half-life of around 11 hours [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] simplifies its prescription compared to linezolid [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although recommended for skin and soft tissue infections [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], its prescription is extending to other infections, such as osteoarticular infections [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and seems promising in certain infections such as nocardiosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] or VABP (ventilator-associated bacterial pneumonia) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, TDZ is alleged to have a lower rate of myelotoxicity and neurotoxicity than linezolid [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eHowever, clinical studies found a limited neuro-meningeal diffusion of TDZ in the cerebrospinal fluid (CSF) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Also, animal model suggested that the diffusion of TDZ seemed moderate with a penetration ratio (AUC\u003csub\u003eCSF\u003c/sub\u003e/AUC\u003csub\u003eplasma\u003c/sub\u003e) between 1.45% and 3.84% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These values appear insufficient in relation to the MICs of the target microorganisms.\u003c/p\u003e \u003cp\u003eIn this context, we report the case of a 68-year-old patient treated for skull base osteomyelitis with acute aseptic meningitis, as well as a mini review of the literature.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 68-year-old female patient with dyslipidemia, genotype 4 hepatitis C treated with glecaprevir/pibrentasvir without chronic liver disease, and a cholesteatoma of the left ear for which she underwent an external auditory canal plasty in 2015 as her medical history. She was hospitalized in the University hospital of Reunion Island in the emergency department in a context of fever associated with headache and diplopia. She reported vertigo evolving for several months with an MRI of the petrous bone finding an aspect of labyrinthitis and a cone beam CT of the left petrous bone in favor of an osteitis of the mastoid for which a specialized ENT management was in progress. She had neck stiffness, without altered level of consciousness neither focal deficit. Diplopia was not accompanied by objective oculomotor paralysis, so the brain scan was carried before lumbar puncture (LP). The LP revealed a hypercellularity with 860 leukocytes/mm\u003csup\u003e3\u003c/sup\u003e including 42% of neutrophiles and 47% of lymphocytes. There was a hyperproteinorachia at 1.05 g/L (N\u0026thinsp;=\u0026thinsp;0.15\u0026ndash;0.4 g/L). Lactatorachia was slightly elevated at 3.9 mmol/L (N\u0026thinsp;=\u0026thinsp;1.1\u0026ndash;2.4 mmol/L) and glycorachia was normal at 0.45 g/L (glycemia was 0.92 g/L). Direct examination was negative. Then, she was treated with cefotaxime 300 mg/kg/d associated with amoxicillin 200 mg/kg/d and dexamethasone 10 mg x 4/day in the hypothesis of a bacterial meningitis. Her BMI was 20,41. Her renal function was normal with an eGFR of 97 mL/min (MDRD).\u003c/p\u003e \u003cp\u003eShe was subsequently admitted to the infectious diseases ward (day 0). The MRI of the brain and petrous bone showed osteitis with a meso-tympanic osteo-dural collection on a possible remnant of cholesteatoma with a perilymphatic fistulization and a sub-arachnoid fistulization behind the acoustic-facial bundle with an empyema of 5 x 4 x 4 mm and a suspicious appearance of leptomeningitis. Amoxicillin was rapidly stopped due to the lack of arguments for a neurolisteriosis. The culture of the CSF was negative imposing the realization of a 16S PCR which was also negative.\u003c/p\u003e \u003cp\u003eIn this context (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), antibiotic therapy was modified with ceftazidime 3 g thrice-daily and TDZ 200 mg once-daily (day 2) in the hypothesis of skull base osteomyelitis with aseptic meningitis. In the absence of possibility of emergency surgical management, we repeated the lumbar puncture on day 6 to check cellularity and measure TDZ in the CSF, i.e., 4 days after the start of treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe latter showed a decrease in cellularity (730 leukocytes/mm\u003csup\u003e3\u003c/sup\u003e) with a proteinorachia of 0.55 g/L and a lactatorachia of 1.8 mmol/L. Plasma and CSF samples were drawn simultaneously, 24 hours after administration, to determine residual TDZ concentrations in both compartments. The samples were analyzed 3 days later at Bichat Hospital in Paris. TDZ concentrations were determined using liquid chromatography coupled with mass tandem spectrometry (LC-MSMS, Waters Xevo TQD, TDZ limit of quantification (LOQ)\u0026thinsp;=\u0026thinsp;0.1 mg/L) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Trough TDZ plasma and CSF concentrations were 0.3 mg/L (expected range of concentrations: 0.1\u0026ndash;0.8 mg/L, [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]) and \u0026lt;\u0026thinsp;LOQ, respectively. In this context, due to a favorable evolution, the patient's treatment was not modified. The prescription of TDZ was justified by a prolonged duration of treatment (6 weeks) and a clinical condition allowing a return at home. After a wash-out period of antibiotics, the patient finally underwent ENT surgery for milling the petrous bone and filling the labyrinthine fistula. Bone samples were sterile. At the medical check-up 3 months after the medical and surgical treatment, the patient was cured.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eLinezolid has become a first-line antibiotic in gram-positive cocci neuromeningeal infections given its excellent bioavailability\u0026nbsp;[12]\u0026nbsp;and neuromeningeal diffusion\u0026nbsp;[13]. The question therefore arose for this new oxazolidinone, TDZ.\u003c/p\u003e\n\u003cp\u003eTDZ had an excellent bioavailability too, with peak and steady-state plasma concentrations reached within approximately 3 hours and 3 days, respectively, of oral administration [14]. C\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ewas an average of 2.0 mg/L and AUC was 23.4 \u0026micro;g.h/mL after oral administration of 200 mg of TDZ in healthy subjects\u0026nbsp;[14], with a linear increase with doses from 200 to 600 mg. C\u003csub\u003emax\u003c/sub\u003e were measured between 1.86 and 3.89 mg/L after infusion of 200 mg of TDZ in healthy subjects [12], globally similar to oral administration. It distributed well into skin and soft tissue [13]. However, CSF diffusion of TDZ is still poorly known. In an animal study, penetration ratio was low, between 1.45% to 3.84%. Clinical studies are lacking and limited to a few case reports (Table 1). In a case report [15], authors reported a CSF concentration of 0.204 mg/L, with a penetration ratio of approximately 50% of the plasma concentration. However, this CSF sample was performed 8.5 hours after the last intravenous administration of 200 mg of TDZ, which is not a residual, and plasma concentration was not measured but extrapolated from its pharmacokinetic characteristics. This ratio was much higher than suggested by other authors [9], where it was around 20%. In this publication, TDZ was increased to 200 mg x 2/day in an attempt to compensate for this lack of neuro-meningeal diffusion but diffusion ratio remained weak (16-27%), however, outcome was favorable [9]. Considering our case report, the CSF concentrations of TDZ measured between 5 and 10 hours after administrations were less than 0.2 mg/L, and the residual concentration at 24 hours after administration was undetectable. However, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) consider most gram-positive cocci sensitive to TDZ with a MIC \u0026lt; 1 mg/L. So the risk of not reaching the MIC during a large part of the exposure to TDZ is significant. This is why it does not appear to be a good candidate for the treatment of neuromeningeal infections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eSummary of the different studies on the subject.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"759\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMicro-organisms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOther treatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDoses\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCSF concentrations (time since last dose)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003econcentrations\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(time since last dose)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDiffusion\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eratios\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(mean)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBouet et al\u0026nbsp;\u003c/strong\u003e[8]\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(patient 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN. \u003cem\u003efarcinica\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e(MIC TZD 0.75 mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSXT / IMI / AMK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e200mg/jday (oral)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.11 mg/L\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(H5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.494 mg/L\u003c/p\u003e\n \u003cp\u003e(H5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUnfavorable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBouet et al\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e[8]\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(patient 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN. \u003cem\u003efarcinica\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e(MIC TZD\u0026nbsp;0.75\u0026nbsp;mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSXT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e200mg x2/day (oral)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.21 mg/L\u003c/p\u003e\n \u003cp\u003e(H10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1mg/L\u003c/p\u003e\n \u003cp\u003e(H10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 \u0026ndash; 27%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFavorable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eWenzler et al\u0026nbsp;\u003c/strong\u003e[11]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eE. faecium\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(VRE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOritavancin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e200mg x2/day (IV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.204 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.30 \u0026ndash; 0.49 mg/L (estimated)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUnfavorable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMatin et al\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN. farcinica\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSXT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e200mg/day\u0026nbsp;(oral)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNot realized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNot\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;realized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNot\u0026nbsp;realized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFavorable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.720316622691293%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOur work\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.158311345646437%\" valign=\"top\"\u003e\n \u003cp\u003eNot documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCeftazidime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.609498680738787%\" valign=\"top\"\u003e\n \u003cp\u003e200mg/day (oral)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.1 mg/L (H24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.435356200527705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.3 mg/L (H24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.026385224274406%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 %\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.005277044854882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFavorable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u003cu\u003eAbbreviations :\u003c/u\u003e\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;AMK : amikacin, MIC : minimum inhibitory concentration. CSF : Cerebrospinal fluid. SXT : sulfamethoxazole/trimethoprim. IMI : imipenem. TZD : tedizolid. VRE : vancomycin resistant enterococcus.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe pathophysiological rationale for the major difference with linezolid may be that TDZ has a higher protein binding, 80% versus 30% for linezolid [1], which might limit its diffusion across the blood-brain barrier. Furthermore, TDZ is the substrate of efflux pumps such as Pgp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein) and inhibition of these proteins slightly increases the concentration of TDZ in the CSF \u003cem\u003ein vitro\u003c/em\u003e [9]. Affinity to these efflux pumps can be different between the two drugs, and between individuals which can explain differences during sampling. Finally, impact of the meningeal inflammation has not been studied for TDZ.\u003c/p\u003e\n\u003cp\u003eOne limit of our case report is the LOQ of our dosage. TDZ trough concentration may not be detectable due to the lack of sensitivity. Nevertheless, if we consider the most optimistic scenario (CSF concentration around 0,09 mg/L), the ratio is still around 30% of the serum concentration. In addition, only one sample of TDZ was available, whereas AUC\u003csub\u003eCSF\u003c/sub\u003e/AUC\u003csub\u003eplasma\u0026nbsp;\u003c/sub\u003eis the best parameter to evaluate CSF diffusion, but this requires repeated sampling incompatible in practice.\u003c/p\u003e\n\u003cp\u003eData concerning TDZ pharmacokinetic, and neuromeningeal diffusion notably, are scarce and heterogenous. That\u0026rsquo;s why more robust studies are needed to definite if neuromeningeal infections should be treated with TDZ or not. Increased dosages strategies should be evaluated.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, TDZ may not be fully adequate for the treatment of neuromeningeal infections due to poor diffusion into the CSF at regular dosing. The use of linezolid in this setting should probably be preferred until more robust data are available.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCSF\u0026nbsp;\u003c/strong\u003eCerebrospinal fluid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVABP\u0026nbsp;\u003c/strong\u003eVentilator Associated Bacterial Pneumonia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTDZ\u0026nbsp;\u003c/strong\u003eTedizolid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u0026nbsp;\u003c/strong\u003eBody Mass Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLOQ\u0026nbsp;\u003c/strong\u003eLimit of quantification\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding received.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e Authors declare no conflict of interest according to ICMJE recommendations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003ePatient\u0026rsquo;s written consent was obtained.\u0026nbsp;This study complied with the ethical and legal requirements of French law (15 April 2019) and the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eSome de-identified data will be shared with other researchers upon reasonable request to the corresponding authors ([email protected]). The sharing will require a detailed proposal to the study investigators, and a data transfer agreement must be signed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Written consent to publish was obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization : X.B; PP.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData curation : X.B; P.P.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInvestigation : X.B; P.P.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethodology : X.B; P.P;M.L; M.L.\u003c/p\u003e\n\u003cp\u003eValidation : X.B; P.P; M.L; M.L.\u003c/p\u003e\n\u003cp\u003eRoles/Writing - original draft, review \u0026amp; editing : X.B; P.P; M.L; M.L.\u003c/p\u003e\n\u003cp\u003eEach author has approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIqbal K, Milioudi A, Wicha SG. Pharmacokinetics and Pharmacodynamics of Tedizolid. Clin Pharmacokinet. 2022;61:489\u0026ndash;503.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurdette SD, Trotman R. Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. Clin Infect Dis. 2015;61:1315\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProkocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections: The ESTABLISH-1 Randomized Trial. JAMA. 2013;309:559.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerry T, Conrad A, Senneville E, et al. Safety of Tedizolid as Suppressive Antimicrobial Therapy for Patients With Complex Implant-Associated Bone and Joint Infection due to Multidrug-Resistant Gram-Positive Pathogens: Results From the TediSAT Cohort Study. Open Forum Infect Dis. 2021;8:ofab351.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatin A, Sharma S, Mathur P, Apewokin SK. Myelosuppression-sparing treatment of central nervous system nocardiosis in a multiple myeloma patient utilizing a tedizolid-based regimen: a case report. Int J Antimicrob Agents. 2017;49:488\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWunderink RG, Roquilly A, Croce M, et al. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia. Clin Infect Dis. 2021;73:e710\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17:760\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchlosser MJ, Hosako H, Radovsky A, et al. Lack of Neuropathological Changes in Rats Administered Tedizolid Phosphate for Nine Months. Antimicrob Agents Chemother. 2015;59:475\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouet M. Diffusion insuffisante du t\u0026eacute;dizolide dans le liquide c\u0026eacute;r\u0026eacute;bro-spinal: 2 cas de nocardiose c\u0026eacute;r\u0026eacute;brale (Abstract). MMIFMC. 2022;1:S103.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu L, Ma M, Zhang Y, et al. Comparative pharmacokinetics of tedizolid in rat plasma and cerebrospinal fluid. Regul Toxicol Pharmacol. 2019;107:104420.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka R, Kai M, Goto K, et al. High-throughput and wide-range simultaneous determination of linezolid, daptomycin and tedizolid in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal. 2021;194:113764.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen R, Shen K, Chang X, Tanaka T, Li L, Hu P. Pharmacokinetics and Safety of Tedizolid after Single and Multiple Intravenous/Oral Sequential Administrations in Healthy Chinese Subjects. Clin Ther. 2016;38:1869\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America\u0026rsquo;s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis*. Clin Infect Dis. 2017;64:e34\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlanagan SD, Bien PA, Mu\u0026ntilde;oz KA, Minassian SL, Prokocimer PG. Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug. Pharmacotherapy. 2014;34:240\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWenzler E, Adeel A, Wu T, et al. Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia. Infect Disease Rep. 2021;13:843\u0026ndash;54.\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":"case report, tedizolid, pharmacokinetics, diffusion, neuromeningeal infections","lastPublishedDoi":"10.21203/rs.3.rs-4378400/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4378400/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Tedizolid, a recent oxazolidinone developed for skin and soft tissues infection with bacteriostatic activity, is believed to have identical pharmacokinetic parameters to linezolid with less myelosuppression and neurotoxicity. However, its neuro-meningeal diffusion seems different than linezolid. This case report and this review aim to investigate the diffusion of this molecule.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e We report a clinical case of meningitis secondary to skull base osteomyelitis and we present a rapid review of literature. Liquid chromatography coupled with mass tandem spectrometry was used to measure tedizolid concentration.\u003c/p\u003e\n\u003cp\u003eThe trough concentration in CSF was under the limit of quantification while serum concentration was appropriate. A short review of the literature seems to confirm that meningeal diffusion is weaker than linezolid.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: It is therefore important to be cautious when prescribing tedizolid in neuro-meningeal infections, especially if targeted pathogens have high MICs.\u003c/p\u003e","manuscriptTitle":"Insufficient diffusion of tedizolid in cerebrospinal fluid: about a case report and mini-review of literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-31 20:37:34","doi":"10.21203/rs.3.rs-4378400/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":"1534bbd9-a720-4265-89a6-9db32d6c50d7","owner":[],"postedDate":"May 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-31T14:51:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-31 20:37:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4378400","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4378400","identity":"rs-4378400","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}