{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T22:13:28Z","timestamp":1773612808954,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Infectious Disease Reports"],"abstract":"<jats:p>Background: Vancomycin-resistant Enterococcus faecium (VRE) in particular has evolved as an important cause of hospital acquired infection, especially in immunocompromised hosts. Methods: We present a complex case of a patient with relapsed acute myeloid leukemia who underwent allogenic hematopoietic stem cell transplantation complicated by persistent VRE bacteremia and meningitis. To optimize therapy, various blood and cerebrospinal fluid (CSF) samples were sent to a research laboratory for extensive susceptibility testing, pharmacokinetic analyses, and time-kill experiments. Results: In vitro testing revealed resistance to all first-line treatment options and CSF sampling demonstrated sub-optimal central nervous system concentrations achieved by each antimicrobial agent administered in relation to their respective MIC value. Time-kill analyses at observed CSF concentrations confirmed the lack of bactericidal activity despite use of a four-drug combination regimen. Conclusions: This work is the first to report CSF concentrations of oritavancin and tedizolid in humans and adds to the limited data regarding in vitro susceptibility of new antimicrobial agents such as eravacycline, omadacycline, and lefamulin against VRE. Our study provides new insights into various aspects of treatment of extensively drug-resistant Enterococcus faecium meningitis and bacteremia and supports the continued pursuit of precision medicine for these challenging cases.<\/jats:p>","DOI":"10.3390\/idr13030076","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T21:28:45Z","timestamp":1631136525000},"page":"843-854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3914-8400","authenticated-orcid":false,"given":"Eric","family":"Wenzler","sequence":"first","affiliation":[{"name":"College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alina","family":"Adeel","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Division of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Jurkovic","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Walder","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Department of Internal Medicine, UMass Medical School, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Ramasra","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Division of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen","family":"Campion","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Department of Pharmacy, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Cerny","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Division of Hematology-Oncology, UMass Medical School, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-8232","authenticated-orcid":false,"given":"Nicole M.","family":"Theodoropoulos","sequence":"additional","affiliation":[{"name":"UMass Memorial Medical Center, Division of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2020, February 20). Antibiotic Resistance Threats in the United States. Available online: https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/2019-ar-threats-report-508.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1080\/14656566.2018.1479397","article-title":"Combatting resistant enterococcal infections: A pharmacotherapy review","volume":"19","author":"Mercuro","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1002\/phar.1922","article-title":"Role of Combination Antimicrobial Therapy for Vancomycin-Resistant Enterococcus faecium Infections: Review of the Current Evidence","volume":"37","author":"Yim","year":"2017","journal-title":"Pharmacotherapy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ofz545","DOI":"10.1093\/ofid\/ofz545","article-title":"In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant Enterococcus faecium and Carbapenem-Resistant Enterobacter cloacae Bacteremia in a Liver Transplant Patient","volume":"7","author":"Wenzler","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1177\/1060028020932513","article-title":"Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin","volume":"54","author":"Lee","year":"2020","journal-title":"Ann. Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijid.2014.01.009","article-title":"Central nervous system infections due to vancomycin-resistant enterococci: Case series and review of the literature","volume":"25","author":"Wang","year":"2014","journal-title":"Int. J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1093\/cid\/ciz1155","article-title":"Monitoring Ceftazidime-Avibactam and Aztreonam Concentrations in the Treatment of a Bloodstream Infection Caused by a Multidrug-Resistant Enterobacter sp. Carrying Both Klebsiella pneumoniae Carbapenemase\u20134 and New Delhi Metallo-\u03b2-Lactamase\u20131","volume":"71","author":"Yasmin","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"02264-19","DOI":"10.1128\/AAC.02264-19","article-title":"Precision Medicine and Mysteries in Clinical Microbiology: Rationalizing Epidemiology, Genotype, and Phenotype To Guide Therapeutics","volume":"64","author":"Perez","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sakoulas, G. (2020). Imipenem\/Cilistatin and Fosfomycin for Refractory Methicillin-Resistant Staphylococcus aureus Infection: A Novel Combination Therapy. Antimicrob. Agents Chemother., 65.","DOI":"10.1128\/AAC.02039-20"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"01746-20","DOI":"10.1128\/AAC.01746-20","article-title":"Imipenem plus Fosfomycin as Salvage Therapy for Vertebral Osteomyelitis","volume":"65","author":"Nakamura","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","unstructured":"Clinical and Laboratory Standards Institute (2020). Performance Standards for Antimicrobial Susceptibility Testing: Thirtieth Informational Supplement M100-S30, CLSI."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1128\/CMR.00007-10","article-title":"Penetration of Drugs through the Blood-Cerebrospinal Fluid\/Blood-Brain Barrier for Treatment of Central Nervous System Infections","volume":"23","author":"Nau","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e02001-17","DOI":"10.1128\/JCM.02001-17","article-title":"Evaluation of Non-Tissue Culture- versus Tissue Culture-Treated Microplates for Oritavancin Susceptibility Testing","volume":"56","author":"Yan","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"ref_14","unstructured":"CLSI (2018). Performance Standards for Antimicrobial Susceptibility Testing: Approved Twenty-Eighth Edition: Document M100-S28, CLSI."},{"key":"ref_15","unstructured":"SIVEXTRO (Tedizolid), and Lexington, M.A. (2020, November 09). Cubist Pharmaceuticals U.S. Revised June 2014. Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/205435s000lbl.pdf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104420","DOI":"10.1016\/j.yrtph.2019.104420","article-title":"Comparative pharmacokinetics of tedizolid in rat plasma and cerebrospinal fluid","volume":"107","author":"Gu","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.1128\/AAC.00051-06","article-title":"Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients","volume":"50","author":"Myrianthefs","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1128\/AAC.00515-06","article-title":"Pharmacokinetics of Intravenous Linezolid in Cerebrospinal Fluid and Plasma in Neurointensive Care Patients with Staphylococcal Ventriculitis Associated with External Ventricular Drains","volume":"51","author":"Beer","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"721","DOI":"10.3109\/00365548.2011.582140","article-title":"Linezolid in the central nervous system: Comparison between cerebrospinal fluid and plasma pharmacokinetics","volume":"43","author":"Viaggi","year":"2011","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ijantimicag.2014.07.001","article-title":"Plasma and cerebrospinal fluid concentrations of linezolid in neurosurgical critically ill patients with proven or suspected central nervous system infections","volume":"44","author":"Luque","year":"2014","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/jac\/dkl403","article-title":"Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose","volume":"58","author":"Rodvold","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1345\/aph.1M480","article-title":"Cerebral Spinal Fluid Penetration of Tigecycline in a Patient with Acinetobacter baumannii Cerebritis","volume":"44","author":"Ray","year":"2010","journal-title":"Ann. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/jac\/43.1.87","article-title":"Quinupristin\/dalfopristin attenuates the inflammatory response and reduces the concentration of neuron-specific enolase in the cerebrospinal fluid of rabbits with experimental Streptococcus pneumoniae meningitis","volume":"43","author":"Trostdorf","year":"1999","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2165\/00003088-200443040-00003","article-title":"Clinical Pharmacokinetics of Quinupristin\/Dalfopristin","volume":"43","author":"Bearden","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1128\/AAC.46.1.188-190.2002","article-title":"Gentamicin Increases the Efficacy of Vancomycin against Penicillin-Resistant Pneumococci in the Rabbit Meningitis Model","volume":"46","author":"Cottagnoud","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1128\/AAC.45.7.2169-2172.2001","article-title":"Activity of LY333328 in Experimental Meningitis Caused by a Streptococcus pneumoniae Strain Susceptible to Penicillin","volume":"45","author":"Gerber","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/jac\/39.suppl_1.129","article-title":"The pharmacokinetics of quinupristin\/dalfopristin in laboratory animals and in humans","volume":"39","author":"Bergeron","year":"1997","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1017\/ice.2015.228","article-title":"VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis","volume":"37","author":"Prematunge","year":"2016","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1017\/ice.2016.254","article-title":"Incidence and Outcomes Associated With Infections Caused by Vancomycin-Resistant Enterococci in the United States: Systematic Literature Review and Meta-Analysis","volume":"38","author":"Chiang","year":"2016","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1016\/j.ijantimicag.2010.11.011","article-title":"Pharmacokinetic\/pharmacodynamic (PK\/PD) considerations in the management of Gram-positive bacteraemia","volume":"36","author":"Scaglione","year":"2010","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1093\/cid\/ciw861","article-title":"2017 Infectious Diseases Society of America\u2019s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis","volume":"64","author":"Tunkel","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1086\/425368","article-title":"Practice Guidelines for the Management of Bacterial Meningitis","volume":"39","author":"Tunkel","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1586\/14787210.6.1.83","article-title":"Pharmacologic options for CNS infections caused by resistant Gram-positive organisms","volume":"6","author":"Peppard","year":"2008","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_34","unstructured":"EUCAST (2021, August 07). Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 10.0., Available online: http:\/\/www.eucast.org\/fileadmin\/src\/media\/PDFs\/EUCAST_files\/Breakpoint_tables\/v_10.0_Breakpoint_Tables.pdf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"106215","DOI":"10.1016\/j.ijantimicag.2020.106215","article-title":"In vitro activity of eravacycline and mechanisms of resistance in enterococci","volume":"56","author":"Boukthir","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1177\/1060028019850173","article-title":"Eravacycline: The Tetracyclines Strike Back","volume":"53","author":"Heaney","year":"2019","journal-title":"Ann. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1093\/cid\/ciz395","article-title":"Microbiology and Preclinical Review of Omadacycline","volume":"69","author":"Karlowsky","year":"2019","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1002\/phar.2166","article-title":"Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic","volume":"38","author":"Veve","year":"2018","journal-title":"Pharmacotherapy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00275-18","DOI":"10.1128\/AAC.00275-18","article-title":"Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits","volume":"62","author":"Petraitis","year":"2018","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Infectious Disease Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2036-7449\/13\/3\/76\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:59:05Z","timestamp":1760165945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2036-7449\/13\/3\/76"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["idr13030076"],"URL":"https:\/\/doi.org\/10.3390\/idr13030076","relation":{},"ISSN":["2036-7449"],"issn-type":[{"value":"2036-7449","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]}}}