{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:37:44Z","timestamp":1791401864920,"version":"4.3.3"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Therapeutic drug monitoring (TDM) of \u03b2-lactams (BL), BL\/\u03b2-lactamase inhibitor (BLI) combinations (BL\/BLIc), and of fosfomycin may play a key role in optimizing antimicrobial therapy and in preventing resistance development, especially when used by continuous infusion in critically ill or immunocompromised patients. Unfortunately, analytical methods for simultaneously quantifying multiple BL\/BLIc in plasma are still lacking. Methods: The aim of this study was to develop and validate two rapid, sensitive, and accurate UPLC\u2013qTOF\u2013MS\/MS methods for the simultaneous quantification of five novel \u03b2-lactam or \u03b2-lactam\/\u03b2-lactamase inhibitor combinations (ceftolozane\/tazobactam, ceftazidime\/avibactam, meropenem\/vaborbactam, cefiderocol, and ceftobiprole) along with fosfomycin. Methods: Human plasma samples were prepared by protein precipitation using methanol containing isotopically labeled internal standards. Chromatographic separation was achieved within 10\u201312 min using two Agilent Poroshell columns (EC-C18 and PFP) under positive and negative electrospray ionization modes. The method was validated according to the EMA guidelines by assessing selectivity, linearity, precision, accuracy, matrix effects, extraction recovery, and stability. Results: The methods exhibited excellent linearity (R2 \u2265 0.998) across the calibration ranges for all of the analytes (1.56\u2013500 \u00b5g\/mL), with limits of quantification ranging from 1.56 to 15.62 \u00b5g\/mL. Intra- and inter-day precision and accuracy were always within \u00b115%. Extraction recovery always exceeded 92%, and the matrix effects were effectively corrected through isotopic internal standards. No carry-over or isobaric interferences were observed. All the analytes were stable for up to five days at 4 \u00b0C, but the BL and BL\/BLIc stability was affected by multiple freeze\u2013thaw cycles. Conclusions: These UPLC-qTOF-MS\/MS multi-analyte methods enabled a simultaneous, reliable quantification in plasma of five novel beta-lactams and of fosfomycin. Robustness, high throughput, and sensitivity make these multi-methods feasible for real-time TDM, supporting personalized antimicrobial dosing and improved therapeutic outcomes in patients with severe or multidrug-resistant infections.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010091","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:25:23Z","timestamp":1768213523000},"page":"91","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Two Comprehensive Liquid Chromatography High-Resolution Mass Spectrometry (UPLC-MS\/MS) Multi-Methods for Real-Time Therapeutic Drug Monitoring (TDM) of Five Novel Beta-Lactams and of Fosfomycin Administered by Continuous Infusion"],"prefix":"10.3390","volume":"18","author":[{"given":"Ilaria","family":"Trozzi","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Giorgi","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Specialisation School of Clinical Pharmacology and Toxicology, Alma Mater Studiorum Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6856-8936","authenticated-orcid":false,"given":"Riccardo","family":"De Paola","sequence":"additional","affiliation":[{"name":"Specialisation School of Clinical Pharmacology and Toxicology, Alma Mater Studiorum Universit\u00e0 di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3018-3779","authenticated-orcid":false,"given":"Milo","family":"Gatti","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6966-7167","authenticated-orcid":false,"given":"Federico","family":"Pea","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1007\/s00134-020-06151-x","article-title":"Incidence and Mortality of Hospital- and ICU-Treated Sepsis: Results from an Updated and Expanded Systematic Review and Meta-Analysis","volume":"46","author":"Mellhammar","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tamma, P.D., Heil, E.L., Justo, J.A., Mathers, A.J., Satlin, M.J., and Bonomo, R.A. 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