Integration of individual preclinical and clinical anti-infective PKPD data to predict clinical study outcomes.
| Autor: | Aranzana-Climent V; Department of Pharmacy, Uppsala University, Uppsala, Sweden.; Université de Poitiers, PHAR2, Inserm U1070, Poitiers, France., van Os W; Department of Pharmacy, Uppsala University, Uppsala, Sweden.; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria., Nutman A; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel., Lellouche J; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.; The Adelson School of Medicine, Ariel University, Ariel, Israel., Dishon-Benattar Y; Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel.; The Cheryl Spencer Department of Nursing, University of Haifa, Haifa, Israel., Rakovitsky N; Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel., Daikos GL; First Department of Medicine, Laikon General Hospital, Athens, Greece.; National and Kapodistrian University of Athens, Athens, Greece., Skiada A; First Department of Medicine, Laikon General Hospital, Athens, Greece.; National and Kapodistrian University of Athens, Athens, Greece., Pavleas I; First Department of Medicine, Laikon General Hospital, Athens, Greece.; National and Kapodistrian University of Athens, Athens, Greece., Durante-Mangoni E; Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.; AORN Ospedali dei Colli-Monaldi Hospital, Naples, Italy., Theuretzbacher U; Center for Anti-Infective Agents, Vienna, Austria., Paul M; Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel.; The Ruth and Bruce Rappaport Faculty of Medicine, Techion - Israel Institute of Technology, Haifa, Israel., Carmeli Y; National Institute for Antibiotic Resistance and Infection Control, Israel Ministry of Health, Tel Aviv, Israel.; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel., Friberg LE; Department of Pharmacy, Uppsala University, Uppsala, Sweden. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical and translational science [Clin Transl Sci] 2024 Jul; Vol. 17 (7), pp. e13870. |
| DOI: | 10.1111/cts.13870 |
| Abstrakt: | The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.) |
| Databáze: | MEDLINE |
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