Vincent Jullien1, Elie Azoulay2, Carole Schwebel3, Thomas Le Saux4, Pierre Emmanuel Charles5, Muriel Cornet6, Bertrand Souweine7, Kadda Klouche8, Samir Jaber9, Jean-Louis Trouillet10, Fabrice Bruneel11, Martin Cour12, Joel Cousson13, Ferhat Meziani14, Didier Gruson15, Adeline Paris16, Michael Darmon17, Maité Garrouste-Orgeas18, Jean-Christophe Navellou19, Arnaud Foucrier20, Bernard Allaouchiche21, Vincent Das22, Jean-Pierre Gangneux23, Stéphane Ruckly24, Michel Wolff25,26, Jean-François Timsit25,26. 1. Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France vincent.jullien@aphp.fr. 2. Saint-Louis University Hospital, Medical ICU, Paris, France. 3. Medical ICU, Albert Michallon University Hospital, Grenoble, France. 4. Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France. 5. Medical ICU, François Mitterand University Hospital, Dijon, France. 6. UMR5525 CNRS-Grenoble Alpes University, Parasitology-Mycology, Grenoble Alpes University Hospital, Grenoble, France. 7. Medical ICU, Gabriel Montpied University Hospital, Clermont-Ferrand, France. 8. Medical ICU, Lapeyronie University Hospital, Montpellier, France. 9. Department of Critical Care Medicine and Anesthesiology (DAR B) Saint Eloi University, Hospital and Montpellier School of Medicine University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France. 10. Medical ICU, Institut de Cardiologie, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 11. Medical ICU, André Mignot Hospital, Versailles, France. 12. Medical ICU, Edouard Herriot University Hospital, Lyon, France. 13. Medical Surgical ICU, CHU Reims, Reims, France. 14. Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 15. Medical ICU, Bordeaux University Hospital, Bordeaux, France. 16. Clinical Research and Innovation Direction, Grenoble Alpes University Hospital, Grenoble F-38043, France. 17. Medical ICU, Saint-Etienne University Hospital, Saint-Priest en Jarez, France. 18. Medical-Surgical ICU, Saint-Joseph Hospital Network, Paris, France. 19. Surgical ICU, CHU Jean Minjoz, Besancon, France. 20. Surgical ICU, APHP, CHU Beaujon, Clichy, France. 21. Surgical ICU, Hospices Civils de Lyon, Hopital Sud, Lyon, France. 22. Polyvalent ICU, CH de Montreuil, Montreuil, France. 23. Mycology Laboratory, Rennes University Hospital, Rennes, France. 24. ICUREsearch, Department of Biostatistics, Paris, France. 25. UMR1137-IAME Inserm, Paris Diderot University, Paris, France. 26. Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
Abstract
OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. RESULTS: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. CONCLUSIONS: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.
OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. RESULTS:Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. CONCLUSIONS: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.
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