Marta Ulldemolins1, Carla Bastida2, Ignacio Martín-Loeches3,4, Dolors Soy2,3,5, Mireia Llauradó-Serra6, Chantal Csajka7,8, Alejandro Rodríguez9,3, Joan Ramon Badia3,10,5. 1. Infectious Diseases - Internal Medicine Departments, Bellvitge University Hospital, University of Barcelona, L'Hopspitalet de Llobregat, Spain. marta.ulldemolins@gmail.com. 2. Pharmacy Department, Division of Medicines, Hospital Clinic de Barcelona, Barcelona, Spain. 3. Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain. 4. Multidisciplinary Intensive Care Research Organization (MICRO), Critical Care Department, St James University Hospital, Trinity Centre for Health Sciences, Dublin, Ireland. 5. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - Fundació Clínic per la Recerca Biomèdica, Barcelona, Spain. 6. Department of Nursing, School of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain. 7. Service of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 8. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. 9. Critical Care Department, Joan XXIII University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira I Virgili, Tarragona, Spain. 10. Respiratory Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
Abstract
PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.
PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.
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