Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Breakthrough Candida guilliermondii (Meyerozyma guilliermondii) fungemia after cord blood transplantation for extranodal NK-cell lymphoma with azole prophylaxis.

Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non-albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long-term azole administration.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

Proyecto Épico: Formulación de unas recomendaciones educativas con metodología DELPHI para pacientes adultos críticos no neutropénicos y con candidiasis invasiva / Épico project. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non-neutropenic critically ill adult patients

Antecedentes. Aunque en la última década ha mejorado el manejo de la candidiasis invasiva, todavía persisten aspectos controvertidos, en especial por lo que respecta a la estrategia diagnóstica y terapéutica. Objetivos. Identificar los conocimientos clínicos esenciales y formular unas recomendaciones con la obtención de un alto grado de consenso, necesarias en la asistencia de pacientes adultos no neutropénicos en estado crítico con candidiasis invasiva. Métodos. Se preparó una encuesta prospectiva cuyo texto se redactó en español, y se obtuvo un consenso mediante técnica DELPHI (un método de reestructuración de un proceso de comunicación con el que se obtiene un grado de consenso de los especialistas sobre el problema planteado). En primer término, se envió de forma anónima por correo electrónico a 25 especialistas nacionales de diferentes disciplinas médicas, expertos en infecciones fúngicas invasivas, de 5 sociedades científicas nacionales, incluidos intensivistas, anestesistas, microbiólogos, farmacólogos e infectólogos, que respondieron a 47 preguntas preparadas por el grupo de coordinación, tras una revisión exhaustiva de los estudios publicados durante los 5 últimos años. Los objetivos educativos contemplaron 5 categorías: epidemiología, instrumentos diagnósticos, scores, estrategias terapéuticas y de desescalada. Para ser seleccionado, el grado de acuerdo alcanzado entre los expertos del panel en cada uno de los ítems debía superar el 75%. En segundo término, después de extraer las recomendaciones de los ítems seleccionados, se celebró una reunión presencial donde se invitó a participar en una segunda ronda a más de 80 especialistas y se les solicitó la validación de las recomendaciones preseleccionadas. ...(AU)

Background. Although there has been an improved management of invasive candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches. Aims. We sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with invasive candidiasis. Methods. A prospective Spanish survey reaching consensus by the DELPHI technique was made. It was anonymously conducted by electronic mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious diseases specialists, who answered to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations. ...(AU)