Systematic Evaluation of Voriconazole Pharmacokinetic Models without Pharmacogenetic Information for Bayesian Forecasting in Critically Ill Patients.

Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from -15.4 to 124.6%/-0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%; rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use.

Serum linezolid concentrations are reduced in critically ill patients with pulmonary infections: A prospective observational study.

RATIONALE: The concentration-time profile of linezolid varies considerably in critically ill patients. Question of interest is, if the site of infection influences linezolid serum concentrations. METHODS: 68 critically ill patients, treated with linezolid, were included. The concentration-time-profile for linezolid was determined using maximum a-posteriori predictions. A trough concentration (Cmin) between 2 and 10 mg/L was defined as the target. A generalized linear model (GLM) was established to evaluate potential covariates. RESULTS: The indications for linezolid therapy were in descending order: peritonitis (38.2%), pneumonia (25.0%), infectious acute respiratory distress syndrome (ARDS) (19.1%), and other non-pulmonary infection (17.7%). 27.2 and 7.9% of Cmin were subtherapeutic and toxic, respectively. In the GLM, ARDS (mean: -2.1 mg/L, CI: -3.0 to -1.2 mg/L) and pneumonia (mean: -2.2 mg/L, CI: -2.8 to -1.6 mg/L) were significant (p < 0.001) determinants of Cmin. Patients with ARDS (mean: 2.3 mg/L, 51.2% subtherapeutic, 0.0% toxic) and pneumonia (mean: 3.5 mg/L, 41.5% subtherapeutic, 7.7% toxic) had significantly (p < 0.001) lower Cmin than those with peritonitis (mean: 5.5 mg/L, 14.4% subtherapeutic, 9.3% toxic) and other non-pulmonary infection (mean: 5.2 mg/L, 3.3% subtherapeutic, 16.5% toxic). CONCLUSION: Linezolid serum concentrations are reduced in patients with pulmonary infections. Future studies should investigate if other linezolid thresholds are needed in those patients due to linezolid pooling in patients´ lung.

Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study.

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5-6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15-2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration-time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: Efficacy and plasma concentrations.

BACKGROUND: Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal-induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis. METHODS: Critically ill lung transplant recipients with postoperative posaconazole or itraconazole prophylaxis and therapeutic drug monitoring from February 2016 to November 2019 were retrospectively included in the study. Positive fungal cultures or Aspergillus antigen tests resulting in a transition from antifungal prophylaxis to therapy were analyzed from the first day of prophylaxis until 7 days after the last sample for each patient. Adequate plasma concentrations were defined as ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole. RESULTS: Two hundred seventy-five samples from 73 patients were included in the analysis. Overall, 60% of the posaconazole and 55% of the itraconazole concentrations were subtherapeutic. Administration of posaconazole suspension resulted significantly (P < .01) more often in subtherapeutic concentrations than tablets (68% vs 10%). Patients treated with posaconazole showed less positive fungal records resulting in a transition from prophylaxis to therapy than patients treated with itraconazole (10% vs 33%, P-value: .029). The detection of a fungal pathogen was not associated with the measured plasma concentrations or the achievement of the target concentrations. CONCLUSION: Our findings suggest that posaconazole should be used instead of itraconazole for systemic prophylaxis in critically ill lung transplant recipients.