Tigecycline Dosing Strategies in Critically Ill Liver-Impaired Patients

This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development of a population pharmacokinetic model. The typical tigecycline clearance was strongly reduced (8.6 L/h) as compared to other populations. Different models were developed based on liver and kidney function-related covariates. Monte Carlo simulations were used to guide dose adjustments with the most predictive covariates: Child–Pugh score, total bilirubin, and MELD score. The best performing covariate, guiding a dose reduction to 25 mg q12h, was Child–Pugh score C, whereas patients with Child–Pugh score A/B received the standard dose of 50 mg q12h. Of note, the obtained 24 h steady-state area under the concentration vs. time curve (AUCss) range using this dosing strategy was predicted to be equivalent to high-dose tigecycline exposure (100 mg q12h) in non-ICU patients. In addition, 26/39 study participants died, and therapy failure was most correlated with chronic liver disease and renal failure, but no correlation between drug exposure and survival was observed. However, tigecycline in special patient populations needs further investigations to enhance clinical outcome

Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study

<div><p>Aim</p><p>To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients.</p><p>Methods</p><p>28 septic patients (8 female, 20 male, age range 35–80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test.</p><p>Results</p><p>Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001).</p><p>Conclusions</p><p>Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.</p></div

Clinical characteristics.

<p>Clinical characteristics.</p

Relationship between liver function and cytokines in septic patients using Spearman’s rank correlation coefficient.

<p><b>(A)</b> LiMAx vs. CT-proET-1, <b>(B)</b> LiMAx vs. TNF-a, <b>(C)</b> LiMAx vs. IL-6.</p

Progression of CT-proET-1 and cytokines by severity of liver dysfunction in sepsis.

<p><b>(A)</b> CT-proET-1, <b>(B)</b> TNF-α, <b>(C)</b> IL-6. White box: group A; LiMAx ≥100μg/kg/h; Shaded box: group B; LiMAx <100μg/kg/h. Bold lines, medians; box plots, 25th to 75th percentiles. Horizontal broken lines indicate the normal range. Outliers are illustrated as circles.</p

Clinical characteristics and severity of illness in the study groups.

<p>Clinical characteristics and severity of illness in the study groups.</p