Tigecycline Interferes with Fibrinogen Polymerization Independent of Peripheral Interactions with the Coagulation System.

Anna Brandtner,Dietmar Fries,Andrea Griesmacher,Martin Hermann,Tobias Hell,Mirjam Bachler,Vilmos Fux,Jacqueline Ruehlicke,Benedikt Treml,Christian Niederwanger

doi:10.3390/antibiotics9020084

Abstract

Tigecycline offers broad anti-bacterial coverage for critically ill patients with complicated infections. A described but less researched side effect is coagulopathy. The aim of this study was to test whether tigecycline interferes with fibrinogen polymerization by peripheral interactions. To study the effect of unmetabolized tigecycline, plasma of healthy volunteers were spiked with increasing concentrations of tigecycline. In a second experimental leg, immortalized human liver cells (HepG2) were treated with the same concentrations to test an inhibitory effect of hepatic tigecycline metabolites. Using standard coagulation tests, only the activated thromboplastin time in humane plasma was prolonged with increasing concentrations of tigecycline. Visualization of the fibrin network using confocal live microscopy demonstrated a qualitative difference in tigecycline treated experiments. Thrombelastometry and standard coagulation tests did not indicate an impairment of coagulation. Although the discrepancy between functional and immunologic fibrinogen levels increased in cell culture assays with tigecycline concentration, fibrinogen levels in spiked plasma samples did not show significant differences determined by functional versus immunologic methods. In our in vitro study, we excluded a direct effect of tigecycline in increasing concentrations on blood coagulation in healthy adults. Furthermore, we demonstrated a rapid loss of mitochondrial activity in hepatic cells with supra-therapeutic tigecycline dosages.

Highlights

Of the expanded broad spectrum glycylcyclines, the substance tigecycline, approved by the Food and Drug Administration (FDA) in 2005 and by the European Medical AssociationAntibiotics 2020, 9, 84; doi:10.3390/antibiotics9020084 www.mdpi.com/journal/antibiotics (EMA) in 2006, respectively, is indicated for complicated skin, soft tissue infections and abdominal infections in adults and infants older than eight years [1,2]
ANOVA, alpha levels were higher than 0.05 in both comparisons. In this in vitro-experiment we sought to elucidate the cause of an erratic fibrinogen decrease in criticalIn ill this patients during tigecycline
We observed small of changes in fibrinogen undin in vitro-experiment we treatment

Summary

Introduction

Of the expanded broad spectrum glycylcyclines, the substance tigecycline (tygacil), approved by the Food and Drug Administration (FDA) in 2005 and by the European Medical AssociationAntibiotics 2020, 9, 84; doi:10.3390/antibiotics9020084 www.mdpi.com/journal/antibiotics (EMA) in 2006, respectively, is indicated for complicated skin, soft tissue infections and abdominal infections in adults and infants older than eight years [1,2]. Another study showed a decrease of fibrinogen in 19 out of 20 patients with severe infections treated with glycylcycline This occurred either with the recommended dose (loading dose of 100 mg, followed by 50 mg twice per day intravenous (iv.)) and during high dose Eight case reports exist in regard to an effect of tigecycline on coagulation [7,8,9,10,11,12,13,14] In reflection to these observations, the manufacturer recommends discontinuing tigecycline, if fibrinogen levels decrease below 100 mg/dL. It is one of few available antibiotics active against key multi-drug resistant pathogens and its use as second line antibiotic is limited to patients with no alternative suitable treatment options [15]

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