March 04, 2022 The impact of advanced cirrhosis on the time course of antibiotic distribution across and elimination from the body, in silico study suggests New study by researchers at EF Clif and Hospital Clínic de Barcelona uncovers alterations of antibiotic pharmacokinetics in patients with decompensated cirrhosis and severe bacterial infections

BARCELONA—Bacterial infections can cause severe complications in the clinical course of cirrhosis and ensuring adequate antimicrobial treatment is crucial to prevent associated complications and improve survival of patients with advanced liver disease. As cirrhosis progresses, liver function gradually deteriorates. Liver dysfunction results in hypoalbuminemia and in changes in bile acid synthesis in hepatocytes which in turn may alter the pharmacokinetic properties of certain drugs. Published on 18 February 2022 in Journal of Antimicrobial Chemotherapy, this study provides evidence of variations in the distribution and excretion of tigecycline, a broad-spectrum antibiotic frequently used for the treatment of severe bacterial infections in critically ill patients with and without cirrhosis.

As a lipophilic drug, tigecycline is widely distributed into tissues and its elimination is mainly promoted by biliary excretion. Results from this prospective observational study conducted in 20 patients admitted to the Liver Intensive Care Unit at Hospital Clínic de Barcelona, Spain, suggest that dosage of tigecycline should be adjusted for treatment of patients with advanced cirrhosis that require critical care. The model for end-stage liver disease (MELD) score was used for dose optimization and model-fitted pharmacokinetic and pharmacodynamic profiles of the antibiotic computed. “This is the first study that characterizes tigecycline pharmacokinetics in critically ill patients with cirrhosis”, said first author of the paper Carla Bastida, Junior Specialist in the Pharmacy Department at Hospital Clínic de Barcelona and the University of Barcelona, Spain.

Deterioration of liver function appeared to have an impact on the pharmacokinetic/pharmacodynamic index of tigecycline, which may alter its concentration at the active site and could potentially compromise its efficacy. These findings put forward for consideration that tigecycline dose optimization in critically ill cirrhotic patients should rely on a continuous variable (i.e., MELD score) and not on a categorical variable such as the Child-Pugh score. “The effectiveness and safety of administering higher doses of tigecycline should be further addressed in the clinical setting”, said Javier Fernandez, Head of Clinical Operations at EF Clif and Head of the Liver Intensive Care Unit at Hospital Clínic de Barcelona, Spain.

“We performed a population pharmacokinetic/pharmacodynamic study in 20 patients with a rich sampling strategy which allowed us to develop a robust pharmacokinetic model. We identified the MELD score as the main covariate that significantly influences tigecycline clearance. By using population pharmacokinetic/pharmacodynamic analysis and further simulations, we were able to recommend several dose regimens. However, this is an in silico study and our results should be confirmed by further clinical trials to evaluate the clinical, microbiological, and safety response in new patients”, explained Dolors Soy, Head of the Pharmacy Department at Hospital Clínic de Barcelona and the University of Barcelona.

This study was supported by the Institute of Health Carlos III (ISCIII), PI16/00885.

Other authors on the study are María Hernández-Tejero, Marcial Cariqueo, Fátima Aziz, Virginia Fortuna, Miquel Sanz, and Mercè Brunet.

Publication information

Bastida, C.; Hernández-Tejero, M.; Cariqueo, M.; Aziz, F.; Fortuna, V.; Sanz, M.; Brunet, M.; Fernandez, J.; Soy, D. Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections. J. Antimicrob. Chemother. 2022. DOI: Journal of Antimicrobial Chemotherapy

The European Foundation for the Study of Chronic Liver Failure (EF Clif) is a private nonprofit organization which mission is to promote research and education in hepatic chronic failure with the aim to contribute to improving the quality of life and to increase the survival of patients with liver cirrhosis. Since its foundation in 2009, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-Clif Consortium, a network of more than 100 European university hospitals and more than 300 clinical researchers. The Grifols Chair promotes translational studies across centers throughout Europe and North America within the framework of the European Network for Translational Research (ENTR) with 25 centers and more than 40 investigators.