Target-Site Pharmacokinetics and -Activity of Echinocandins

Background: The echinocandins caspofungin, anidulafungin and micafungin are recommended for treatment of invasive candidiasis. Whereas echinocandins are highly active against candidaemia, their efficacy against deep seated or disseminated Candida infections is less clear. Data on echinocandin target-site pharmacokinetics is sparse and suggest sufficient penetration into liver and spleen whereas concentrations in central nervous system (CNS) and cerebrospinal fluid (CSF) are low. Although echinocandins are relatively safe, micafungin caused foci of altered hepatocytes (FAH) in rats. Hypotheses: Echinocandin treatment with standard doses results in efficacious echinocandin exposure in several human body fluids and tissues, but in sub-inhibitory exposure at some other sites. Antifungal activity of echinocandins is influenced by the ambiance (e. g. human body fluids). FAH occur after therapeutic echinocandin doses. Objectives: Quantification of echinocandins in various human body fluids and tissues after standard doses. Assessment of echinocandin pharmacokinetics and antifungal efficacy in body fluids. Detection of FAH. Patients: Critically ill patients on echinocandin treatment with indication for paracentesis (or peritoneal drainage), thoracentesis (or pleural drainage), lumbar puncture (or external ventriculostomy), bile deviation (via drainage or T-tube) or sampling by endoscopy or for vacuum assisted closure of wounds (VAC) will be enrolled. When sampling is performed via drainage echinocandin kinetics will be determined in the respective body fluid. Blood samples will be taken simultaneously for assessment of plasma pharmacokinetics. A total of up to 126 patients providing up to 882 body fluid samples and the same number of blood samples will be included. In addition, tissue samples will be taken during routine autopsies from 30 patients who have died during or up to 30 days after treatment with caspofungin, anidulafungin or micafungin. Methods: Echinocandin concentrations in ascites, pleural effusion, bile, wound secretion, CSF and in plasma will be measured by high-pressure-liquid-chromatography (HPLC). For quantification in tissue, samples of brain, lung, kidney, liver, pancreas, thyroid, spleen, myocardium and skeletal muscle will be taken during autopsies. The echinocandins will also be quantified by HPLC. In addition, liver slices will be stained and screened for FAH. For assessment of eventual effects of the various body fluids on echinocandin pharmacodynamics, growth of relevant Candida (C.) species (C. albicans, C. tropicalis, C. krusei, C. glabrata) will be analysed ex-vivo in the body fluid samples drawn from study patients. In addition, in-vitro simulation will be performed with echinocandin- spiked fluids. Implications: The results will allow for more individualized and effective treatment of invasive fungal infections, particularly when they are located at sanctuary sites.

Our investigations revealed inhomogeneous target-site distribution of echinocandin antifungals with relatively high penetration into some clinically relevant tissues e.g., liver, spleen, and lung, but low concentrations in myocardium, muscle, and in central nervous system. This might encourage clinicians to consider treatment of deep-seated candidiasis, in particular hepato-splenic candidiasis, with echinocandins and might prompt clinical outcome studies on the potential role of echinocandins in deep-seated candidiasis. We also have demonstrated limited penetration of echinocandins into various body fluids. In addition, their antifungal activity in ascites fluid and in pleural effusion appears to be much lower than in culture medium. Therefore, treatment of Candida peritonitis or pleural empyema with echinocandins does not appear to be promising. Because of low target-site penetration, this is probably also true for wound and for cholangitis caused by Candida although pharmacodynamic investigations have not yet been performed in wound secretion and in bile. In the absence of clinical outcome data, these observations might guide the choice of antifungals for treatment of deep-seated candidiasis in clinical practice.