PHARMACOLOGY AND PHARMACODYNAMICS OF ANTIFUNGAL AGENTS (J AMSDEN,, SECTION EDITOR) Antifungal Penetration and Distribution into Organs and Tissue Kayla R. Stover 1 & John D. Cleary 2 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review Properties of penetration of antifungals into the body compartments have been reviewed extensively by Felton et al. in 2014, so the goal of this review was to identify new data, including information on ibrexafungerp and rezafungin, in order to provide an updated pharmacotherapy approach in difficult-to-treat infections. Recent Findings Along with early identification and early initiation of treatment, assuring sufficient distribution into the infected site is essential for successful therapy. Although there are a limited number, the penetration and distribution of antifungals into organs and tissue are widely variable between agents and classes, and can be affected by factors such as weight, genetics, comorbidities, and inflammation. Summary Clinicians should be aware of the challenges of tissue and organ penetration. Using existing human and animal data can help assure that penetration will be sufficient with the chosen antifungal prior to initiating therapy. Keywords Concentrations . Ibrexafungerp . Rezafungin . Azoles . Echinocandins . Polyenes Introduction One of the most challenging areas in infectious diseases is the treatment of pathogens in exclusive sites of infection (i.e., prostate or brain), in compartments formed by inflammation (i.e., abscess), or with unusual pharmacokinetics secondary to polymorphisms. The complexity of pharmacotherapy in- creases significantly when one is treating a eukaryotic patho- gen that is found inside a eukaryotic host. These variables have historically led to high attributable morbidity and mor- tality. Mycotic infections in exclusive sites exemplify two critical elements of patient care: early identification and early initiation of treatment. Hallmarks of good drug distribution traditionally have been small molecular weight, low protein binding, and ionized structures with a pH close to 7.4 [1]. Unfortunately, many antifungals do not have these attributes. Molar gradi- ents resulting from high plasma concentrations also often lead to high tissue concentrations. Three interesting caveats, how- ever, impact penetration for these lower molecular weight antifungals. The first can be seen with gender/race or cyto- chrome activity. Patients expressing cytochromic liver en- zymes (i.e., CYP3A4) would increase metabolism of the an- tifungal. This is demonstrative in cases where males treated with posaconazole (99% received oral suspection) had lower plasma concentrations than females [2] and Asians had lower plasma concentrations versus Caucasians [3, 4]. Interestingly, increases in C-reactive protein downregulate CYP2C19 and has been associated with decreased clearance of antifungals using this metabolic pathway (i.e., voriconazole) [5, 6]. A second significant impactor has been weight, with obesity leading to lower volumes of distribution for many of the antifungals (i.e., voriconazole, caspofungin) [7, 8]. Finally, hypoalbuminemia (albumin < 35 g/L) has been correlated with increased free antifungal concentrations, especially with elevations in serum bilirubin [1]. Many of these topics have been reviewed extensively by Felton et al. in 2014 [9••]. Our goal was to identify new data, in human patients when pos- sible, in order to provide an updated pharmacotherapy ap- proach in these difficult-to-treat patients. This article is part of the Topical Collection on Pharmacology and Pharmacodynamics of Antifungal Agents * Kayla R. Stover kstover@umc.edu 1 Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 North State Street, Jackson, MS 39216, USA 2 Department of Pharmacy, St. Dominic-Jackson Memorial Hospital, Jackson, MS, USA Current Fungal Infection Reports https://doi.org/10.1007/s12281-020-00390-7