Antifungal drugs: An updated review of central nervous system pharmacokinetics.

Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

Antifungal pharmacodynamics: Latin America's perspective

Abstract The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

Antifungal pharmacodynamics: Latin America's perspective.

The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex.

Candida parapsilosis complex comprises three closely related species, C. parapsilosis sensu stricto, Candida metapsilosis and Candida orthopsilosis. In the last decade, antifungal resistance to azoles and caspofungin among C. parapsilosis sensu lato strains has been considered a matter of concern worldwide. In the present study, we evaluated the synergistic potential of antifungals and the calcineurin inhibitor cyclosporin A (Cys) against planktonic and biofilms of C. parapsilosis complex from clinical sources. Susceptibility assays with amphotericin, fluconazole, voriconazole, caspofungin and Cys were performed by microdilution in accordance with Clinical and Laboratory Standards Institute guidelines. Synergy testing against planktonic cells of C. parapsilosis sensu lato strains was assessed by the chequerboard method. Combinations formed by antifungals with Cys were evaluated against mature biofilms in microtitre plates. No differences in the antifungal susceptibility pattern among species were observed, but C. parapsilosis sensu stricto strains were more susceptible to Cys than C. orthopsilosis and C. metapsilosis. Synergism between antifungals and Cys was observed in C. parapsilosis sensu lato strains. Combinations formed by antifungals and Cys were able to prevent biofilm formation and showed an inhibitory effect against mature biofilms of C. parapsilosis sensu stricto, C. metapsilosis and C. orthopsilosis. These results strengthen the potential of calcineurin inhibition as a promising approach to enhance the efficiency of antifungal drugs.

Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age.

Candida infections represent a major threat in neonatal intensive care units. This is the first prospective study to obtain caspofungin plasma levels and safety data for neonates and very young infants. Patients of <3 months of age receiving intravenous amphotericin B for documented or highly suspected candidiasis were enrolled in a single-dose (n = 6) or subsequent multiple-dose (n = 12) panel; all received caspofungin at 25 mg/m(2) once daily as a 1-hour infusion. Caspofungin plasma levels were measured by high-performance liquid chromatography and compared to historical data from adults. Patient chronological ages ranged from 1 to 11 weeks, and weights ranged from 0.68 to 3.8 kg. Gestational ages ranged from 24 to 41 weeks. Geometric mean (GM) peak (C(1 h)) and trough (C(24 h)) caspofungin levels were 8.2 and 1.8 microg/ml, respectively, on day 1, and 11.1 and 2.4 microg/ml, respectively, on day 4. GM ratios for C(1 h) and C(24 h) for neonates/infants relative to adults receiving caspofungin at 50 mg/day were 1.07 and 1.36, respectively, on day 1, and 1.18 and 1.21, respectively, on day 4. Clinical and laboratory adverse events occurred in 17 (94%) and 8 (44%) patients, respectively. Five patients (28%) had serious adverse events, none of which were considered drug related. Caspofungin at 25 mg/m(2) once daily was well tolerated in this group of neonates/infants of <3 months of age and appears to provide relatively similar plasma exposure to that obtained in adults receiving 50 mg/day. However, the small number of patients studied precludes any definitive recommendations about caspofungin dosing for this group comprising a broad range of ages and weights.