Pharmacokinetics of echinocandins in suspected candida peritonitis: A potential risk for resistance.

INTRODUCTION: A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid. MATERIALS/METHODS: Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay. RESULTS: Twenty-three critically ill patients with suspected abdominal fungal infection who were receiving an echinocandin were prospectively recruited. No specific criteria were applied to prescribe one specific echinocandin. No special clinical differences were observed among the three groups of patients. All were receiving antibiotic therapy, 80% required inotropic drugs, and fungal peritonitis was confirmed in 74% of them. The AUC0_24h (mg × h/L) obtained in serum and peritoneal fluid were: 126.84 and 34.38, 98.52 and 18.83, and 66.9 and 8.78 for anidulafungin, micafungin and caspofungin, respectively. The median concentration in peritoneal fluid ranged from 0.66 to 1.82 µg/mL for anidulafungin, 0.68-0.88 µg/mL for micafungin and 0.21-0.46 µg/mL for caspofungin. CONCLUSION: The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.

Pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is widespread. To evaluate pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients by comparing the differences in pharmacokinetic parameters between critically ill patients and healthy volunteers or general patients. METHODS: MEDLINE, EMBASE, The Cochrane Library and Pubmed were searched from inception until 6 September 2018. Studies investigating the pharmacokinetic parameters of echinocandins in critically ill patients, healthy volunteers or general patients were included. Our primary outcomes included AUC0-24 h , Cmax and Cmin (24 hours). Two reviewers independently reviewed all titles, abstracts and text, and extracted data. We applied R software (R 2017) to conduct meta-analysis. RESULTS AND DISCUSSION: Of 3235 articles screened, 17 studies were included in the data synthesis. Descriptive data from single-arm studies show that critically ill patients who received caspofungin had more stable AUC0-24 h than those who received anidulafungin and micafungin. The Cmax of critically ill patients who received caspofungin and micafungin was similar to healthy volunteers. However, the Cmax in critically ill patients who received anidulafungin was lower than in healthy volunteers. The Cmin and T1/2 of critically ill patients who received caspofungin were larger than in healthy volunteers. The Vd and CL of critically ill patients receiving anidulafungin and micafungin were larger than in healthy volunteers. WHAT IS NEW AND CONCLUSION: This systematic review provides an analysis of the pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients. Based on the limited data available, caspofungin has less pharmacokinetic/pharmacodynamics variability than anidulafungin and micafungin.

Population Analysis of Anidulafungin in Infants to Older Adults With Confirmed or Suspected Invasive Candidiasis.

In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients with confirmed, suspected, or at high risk of invasive candidiasis (IC). Relationships between anidulafungin exposure and key efficacy end points (global response of success and all-cause mortality) and safety end points (all-cause hepatic or gastrointestinal adverse events) in all patients and separately in pediatric patients and the appropriate dosing regimen for IC treatment in pediatric patients were evaluated. Pediatric patients received a 3.0 mg/kg (maximum 200 mg) i.v. loading dose and 1.5 mg/kg (maximum 100 mg) daily thereafter. Adults received a 200 mg i.v. loading dose and 100 mg daily thereafter. Estimated systemic anidulafungin exposures were similar across age groups (neonates to adults) at the weight-based doses studied in pediatric patients. No clear associations were identified between anidulafungin exposure and efficacy or safety end points.

Safety, Efficacy and Pharmacokinetics of Anidulafungin in Patients 1 Month to <2 Years of Age With Invasive Candidiasis, Including Candidemia.

Nineteen patients 1 month to <2 years of age with (n = 16) or at high risk of (n = 3) invasive candidiasis received anidulafungin for 5-35 days (3 mg/kg day 1, 1.5 mg/kg daily thereafter) followed by optional fluconazole (NCT00761267). Most treatment-emergent adverse events were mild/moderate, and no treatment-related deaths occurred. End of intravenous therapy global response success rate was 68.8%. Pharmacokinetics were similar to adult patients.

Pharmacokinetics of anidulafungin in critically ill patients with Candida peritonitis.

OBJECTIVE: To describe the pharmacokinetic (PK) profile of anidulafungin and to evaluate its concentration in the peritoneal fluid (PF) of patients suspected of suffering from peritoneal infection undergoing abdominal surgery, in order to ensure that therapeutic levels are achieved within the peritoneal cavity. METHODS: A descriptive, open, prospective, observational, multicentre and non-interventional study was performed. Anidulafungin was used at conventional doses. Blood and PF samples were obtained on day 2 of treatment or on any of the following days. RESULTS: A total of 31 patients in a serious clinical condition, as demonstrated by high mean clinical severity scale scores (APACHE II and SOFA scores), were included in the study. The mean area under the curve (AUC) in PF was 30% (31±19%) of that determined in the plasma and the maximum concentration (Cmax) reached in PF (mg/l) was close to 1 (0.9±0.5). No adverse effects were observed in any of the 31 patients. CONCLUSIONS: Anidulafungin at conventional doses reaches PF concentrations that exceed the minimum inhibitory concentration of the usual Candida spp, which explains the proven efficacy of this echinocandin in the treatment of Candida peritonitis in critically ill patients.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients.

A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.

Postantifungal effect of anidulafungin against Candida albicans, Candida dubliniensis, Candida africana, Candida parapsilosis, Candida metapsilosis and Candida orthopsilosis / Efecto postantifúngico de anidulafungina contra Candida albicans, Candida dubliniensis, Candida africana, Candida parapsilosis, Candida metapsilosis y Candida orthopsilosis

Objetivos. Candida albicans continúa siendo la causa más frecuente de candidiasis invasiva; sin embargo, la incidencia de candidiasis causadas por especies diferentes a C. albicans, como Candida parapsilosis, está aumentando. El efecto postantifúngico (PAFE) es relevante para establecer pautas de dosificación en la terapia antifúngica, ya que la frecuencia de administración de los fármacos antifúngicos podría cambiar dependiendo del PAFE. El objetivo de este estudio fue evaluar el PAFE de anidulafungina contra C. albicans, Candida dubliniensis, Candida africana, C. parapsilosis, Candida metapsilosis y Candida orthopsilosis. Material y métodos: Se evaluaron 21 cepas de Candida. Para llevar a cabo los estudios PAFE, las células se expusieron durante 1 h a concentraciones entre 0,12 y 8 mg/L de anidulafungina. Las curvas de letalidad (TK) se obtuvieron empleando las mismas concentraciones. Los experimentos se realizaron utilizando un inóculo de 1-5 x 105 células/mL, durante 48 h de incubación. Las lecturas de PAFE y TK se realizaron a las 0, 2, 4, 6, 24 y 48 h. Resultados: Anidulafungina, en los experimentos PAFE, fue fungicida contra 2 de 14 (14%) cepas de las especies relacionadas con C. albicans y ejerció un PAFE prolongado (≥ 33,6 h) contra 13 de 14 (93%) cepas (2 mg/L). El límite fungicida de anidulafungina se alcanzó contra 1 de 7 (14%) cepas del complejo C. parapsilosis, con un PAFE prolongado (≥ 42 h) contra 6 de 7 (86%) cepas. Conclusiones: Anidulafungina produce un PAFE significativo y prolongado contra C. albicans y C. parapsilosis y las especies relacionadas con estas

Objectives: Candida albicans remains the most common aetiology of invasive candidiasis, leading to high morbidity and mortality. Nevertheless, the incidence of candidiasis due to non-C. albicans species, such as Candida parapsilosis, is increasing. Postantifungal effect (PAFE) is relevant for establishing dosage schedules in antifungal therapy, as the frequency of antifungal administration could change depending on PAFE. The aim of this study was to evaluate the PAFE of anidulafungin against C. albicans, Candida dubliniensis, Candida africana, C. parapsilosis, Candida metapsilosis and Candida orthopsilosis. Material and methods: Twenty-one Candida strains were evaluated. Cells were exposed to anidulafungin for 1 h at concentrations ranging from 0.12 to 8 mg/L for PAFE studies. Time-kill experiments (TK) were conducted at the same concentrations. The experiments were performed using an inoculum of 1-5 x 105 cells/mL and 48 h incubation. Readings of PAFE and TK were done at 0, 2, 4, 6, 24 and 48 h. Results: Anidulafungin was fungicidal against 2 out of 14 (14%) strains of C. albicans related species in PAFE experiments. Moreover, 2 mg/L of anidulafungin exerted a prolonged PAFE (≥ 33.6 h) against 13 out of 14 (93%) strains. Similarly, fungicidal endpoint was achieved against 1 out of 7 (14%) strains of C. parapsilosis complex, being PAFE prolonged (≥ 42 h) against 6 out of 7 (86%) strains. Conclusions: Anidulafungin induced a significant and prolonged PAFE against C. albicans and C. parapsilosis and their related species

Killing kinetics of anidulafungin, caspofungin and micafungin against Candida parapsilosis species complex: Evaluation of the fungicidal activity.

BACKGROUND: Candida parapsilosis, Candida metapsilosis and Candida orthopsilosis are emerging as relevant causes of candidemia. Moreover, they show differences in their antifungal susceptibility and virulence. The echinocandins are different in terms of in vitro antifungal activity against Candida. Time-kill (TK) curves represent an excellent approach to evaluate the fungicidal activity of antifungal drugs. AIMS: To compare the fungicidal activities of anidulafungin, caspofungin and micafungin against C. parapsilosis species complex by TK curves. METHODS: Antifungal activities of three echinocandins against C. parapsilosis, C. metapsilosis and C. orthopsilosis were studied by TK curves. Drug concentrations assayed were 0.25, 2 and 8µg/ml. CFU/ml were determined at 0, 2, 4, 6, 24 and 48h. RESULTS: Killing activities of echinocandins were species-, isolates- and concentration-dependent. Anidulafungin reached the fungicidad endpoint for 6 out of 7 isolates (86%); it required between 13.34 and 29.67h to reach this endpoint for the three species studied, but more than 48h were needed against one isolate of C. orthopsilosis (8µg/ml). Caspofungin fungicidal endpoint was only achieved with 8µg/ml against one isolate of C. metapsilosis after 30.12h (1 out of 7 isolates; 14%). Micafungin fungicidal endpoint was reached in 12.74-28.38h (8µg/ml) against one isolate each of C. parapsilosis and C. orthopsilosis, and against both C. metapsilosis isolates (4 out of 7 isolates; 57%). CONCLUSIONS: C. metapsilosis was the most susceptible species to echinocandins, followed by C. orthopsilosis and C. parapsilosis. Anidulafungin was the most active echinocandin against C. parapsilosis complex.

Killing kinetics of anidulafungin, caspofungin and micafungin against Candida parapsilosis species complex: Evaluation of the fungicidal activity / Cinéticas de letalidad de la anidulafungina, la caspofungina y la micafungina frente a las especies del complejo Candida parapsilosis: evaluación de la actividad fungicida

Background: Candida parapsilosis, Candida metapsilosis and Candida orthopsilosis are emerging as relevant causes of candidemia. Moreover, they show differences in their antifungal susceptibility and virulence. The echinocandins are different in terms of in vitro antifungal activity against Candida. Time-kill (TK) curves represent an excellent approach to evaluate the fungicidal activity of antifungal drugs. Aims: To compare the fungicidal activities of anidulafungin, caspofungin and micafungin against C. parapsilosis species complex by TK curves. Methods: Antifungal activities of three echinocandins against C. parapsilosis, C. metapsilosis and C. orthopsilosis were studied by TK curves. Drug concentrations assayed were 0.25, 2 and 8 μg/ml. CFU/ml were determined at 0, 2, 4, 6, 24 and 48 h. Results: Killing activities of echinocandins were species-, isolates- and concentration-dependent. Anidulafungin reached the fungicidad endpoint for 6 out of 7 isolates (86%); it required between 13.34 and 29.67h to reach this endpoint for the three species studied, but more than 48h were needed against one isolate of C. orthopsilosis (8 μg/ml). Caspofungin fungicidal endpoint was only achieved with 8μg/ml against one isolate of C. metapsilosis after 30.12 h (1 out of 7 isolates; 14%). Micafungin fungicidal endpoint was reached in 12.74-28.38h (8μg/ml) against one isolate each of C. parapsilosis and C. orthopsilosis, and against both C. metapsilosis isolates (4 out of 7 isolates; 57%). Conclusions: C. metapsilosis was the most susceptible species to echinocandins, followed by C. orthopsilosis and C. parapsilosis. Anidulafungin was the most active echinocandin against C. parapsilosis complex

Antecedentes: Candida parapsilosis, Candida metapsilosis y Candida orthopsilosis son causas relevantes de candidemia. Además, muestran diferencias en la sensibilidad a los fármacos antifúngicos. Las equinocandinas muestran diferente actividad antifúngica in vitro frente a Candida. Las curvas de tiempo-letalidad (TK) representan una excelente aproximación para evaluar la actividad fungicida de los fármacos antifúngicos. Objetivos: Comparar la actividad fungicida de la anidulafungina, la caspofungina y la micafungina frente al complejo C. parapsilosis mediante las curvas de TK. Métodos: Se estudió la actividad de tres equinocandinas frente a C. parapsilosis, C. metapsilosis y C. orthopsilosis mediante las curvas de TK. Las concentraciones ensayadas fueron 0,25, 2 y 8 μg/ml. Se determinaron las UFC/ml a las 0, 2, 4, 6, 24 y 48 h. Resultados: La actividad de las equinocandinas fue especie-, aislamiento- y concentración-dependiente. La anidulafungina alcanzó el límite fungicida frente a 6 de 7 aislamientos (86%), y necesitó 13,34-29,67h para alcanzar este límite en las tres especies estudiadas; para un aislamiento de C. orthopsilosis, requirió más de 48h (8μg/ml). El límite fungicida de la caspofungina solo se alcanzó con 8 μg/ml frente a un aislamiento de C. metapsilosis después de 30,12h (1 de 7 aislamientos; 14%). La micafungina alcanzó este límite en 12,74-28,38 h (8 μg/ml) frente a un aislamiento de C. parapsilosis y C. orthopsilosis y frente a ambos aislamientos de C. metapsilosis (4 de 7 aislamientos; 57%). Conclusiones: C. metapsilosis fue la especie más sensible a las equinocandinas, seguida de C. orthopsilosis y C. parapsilosis. La anidulafungina fue la equinocandina más activa frente al complejo C. parapsilosis

Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults.

In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg · h/liter (the reference value for normal-weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg.

Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients.

Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 µg/ml) and in pleural effusion (0.32 to 2.02 µg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 µg/ml, respectively) and below the MIC values for several pathogenic Candida strains.

A New Marker of Echinocandin Activity in an In Vitro Pharmacokinetic/Pharmacodynamic Model Correlates with an Animal Model of Aspergillus fumigatus Infection.

The lack of a quantifiable marker for echinocandin activity hinders in vitro pharmacokinetic/pharmacodynamic (PK/PD) studies for Aspergillus spp. We developed an in vitro PK/PD model simulating the pharmacokinetics of anidulafungin and assessing its pharmacodynamics against Aspergillus fumigatus with a new, easily quantifiable, sensitive, and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196 and V52-35) with identical anidulafungin EUCAST (0.03 µg/ml) and CLSI (0.015 µg/ml) minimal effective concentrations (MEC) and one isolate (strain AFU79728) with an MEC of >16 µg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane (DM) tube inoculated with 103 CFU/ml. During anidulafungin exposure, two types of fungal forms were observed inside the DM tube: floating conidia that were quantified by cultures and aberrant mycelia that were quantified by the vertical height of the mycelia attached on the DM tube. No aberrant mycelia were found for the resistant isolate or in the drug-free controls. An in vitro exposure-effect relationship was similar to that found in animals using survival as an endpoint, with a free-drug area under the concentration-time curve from 0 to 24 h (fAUC0-24) associated with 50% of maximal activity of 2.21 (range, 1.81 to 2.71) mg · h/liter in vitro versus 2.62 (range, 1.88 to 3.65) mg · h/liter in vivo (P = 0.41). The hillslopes were also similar, with 1.96 versus 1.34 (P = 0.29). Analysis of each isolate separately showed increased antifungal susceptibility between AZN8196 and V52-35 (P < 0.001) even though they have the same CLSI and EUCAST MECs, but the strains have two 2-fold dilutions lower MICs using Etest and the XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide} method. Dose fractionation studies with all three echinocandins showed that their activities are best described by fAUC and not the maximum concentration of free drug (fCmax). The new marker correlated with in vivo outcome and can be used for in vitro PK/PD studies exploring the pharmacodynamics of echinocandins against Aspergillus spp.