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British Journal of Clinical Pharmacology Mar 2021The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of...
AIMS
The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of evaluating and optimizing dosing regimens.
METHODS
A PK study was conducted in a cohort of 13 patients treated with anidulafungin using intensive sampling during multiple periods per patient and the high-performance liquid chromatography method for drug quantification. A population PK model was developed to describe the concentration-time course of anidulafungin and the inter-individual (IIV) and interoccasion variability (IOV) of the PK parameters. Model-based PK simulations have been performed to estimate the probability of target attainment (PTA), given the pharmacokinetic/pharmacodynamic target of free 24-hour area under the free drug concentration-time curve over minimum inhibitory concentration for several dosing regimens.
RESULTS
A two-compartment PK model, with first-order elimination, best described the data with population clearance (CL) and central/peripheral volume of distribution (V1/V2) of 0.778 L/h and 10.2/21.1 L, respectively, and a mean ± s.d. AUC of 119.97 ± 46.23 mg·h/L. Pronounced IIV and IOV variability was found for CL (38% and 31%) and V1 (47% and 30%), respectively. Sequential Organ Failure Assessment (SOFA) and Body Mass Index (BMI) were found to be covariates on CL and V1, respectively. Low PTA values were calculated for borderline Clinical & Laboratory Standards Institute (CLSI)-susceptible Candida strains.
CONCLUSIONS
Although anidulafungin exposure was found comparable to that in healthy volunteers, elevated interindividual and significant interoccasion variability was found in critically ill ICU patients, which resulted in reduced PTA values in these patients.
Topics: Anidulafungin; Anti-Bacterial Agents; Cohort Studies; Critical Illness; Humans; Intensive Care Units; Microbial Sensitivity Tests
PubMed: 32633039
DOI: 10.1111/bcp.14457 -
Journal of Fungi (Basel, Switzerland) Dec 2021In different regions worldwide, there exists an intra-and inter-regional variability in the rates of resistance to antifungal agents in , highlighting the importance of... (Review)
Review
In different regions worldwide, there exists an intra-and inter-regional variability in the rates of resistance to antifungal agents in , highlighting the importance of understanding the epidemiology and antifungal susceptibility profiles of in each region. However, in some regions, such as Ibero-America, limited data are available in this context. Therefore, in the present study, a systematic review was conducted to determine the antifungal resistance in in Ibero-America over the last five years. A literature search for articles published between January 2015 and December 2020 was conducted without language restrictions, using the PubMed, Embase, Cochrane Library, and LILACS databases. The search terms that were used were "" AND "antifungal resistance" AND "Country", and 22 publications were retrieved from different countries. The use of azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, ketoconazole, and miconazole) varied between 4.0% and 100%, and that of echinocandins (micafungin, caspofungin, and anidulafungin) between 1.1% and 10.0%. The limited information on this subject in the region of Ibero-America emphasizes the need to identify the pathogens at the species level and perform antifungal susceptibility tests that may lead to the appropriate use of these drugs and the optimal doses in order to avoid the development of antifungal resistance or multi-resistance.
PubMed: 35049954
DOI: 10.3390/jof8010014 -
Clinical Pharmacology and Therapeutics May 2011Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and... (Comparative Study)
Comparative Study
Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and safety of the drug in infants and neonates are unknown. The object of our study was to determine the PK and safety of anidulafungin in infants and neonates at risk for invasive candidiasis. Intravenous anidulafungin (1.5 mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were collected after the first dose and again after the third to fifth doses. The pharmacokinetic parameters of the drug were determined by noncompartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria. The study showed that drug exposure levels were similar between neonates and infants; the median areas under the concentration-time curve (range) was 75 (30-109) µg·h/ml and 98 (55-278) µg·h/ml (P = 0.12) for neonates and infants, respectively. No drug-related serious adverse events were observed. The study results indicate that neonates and infants receiving 1.5 mg/kg/day have anidulafungin exposure levels similar to those in children receiving similar weight-based dosing and in adult patients receiving 100 mg/day.
Topics: Age Factors; Anidulafungin; Antifungal Agents; Area Under Curve; Candida; Candidiasis, Invasive; Dose-Response Relationship, Drug; Echinocandins; Female; Humans; Infant; Infant, Newborn; Male
PubMed: 21412233
DOI: 10.1038/clpt.2011.26 -
Journal of Fungi (Basel, Switzerland) Sep 2020Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive... (Review)
Review
Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive aspergillosis. The persistently neutropenic rabbit model of invasive pulmonary aspergillosis (IPA) has been a highly predictive system in identifying new antifungal agents for treatment and prevention of this frequently lethal infection. Since its initial development, the persistently neutropenic rabbit model of IPA has established a strong preclinical foundation for dosages, drug disposition, pharmacokinetics, safety, tolerability, and efficacy for deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, caspofungin, micafungin, anidulafungin, voriconazole, posaconazole, isavuconazole, and ibrexafungerp in treatment of patients with invasive aspergillosis. The findings of combination therapy with a mould-active triazole and an echinocandin in this rabbit model also predicted the outcome of the clinical trial for voriconazole plus anidulafungin for treatment of IPA. The plasma pharmacokinetic parameters and tissue disposition for most antifungal agents approximate those of humans in persistently neutropenic rabbits. Safety, particularly nephrotoxicity, has also been highly predictive in the rabbit model, as exemplified by the differential glomerular filtration rates observed in animals treated with deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. A panel of validated outcome variables measures therapeutic outcome in the rabbit model: residual fungal burden, markers of organism-mediated pulmonary injury (lung weights and infarct scores), survival, and serum biomarkers. In selected antifungal studies, thoracic computerized tomography (CT) is also used with diagnostic imaging algorithms to measure therapeutic response of pulmonary infiltrates, which exhibit characteristic radiographic patterns, including nodules and halo signs. Further strengthening the predictive properties of the model, therapeutic response to successfully developed antifungal agents for treatment of IPA has been demonstrated over the past two decades by biomarkers of serum galactomannan and (1→3)-β-D-glucan with patterns of resolution, that closely mirror those documented responses in patients with IPA. The decision to move from laboratory to clinical trials should be predicated upon a portfolio of complementary and mutually validating preclinical laboratory animal models studies. Other model systems, including those in mice, rats, and guinea pigs, are also valuable tools in developing clinical protocols. Meticulous preclinical investigation of a candidate antifungal compound in a robust series of complementary laboratory animal models will optimize study design, de-risk clinical trials, and ensure tangible benefit to our most vulnerable immunocompromised patients with invasive aspergillosis.
PubMed: 33007839
DOI: 10.3390/jof6040198 -
Antimicrobial Agents and Chemotherapy Mar 2021A total of 15 isolates from the SENTRY antimicrobial surveillance program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation...
Evaluation of Synergistic Activity of Isavuconazole or Voriconazole plus Anidulafungin and the Occurrence and Genetic Characterization of Candida auris Detected in a Surveillance Program.
A total of 15 isolates from the SENTRY antimicrobial surveillance program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation of antifungal susceptibility and synergy against anidulafungin plus voriconazole or isavuconazole using the checkerboard method. Surveillance isolates were analyzed for genetic relatedness and resistance mechanisms. Applying the tentative statistical epidemiological cutoff values and the Centers for Disease Control tentative breakpoints, 32/36 isolates were resistant to fluconazole, 5/36 were resistant to amphotericin B, 5/36 were non-wild-type (NWT) to anidulafungin, 3/36 were NWT to micafungin, and 1/36 and 10/36 were NWT to isavuconazole and voriconazole, respectively. Of these, 10 isolates were multidrug resistant, which means that these isolates were resistant to 2 antifungal classes. Synergy or partial synergy was noted in 5/36 and 22/36, respectively, of the isolates with the combination of anidulafungin plus voriconazole, and 11/36 and 19/36 isolates, respectively, for the combination of anidulafungin plus isavuconazole. Multilocus sequence type (MLST) analysis of the 15 SENTRY isolates demonstrated that the isolates from the US were genetically related to, but different from, isolates from Latin America (Panama and Colombia) and Germany. Single nucleotide polymorphism (SNP) analysis showed that the 15 SENTRY isolates belonged to the described international clades and had associated Erg11 alterations, including 11 isolates displaying K143R, one displaying F126L, and one displaying Y501H alterations and a fluconazole MIC result of ≥64 mg/liter. Resistance mechanisms were not observed in the two isolates displaying fluconazole MIC values at 4 and 16 mg/liter. Isavuconazole displayed activity and greater synergy when tested with anidulafungin than seen with anidulafungin plus voriconazole against the clinical isolates that displayed resistance phenotypes.
Topics: Anidulafungin; Antifungal Agents; Candida; Colombia; Drug Resistance, Fungal; Drug Synergism; Echinocandins; Germany; Microbial Sensitivity Tests; Multilocus Sequence Typing; Nitriles; Pyridines; Triazoles; Voriconazole
PubMed: 33431416
DOI: 10.1128/AAC.02031-20 -
Journal of Fungi (Basel, Switzerland) Nov 2020Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new... (Review)
Review
Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC) and half enzyme maximal inhibitory concentration 50% (IC)) and spectrum, the same target, and the same mechanisms of resistance. The selection of mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.
PubMed: 33139650
DOI: 10.3390/jof6040262 -
Molecules (Basel, Switzerland) Jan 2023The use of essential oils is increasingly being investigated among new therapeutic approaches based on medicinal plants and their extracts. With the wide use of... (Review)
Review
The use of essential oils is increasingly being investigated among new therapeutic approaches based on medicinal plants and their extracts. With the wide use of synthetic and semi-synthetic antimicrobial drugs, the spread of drug-resistant clinical isolates has increased, and research is directed towards natural products, such as essential oils, as useful antimicrobial resources. In the context of a prospective infection, we compared the impact of essential oils and common antimicrobial agents on the microbicidal activity of human phagocytes. Here, we present the results of our decades-long investigation into the effectiveness of thyme red oil (26.52% thymol chemotype), tea tree oil (TTO), and Mentha of Pancalieri [( (Huds) var. (Sole), form (Camus) ()] essential oils on human polymorphonuclear leukocytes (PMNs) capacity to kill clinical strains of and when compared to three antifungal drugs used to treat candidiasis (fluconazole, anidulafungin, and caspofungin) These essential oils demonstrate antifungal drug-like and/or superior efficacy in enhancing intracellular killing by PMNs, even at subinhibitory concentrations. Our results are compared with data in the literature on essential oils and immune system interactions. This comparison would aid in identifying therapeutic solutions to the increasingly prevalent antibiotic resistance as well as filling in any remaining knowledge gaps on the bioactivity of essential oils.
Topics: Humans; Oils, Volatile; Antifungal Agents; Prospective Studies; Fluconazole; Plant Oils; Anti-Infective Agents; Microbial Sensitivity Tests
PubMed: 36615625
DOI: 10.3390/molecules28010435 -
Antimicrobial Agents and Chemotherapy Mar 2018We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the...
We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the mutation frequency. We studied 20 echinocandin-susceptible, fluconazole-intermediate, and wild-type isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/liter were selected for antifungal susceptibility testing. The genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, MSW, and mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence ( model) of the resulting individual mutant colonies were studied. For micafungin and anidulafungin, we found similar results for the MPC (0.06 to 2 mg/liter and 0.25 to 2 mg/liter, respectively), MSW (0.015 to 2 mg/liter for both echinocandins), and mutation frequency (3.7 × 10 and 2.8 × 10, respectively). A total of 12 isolates were able to grow at 1 mg/liter on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however, mutations (ΔF658, S663P, W715L, and E655A) were observed only in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual mutant colonies. Echinocandin concentrations lower than 2 mg/liter can lead to selection of resistance mutations in isolates .
Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Humans; Micafungin; Mutation
PubMed: 29311063
DOI: 10.1128/AAC.01982-17 -
Pharmacy Practice 2022The inappropriate use of antimicrobials has substantially contributed to the development of antimicrobial drug resistance. Appropriate antibacterial prescribing has been...
BACKGROUND
The inappropriate use of antimicrobials has substantially contributed to the development of antimicrobial drug resistance. Appropriate antibacterial prescribing has been emphasised, with minimal focus on appropriate prescribing of antifungals. Evaluation of antifungal use in the clinical setting is essential to prevent unnecessary drug exposure, development of resistance, adverse effects, and high hospitalisation costs.
OBJECTIVE
The purpose of this study was to assess the appropriateness of antifungal prescribing among adult patients at the Sultan Qaboos University Hospital (SQUH) in Oman.
METHODS
In this retrospective, observational study, the study population comprised adult patients treated with oral or intravenous antifungals between July 2018 and December 2019. The appropriateness of treatment was assessed using guidelines from the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN), as well as a set of literature-based criteria that were modified by SQUH infectious diseases team to suit local practices. These criteria included indication, dosage, and potential drug interactions. The primary outcome was the frequency of adherence to the treatment guidelines for fungal infections. Descriptive statistics were used for data analysis.
RESULTS
A total of 400 prescriptions were collected, of which 158 (39.5%) were for empirical therapy, 135 (33.8%) for targeted therapy, 69 (17.3%) for prophylactic therapy, and 38 (9.5%) for pre-emptive therapy. The overall appropriateness was 74.8%. The indication, dosage, and potential for antifungal-drug interactions were considered appropriate in 391 (97.8%), 314 (78.5%), and 381 (95.3%) prescriptions, respectively. Anidulafungin was the most prescribed antifungal agent, with 210 prescriptions (52.5%), followed by fluconazole with 102 prescriptions (25.5%), and voriconazole with 48 prescriptions (12%).
CONCLUSION
In comparison with publised literature, our study revealed appropriate antifungal drug prescribing practices. However, studies with larger sample size in various hospital settings are necessary to confirm our findings on a national scale, and to obtain better statistical inferences and generalisability.
PubMed: 35497908
DOI: 10.18549/PharmPract.2022.1.2613 -
Frontiers in Pharmacology 2022We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. We...
We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. We performed disproportionality and Bayesian analyses based on data from the first quarter in 2004 to the third quarter in 2021 in the Food and Drug Administration Adverse Event Reporting System to characterize the signal differences of antifungal drugs-related DILI. We also compared the onset time and mortality differences of different antifungal agents. A total of 2943 antifungal drugs-related DILI were identified. Affected patients tended to be aged >45 years (51.38%), with more males than females (49.03% vs. 38.09%). Antifungal drug-induced liver injury is most commonly reported with voriconazole (32.45%), fluconazole (19.37%), and itraconazole (14.51%). Almost all antifungal drugs were shown to be associated with DILI under disproportionality and Bayesian analyses. The intraclass analysis of correlation between different antifungal agents and DILI showed the following ranking: caspofungin (ROR = 6.12; 95%CI: 5.36-6.98) > anidulafungin (5.15; 3.69-7.18) > itraconazole (5.06; 4.58-5.60) > voriconazole (4.58; 4.29-4.90) > micafungin (4.53; 3.89-5.27) > posaconazole (3.99; 3.47-4.59) > fluconazole (3.19; 2.93-3.47) > ketoconazole (2.28; 1.96-2.64). The onset time of DILI was significantly different among different antifungal drugs ( < 0.0001), and anidulafungin result in the highest mortality rate (50.00%), while ketoconazole has the lowest mortality rate (9.60%). Based on the Food and Drug Administration Adverse Event Reporting System database, antifungal drugs are significantly associated with DILI, and itraconazole and voriconazole had the greatest risk of liver injury. Due to indication bias, more clinical studies are needed to confirm the safety of echinocandins.
PubMed: 35571077
DOI: 10.3389/fphar.2022.891336