-
Antimicrobial Agents and Chemotherapy Aug 2009We established a murine model of Candida albicans central nervous system (CNS) infection and evaluated the efficacy of anidulafungin. Ten milligrams/kg/day...
We established a murine model of Candida albicans central nervous system (CNS) infection and evaluated the efficacy of anidulafungin. Ten milligrams/kg/day anidulafungin, amphotericin B, or voriconazole significantly reduced mortality and fungal burden in brain tissue, although amphotericin B and 10 mg/kg/day anidulafungin reduced fungal burden in brain tissue to a greater extent than did voriconazole. This suggests a potential role for anidulafungin in the treatment of candidal CNS infection.
Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Candida albicans; Candidiasis; Central Nervous System Infections; Disease Models, Animal; Echinocandins; Female; Mice; Pyrimidines; Triazoles; Voriconazole
PubMed: 19506064
DOI: 10.1128/AAC.00646-09 -
Journal of Chromatography. B,... Feb 2020The echinocandins anidulafungin (ANID) and micafungin (MICA) are recommended for treatment of invasive Candida infections. As target-site concentrations of antimicrobial...
The echinocandins anidulafungin (ANID) and micafungin (MICA) are recommended for treatment of invasive Candida infections. As target-site concentrations of antimicrobial agents are crucial for eradication of pathogens, we established and validated high-performance liquid chromatography-UV detection (HPLC-UV) assays for quantification of ANID and MICA in human plasma, ascites fluid, pleural effusion, and in cerebrospinal fluid (CSF). Sample pre-purification was performed by protein precipitation with acetonitrile followed by solid phase extraction. For both assays, intra- and interday precision, and accuracy fulfilled the requirements for bioanalytical methods issued by the European Medicine Agency (EMA). The lower limit of quantification was 0.01 mg/L for both drugs. At 25 °C, ANID and MICA concentrations declined by up to 70% within 24 h. Concentrations remained stable over 24 h at 4 °C and over four weeks at -80 °C. In conclusion, the developed methods are fit for the assessment of target-site pharmacokinetics of ANID and MICA in clinical studies.
Topics: Anidulafungin; Ascitic Fluid; Candidiasis, Invasive; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Limit of Detection; Linear Models; Micafungin; Reproducibility of Results; Solid Phase Extraction; Spectrophotometry, Ultraviolet
PubMed: 31958565
DOI: 10.1016/j.jchromb.2019.121937 -
Antimicrobial Agents and Chemotherapy 2014The efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Patients in intensive care may be at risk for underexposure. In...
The efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Patients in intensive care may be at risk for underexposure. In critically ill patients with an invasive Candida infection, the anidulafungin exposure and a possible correlation with disease severity or plasma protein levels were explored. Concentration-time curves were therefore obtained at steady state. Anidulafungin concentrations were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MIC values of the Candida species were determined with the Etest. The target AUC/MIC ratio was based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) data. Twenty patients were included. The patients received a maintenance dose of 100 mg once daily after a loading dose of 200 mg on the first day. The mean (±standard deviation) AUC, maximum concentration of drug in plasma (Cmax), and minimum concentration of drug in plasma (Cmin) were 69.8 ± 24.1 mg · h/liter, 4.7 ± 1.4 mg/liter, and 2.2 ± 0.8 mg/liter, respectively. The MIC values of all cultured Candida species were below the EUCAST MIC breakpoints. The exposure to anidulafungin in relation to the MIC that was determined appeared sufficient in all patients. The anidulafungin exposure was low in our critically ill patients. However, combined with the low MICs of the isolated Candida strains, the lower exposure observed in comparison to the exposure in the general patient population resulted in favorable AUC/MIC ratios, based on EUCAST data. No correlation was observed between anidulafungin exposure and disease severity or plasma protein concentrations. In patients with less-susceptible Candida albicans or glabrata strains, we recommend considering determining the anidulafungin exposure to ensure adequate exposure. (This trial has been registered at ClinicalTrials.gov under registration no. NCT01047267.).
Topics: Aged; Anidulafungin; Antifungal Agents; Candida; Candidiasis; Critical Illness; Echinocandins; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged
PubMed: 24165173
DOI: 10.1128/AAC.01607-13 -
Journal de Mycologie Medicale Nov 2023Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed...
INTRODUCTION
Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole is not widely available. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction.
METHODS
This is a retrospective cohort encompassing newly diagnosed AML adult patients. All subjects received intensive chemotherapy and were divided into three groups: patients who did not receive any AP and patients who received fluconazole (150-400 mg/day) or anidulafungin (100 mg/day).
RESULTS
During AML induction, 82 patients did not receive AP, 108 and 14 patients received anidulafungin and fluconazole, respectively. IFI incidence was 27%, classified as possible, probable, and proven in 65, 2 and 33%, respectively. Multivariable analysis showed that lower neutrophil counts are associated with IFI (OR = 2.8), whereas age, genetic classification, and lymphocyte counts were not. To examine the impact of anidulafungin in comparison with 'no AP', a propensity score matching analysis was performed. Use of anidulafungin was not related to less IFI during induction, while neutrophil counts remained significant. Patients under prophylactic anidulafungin received less amphotericin B (p < 0.001) but not voriconazole (p = 0.49).
DISCUSSION
To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the incidence of mold infections did not decrease with AP, suggesting that in a setting with a high incidence of IFI, broad spectrum AP might be more suitable.
Topics: Adult; Humans; Antifungal Agents; Fluconazole; Anidulafungin; Retrospective Studies; Propensity Score; Remission Induction; Leukemia, Myeloid, Acute
PubMed: 37683564
DOI: 10.1016/j.mycmed.2023.101434 -
Antimicrobial Agents and Chemotherapy Feb 2015Efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can...
Efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW\Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC0-24) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression (R2=0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model (R2=0.89; bias, -0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.).
Topics: Adult; Aged; Anidulafungin; Bayes Theorem; Candidiasis, Invasive; Critical Illness; Echinocandins; Female; Humans; Male; Middle Aged; Prospective Studies; Young Adult
PubMed: 25487797
DOI: 10.1128/AAC.03375-14 -
Antiviral Research Nov 2021Zika virus (ZIKV) has been the cause of some epidemics since 2007. The correlations of microcephaly and Guillain-Barré syndrome with ZIKV have been noticed....
Zika virus (ZIKV) has been the cause of some epidemics since 2007. The correlations of microcephaly and Guillain-Barré syndrome with ZIKV have been noticed. Unfortunately, researchers have yet to develop an effective vaccine or drug approved for ZIKV infection. Anidulafungin is a member of echinocandins that is used to treat candida infections. This study assessed the antiviral capability of anidulafungin against ZIKV. Anidulafungin was shown to significantly decrease viral RNA levels, protein expression levels, viral yields, and the rate of infection. In time of addition assays, anidulafungin exhibited inhibitory activities in the early stages of ZIKV infection. In binding and entry assays, administering anidulafungin did not lead to a corresponding decrease in quantity of viral RNA, but a significant decrease in ZIKV infectivity was observed in virucidal assays. This indicated that anidulafungin interferes directly with virions. T-1105 is a viral polymerase inhibitor, which functions in the late stage of ZIKV infection. When anidulafungin was administered in combination with T-1105, an obvious synergistic effect was observed, resulting in a combination index (CI) value of 0.85 ± 0.13. Finally, we evaluated the effects of echinocandins in terms of half-maximal inhibitory concentration (IC), calculation of cytotoxicity concentration 50% (CC), selectivity index (SI), and Patchdock score. Among the tests, anidulafungin bears the lowest IC and highest Patchdock score. Although anidulafungin is classified as a pregnancy category C agent; however, combination therapy of anidulafungin with a viral RNA replication inhibitor could expand treatment options for ZIKV infection.
Topics: Anidulafungin; Animals; Antiviral Agents; Chlorocebus aethiops; Drug Synergism; Humans; Inhibitory Concentration 50; Pyrazines; RNA, Viral; Vero Cells; Virion; Virus Attachment; Zika Virus; Zika Virus Infection
PubMed: 34648875
DOI: 10.1016/j.antiviral.2021.105188 -
International Journal of Antimicrobial... Mar 2016The aim of this study was to fit anidulafungin in vitro static time-kill data from nine strains of Candida with a pharmacodynamic (PD) model in order to describe the...
The aim of this study was to fit anidulafungin in vitro static time-kill data from nine strains of Candida with a pharmacodynamic (PD) model in order to describe the antifungal activity of this drug against Candida spp. Time-kill data from strains of Candida albicans, Candida glabrata and Candida parapsilosis clades were best fit using an adapted sigmoidal Emax model and resulted in a set of PD parameters (Emax, EC50 and Hill factor) for each fungal strain. The data were analysed with NONMEM 7. Anidulafungin was effective in a species- and concentration-dependent manner against the strains of C. glabrata and C. parapsilosis clades as observed with the EC50 estimates. Maximum killing rate constant (Emax) values were higher against C. glabrata and C. parapsilosis complex strains. In conclusion, we demonstrated that the activity of anidulafungin against Candida can be accurately described using an adapted sigmoidal Emax model.
Topics: Anidulafungin; Antifungal Agents; Candida albicans; Candida glabrata; Candidiasis; Echinocandins; Humans; Microbial Sensitivity Tests; Models, Statistical
PubMed: 26857078
DOI: 10.1016/j.ijantimicag.2015.12.011 -
Birth Defects Research. Part B,... Feb 2012Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections...
Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma Cmax and AUC0-24 values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.
Topics: Aging; Anidulafungin; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Echinocandins; Female; Male; Rats; Rats, Inbred F344; Time Factors; Tissue Distribution
PubMed: 22311649
DOI: 10.1002/bdrb.20347 -
BMC Infectious Diseases Sep 2011Candida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to... (Comparative Study)
Comparative Study Randomized Controlled Trial
Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome.
BACKGROUND
Candida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic Candida infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by C. albicans, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.
METHODS
Global responses at end of intravenous study treatment in patients with C. albicans infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival.
RESULTS
In total, 135 patients with C. albicans infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank p < 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; p < 0.05). Survival through 6 weeks did not differ between treatment groups.
CONCLUSIONS
In patients with C. albicans infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT00058682.
Topics: Anidulafungin; Antifungal Agents; Candida albicans; Candidiasis, Invasive; Echinocandins; Fluconazole; Humans; Multivariate Analysis; Survival Analysis; Treatment Outcome
PubMed: 21961941
DOI: 10.1186/1471-2334-11-261 -
Peptides Mar 2019Lipopeptide antibiotics have linear or cyclic structures with one or more hydrocarbon tails linked to the N-terminus of a short oligopeptide that may be chemically... (Review)
Review
Lipopeptide antibiotics have linear or cyclic structures with one or more hydrocarbon tails linked to the N-terminus of a short oligopeptide that may be chemically modified and/or contain unusual amino acid residues in their structures. They possess huge potential as pharmaceutical drugs and biocontrol agents, and ˜30 representative genera of fungi are known to produce them. Some chemically synthesised derivatives have already been developed into commercial products or subjected to clinical trials, including cilofungin, caspofungin, micafungin, anidulafungin, rezafungin, emodepside, fusafungine and destruxins. This review summarizes 200 fungi-derived compounds reported since 2000, including 95 cyclic depsipeptides, 67 peptaibiotics (including 35 peptaibols, eight lipoaminopeptides, and five lipopeptaibols), and 38 non-depsipeptide and non-peptaibiotic lipopeptides. Their sources, structural sequences, antibiotic activities (e.g. antibacterial, antifungal, antiviral, antimycobacterial, antimycoplasmal, antimalarial, antileishmanial, insecticidal, antitrypanosomal and nematicidal), structure-activity relationships, mechanisms of action, and specific relevance are discussed. These compounds have attracted considerable interest within the pharmaceutical and agrochemical industries.
Topics: Anidulafungin; Anti-Infective Agents; Caspofungin; Depsipeptides; Echinocandins; Fungal Proteins; Fungi; Lipopeptides; Micafungin; Structure-Activity Relationship
PubMed: 30738838
DOI: 10.1016/j.peptides.2019.02.002