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Antimicrobial Agents and Chemotherapy Jul 2018In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs....
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.
Topics: Adult; Aged; Anidulafungin; Antifungal Agents; Body Weight; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Obesity, Morbid; Young Adult
PubMed: 29712664
DOI: 10.1128/AAC.00063-18 -
Antimicrobial Agents and Chemotherapy Apr 2017CD101 is a novel semisynthetic echinocandin with antifungal activity against and spp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats,...
CD101 is a novel semisynthetic echinocandin with antifungal activity against and spp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats, dogs, cynomolgus monkeys, and chimpanzees are presented. CD101 consistently exhibited very low clearance, a modest volume of distribution at steady state (), and a long half-life () across all species tested. In mouse, rat, dog, cynomolgus monkey, and chimpanzee, CD101 clearance was 0.10, 0.47, 0.30, 0.41, and 0.06 ml/min/kg, respectively; was 206, 1,390, not determined, 597, and 400 ml/kg, respectively; and was 25, 39, 53, 40, and 81 h, respectively. CD101 demonstrated a lower clearance and correspondingly longer half-life than those of anidulafungin, with more pronounced differences in higher species (anidulafungin , 8 h in cynomolgus monkey and 30 h in chimpanzee). In the rat, tissue/plasma area under the concentration-time curve (AUC) ratios, in descending order, were 4.62 (kidney), 4.33 (lung), 4.14 (liver), 3.87 (spleen), 1.09 (heart), and 0.609 (brain), indicating that CD101 exposure relative to plasma levels was comparable for major organs (approximately 4-fold higher in tissue than in plasma), with the exception of the heart and brain. Biliary elimination of intact CD101 was the predominant route of excretion; the mean cumulative amount of CD101 excreted into the bile and feces over the course of 5 days accounted for 22.6% and 27.7% of the total dose administered, respectively. There were no sex differences in the pharmacokinetics of CD101. Given its low clearance, long half-life, and wide tissue distribution, CD101 once weekly is expected to provide appropriate systemic levels for treatment and prevention of invasive fungal infections.
Topics: Animals; Antifungal Agents; Area Under Curve; Bile; Brain Chemistry; Dogs; Echinocandins; Feces; Female; Half-Life; Hepatobiliary Elimination; Intestinal Elimination; Kidney; Liver; Lung; Macaca fascicularis; Male; Mice; Myocardium; Pan troglodytes; Rats; Spleen; Tissue Distribution
PubMed: 28137817
DOI: 10.1128/AAC.01626-16 -
Frontiers in Cellular and Infection... 2023Opportunistic fungal infections by species arise among cancer patients due to the weakened immune system following extensive chemotherapy. Prophylaxis with antifungal...
OBJECTIVE
Opportunistic fungal infections by species arise among cancer patients due to the weakened immune system following extensive chemotherapy. Prophylaxis with antifungal agents have developed the resistance of spp. to antifungals. Accurate identification of yeasts and susceptibility patterns are main concerns that can directly effect on the treatment of patients.
METHODS
Over a period of three years, 325 cancer patients suspected to infections were included in the current investigation. The clinical isolates were molecularly identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). All strains, were examined for susceptibility to the amphotericin B, itraconazole, fluconazole, and anidulafungin according to the CLSI M27 document.
RESULTS
Seventy-four cancer patients had infections (22.7%). was the most common species (83.8%). Antifungal susceptibility results indicated that 100% of the isolates were sensitive to amphotericin B; however, 17.6%, 9.4%, and 5.4% of clinical isolates were resistant to anidulafungin, fluconazole, and itraconazole, respectively.
CONCLUSION
The findings of the present work shows a warning increase in resistance to echinocandins. Since all fluconazole resistance isolates were obtained from candidemia, we recommend amphotericin B as the first line therapy for this potentially fatal infection.
Topics: Humans; Antifungal Agents; Fluconazole; Amphotericin B; Itraconazole; Anidulafungin; Microbial Sensitivity Tests; Candidiasis; Candida; Candidemia; Neoplasms; Drug Resistance, Fungal
PubMed: 37249981
DOI: 10.3389/fcimb.2023.1152552 -
Journal of Fungi (Basel, Switzerland) Mar 2022Susceptibility testing can yield variable results because it is method (commercial or reference), agent, and species dependent. Therefore, in order for results to be... (Review)
Review
Susceptibility testing can yield variable results because it is method (commercial or reference), agent, and species dependent. Therefore, in order for results to be clinically relevant, MICs (minimal inhibitory concentrations) or MECs (minimal effective concentrations) should help in selecting the best treatment agent in the clinical setting. This is accomplished by categorical endpoints, ideally, breakpoints (BPs) and/or ECVs/ECOFFs (epidemiological cutoff values). BPs and ECVs are available by the reference methods (CLSI [Clinical and Laboratory Standards Institute] and EUCAST [European Committee on Antifungal Susceptibility Testing]) for a variety of species/agent combinations. The lack of clinical data precludes establishment of BPs for susceptibility testing by the commercial methods and ECVs have only been calculated for the Etest and SYO assays. The goal of this review is to summarize the variety of commercial methods for antifungal susceptibility testing and the potential value of Etest and SYO ECVs for detecting mutants/non-wild type (NWT) isolates. Therefore, the literature search focused on publications where the commercial method, meaning MICs and ECVs, were reported for specific NWT isolates; genetic mutations have also been listed. For the Etest, the best performers recognizing the NWT were anidulafungin ECVs: 92% for the common species; 97% for and fluconazole ECVs, mostly for (45 NWT isolates). By the SYO, posaconazole ECVs recognized 93% of the and 96% of the NWT isolates and micafungin ECVs 94% (mostly and ). Smaller sets, some with clinical data, were also listed. These are promising results for the use of both commercial methods to identify antifungal resistance (NWT isolates). However, ECVs for other species and methods need to be defined, including the complex and emerging species.
PubMed: 35330310
DOI: 10.3390/jof8030309 -
Antimicrobial Agents and Chemotherapy May 2022Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main...
Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
Topics: Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation
PubMed: 35412354
DOI: 10.1128/aac.01725-21 -
Frontiers in Genetics 2022Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2...
Drug repositioning continues to be the most effective, practicable possibility to treat COVID-19 patients. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters target cells by binding to the ACE2 receptor its spike (S) glycoprotein. We used molecular docking-based virtual screening approaches to categorize potential antagonists, halting ACE2-spike interactions by utilizing 450 FDA-approved chemical compounds. Three drug candidates (i.e., anidulafungin, lopinavir, and indinavir) were selected, which show high binding affinity toward the ACE2 receptor. The conformational stability of selected docked complexes was analyzed through molecular dynamics (MD) simulations. The MD simulation trajectories were assessed and monitored for ACE2 deviation, residue fluctuation, the radius of gyration, solvent accessible surface area, and free energy landscapes. The inhibitory activities of the selected compounds were eventually tested using Vero and HEK-ACE2 cells. Interestingly, besides inhibiting SARS-CoV-2 S glycoprotein induced syncytia formation, anidulafungin and lopinavir also blocked S-pseudotyped particle entry into target cells. Altogether, anidulafungin and lopinavir are ranked the most effective among all the tested drugs against ACE2 receptor-S glycoprotein interaction. Based on these findings, we propose that anidulafungin is a novel potential drug targeting ACE2, which warrants further investigation for COVID-19 treatment.
PubMed: 35401674
DOI: 10.3389/fgene.2022.866474 -
Revista Do Instituto de Medicina... 2023Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive...
Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.
Topics: Humans; Candidemia; Anidulafungin; Brazil; Cost-Effectiveness Analysis; Candidiasis, Invasive
PubMed: 36722671
DOI: 10.1590/S1678-9946202365009 -
Antimicrobial Agents and Chemotherapy Nov 2023Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective...
Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m. A single 100-mg dose of anidulafungin was administered, followed by intensive sampling over 72 h. Population PK analysis was used to identify and compare covariates of anidulafungin PK parameters. Monte Carlo simulations were performed to compute the probability of target attainment (PTA) based on alternative dosing regimens. Participants (45% males) had a median (range) age of 45 (21-78) years and a median (range) weight of 82.7 (42.4-208.3) kg. The observed median (range) of AUC was 106.4 (51.9, 138.4) mg∙h/L. Lean body weight (LBW) and adjusted body weight (AdjBW) were more influential than weight as covariates of anidulafungin PK parameters. The conventional 100 mg daily maintenance is predicted to have a PTA below 90% in adults with an LBW > 55 kg or an AdjBW > 75 kg. A daily maintenance dose of 150-200 mg is predicted in these heavier adults. Anidulafungin AUC declines with increasing body size. A higher maintenance dose will increase the PTA compared to the current approach in obese patients.
Topics: Adult; Male; Humans; Adolescent; Young Adult; Middle Aged; Aged; Aged, 80 and over; Female; Anidulafungin; Antifungal Agents; Obesity; Body Weight; Candidiasis, Invasive; Body Size; Monte Carlo Method
PubMed: 37850741
DOI: 10.1128/aac.00820-23 -
Farmacia Hospitalaria : Organo Oficial... Sep 2019To determine by experimentation whether micafungin and anidulafungin possess physicochemical properties suitable for nebulization.
OBJECTIVE
To determine by experimentation whether micafungin and anidulafungin possess physicochemical properties suitable for nebulization.
METHOD
PH, osmolality, viscosity, density and chloride content were determined by pH monitoring, osmometry, viscometry, densitometry and potentiometry in two samples of different concentrations, 5 and 10 mg/mL each echinocandin. Results: The results obtained for micafungin solution were: pH 5.80 (0.14), osmolality 293.33 (1.53) mOsm/kg, chloride content 134.67 (0.58) mmol/L and density 1,009.4 (0,1) kg/m3; while for 10 mg/mL solution: osmolality 342.00 (1.00) mOsm/kg, chloride content 139.67 (0.58) mmol/L and density 1,014.5 (0.2) kg/m3. The results obtained for 5 mg/mL anidulafungin were: pH 4.22 (0.01), osmolality 464.67 (2.52) mOsm/kg, chloride content 137.00 (0.00) mmol/L and density 1,016.5 (0,2) kg/m3; while for 10 mg/mL solution: osmolality 656.33 (1.15) mOsm/kg, chloride content 132.00 (0.00) mmol/L and density 1,029.8 (0.4) kg/m3. Conclusions: PH, osmolality, chloride content and density values proved to be suitable for proper tolerability by nebulization.
Topics: Administration, Inhalation; Anidulafungin; Antifungal Agents; Chlorides; Humans; Hydrogen-Ion Concentration; Micafungin; Nebulizers and Vaporizers; Osmometry; Viscosity
PubMed: 31469629
DOI: 10.7399/fh.11226 -
Therapeutic Advances in Hematology Dec 2016Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and... (Review)
Review
Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, and species are involved. However, other non- molds are increasingly be identified in cases of documented IFDs. Important risk factors are long lasting granulocytopenia with neutrophil counts below 500/μl for more than 10 days or graft--host disease resulting from allogeneic stem-cell transplantation. For definite diagnosis of IFD, various diagnostic tools have to be applied, including conventional mycological culture and nonconventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. In the last few years, various laboratory methods, like the GM immunoassay ( GM EIA), 1,3-ß-D-glucan (BG) assay or polymerase chain reaction (PCR) techniques have been developed for better diagnosis. Since no single indirect test, including radiological methods, provides the definite diagnosis of an invasive fungal infection, the combination of different diagnostic procedures, which include microbiological cultures, histological, serological and molecular methods like PCR together with the pattern of clinical presentation, may currently be the best strategy for the prompt diagnosis, initiation and monitoring of IFDs. Early start of antifungal therapy is mandatory, but clinical diagnostics often do not provide clear evidence of IFD. Integrated care pathways have been proposed for management and therapy of IFDs with either the diagnostic driven strategy using the preemptive antifungal therapy as opposed to the clinical or empirical driven strategy using the 'traditional' empirical antifungal therapy. Antifungal agents preferentially used for systemic therapy of invasive fungal infections are amphotericin B preparations, fluconazole, voriconazole, posaconazole, caspofungin, anidulafungin, micafungin, and most recently isavuconazole. Clinical decision making must consider licensing status, local experience and availability, pharmacological and economic aspects.
PubMed: 27904738
DOI: 10.1177/2040620716656381