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Antimicrobial Agents and Chemotherapy Jun 2020Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin...
Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 μg/ml) and micafungin levels (<0.01 to 0.16 μg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 μg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 μg/g, respectively. Thus, MIC values of several pathogenic strains exceed concentrations in CSF and in brain.
Topics: Adult; Anidulafungin; Antifungal Agents; Cerebral Cortex; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests
PubMed: 32340985
DOI: 10.1128/AAC.00275-20 -
The Journal of Antimicrobial... Sep 2020The voriconazole and echinocandin combination has been found to be synergistic in vitro and in vivo against most Aspergillus fumigatus isolates, both with a WT azole...
BACKGROUND
The voriconazole and echinocandin combination has been found to be synergistic in vitro and in vivo against most Aspergillus fumigatus isolates, both with a WT azole phenotype and an azole-resistant phenotype. The interaction between isavuconazole and echinocandins is less well studied. This is especially true for azole-resistant isolates.
OBJECTIVES
We investigated the in vitro interaction between isavuconazole and anidulafungin for 30 A. fumigatus isolates including 18 azole-resistant isolates with various isavuconazole resistance phenotypes.
METHODS
The isavuconazole/anidulafungin interaction was studied by using an adapted EUCAST-based 2D (12 × 8) chequerboard broth microdilution colorimetric assay using XTT. The interaction was analysed by FIC index (FICi) analysis and Bliss independence (BI) interaction analysis.
RESULTS
Both the FICi analysis and the BI analysis showed synergistic interaction between isavuconazole and anidulafungin for the majority of WT and azole-resistant isolates. As we did not see significant beneficial effects of combination therapy in TR46/Y121F/T289A isolates at clinically achievable drug concentrations, it is unlikely that TR46/Y121F/T289A infections would benefit from isavuconazole and anidulafungin combination therapy.
CONCLUSIONS
In regions with high azole resistance rates this combination may benefit patients with WT disease, azole-resistant invasive aspergillosis and those with mixed azole-susceptible and azole-resistant infection, but may not be beneficial for aspergillosis due to isolates with high isavuconazole resistance, such as TR46/Y121F/T289A isolates.
Topics: Anidulafungin; Antifungal Agents; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Fungal Proteins; Humans; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles
PubMed: 32516368
DOI: 10.1093/jac/dkaa185 -
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 -
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 -
Microbiology Spectrum Dec 2022To understand the changes of resistance in clinically commonly encountered fungi, we used the Antimicrobial Testing Leadership and Surveillance (ATLAS) database to...
Susceptibilities of Worldwide Isolates of Intrapulmonary Species and Important Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017-2020.
To understand the changes of resistance in clinically commonly encountered fungi, we used the Antimicrobial Testing Leadership and Surveillance (ATLAS) database to explore antifungal susceptibilities against clinically important isolates of and species (collected from intrapulmonary and sterile body areas, respectively). We applied the CLSI antifungal 2020 and the EUCAST antifungal 2020 guidelines. From 2017 to 2020, isolates of intrapulmonary Aspergillus fumigatus ( = 660), Aspergillus niger ( = 107), Aspergillus flavus ( = 96), Aspergillus terreus ( = 40), and Aspergillus nidulans species complex ( = 26) and sterile site-originated isolates of Candida albicans ( = 1,810), Candida glabrata ( = 894), Candida krusei ( = 120), Candida dubliniensis ( = 107), Candida lusitaniae ( = 82), Candida guilliermondii ( = 28), and Candida auris ( = 7) were enrolled in this study. Using the EUCAST 2020 breakpoints, it was demonstrated that amphotericin B and posaconazole displayed poor susceptibility rates against A. fumigatus isolates (<50% and 18.9%, respectively). In contrast, isavuconazole and itraconazole showed high potency against most isolates (>92%). Most intrapulmonary isolates exhibited MICs of ≤0.06 μg/mL to anidulafungin. Furthermore, intrapulmonary A. fumigatus isolates collected from Italy and the United Kingdom exhibited lower susceptibility to isavuconazole (72.2% and 69%, respectively) than those in the remaining ATLAS participant countries (>85%). Higher isavuconazole MICs against C. auris and C. guilliermondii (1 and 4 μg/mL, respectively) were observed compared to the other five species. Despite the aforementioned MICs and susceptibilities against fungi, research needs to consider the pharmacokinetic (PK) profiles, pharmacodynamic (PD) parameters, and clinical treatment experience with antifungals against specific species. In addition to monitoring the antifungal susceptibilities of clinically important fungi, reviewing the PK/PD indices and the clinical therapy experience of antifungals under evaluation are important to guide an appropriate antifungal prescription. The efficacies of liposomal amphotericin B complex and anidulafungin for the treatment of pulmonary aspergillosis caused by different species need to be periodically evaluated in the future.
Topics: Anidulafungin; Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Microbial Sensitivity Tests
PubMed: 36314941
DOI: 10.1128/spectrum.02965-22 -
Pharmaceutics Apr 2023is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences...
is a multidrug-resistant pathogen against which echinocandins are the drug of choice. However, information on how the chitin synthase inhibitor nikkomycin Z influences the killing activities of echinocandins against is currently lacking. We determined the killing activities of anidulafungin and micafungin (0.25, 1, 8, 16 and 32 mg/L each) with and without nikkomycin Z (8 mg/L) against 15 isolates representing four clades (South Asian n = 5; East Asian n = 3; South African n = 3; South American n = 4, two of which were of environmental origin). Two and one isolates from the South Asian clade harbored mutations in the hot-spot 1 (S639Y and S639P) and 2 (R1354H) regions of the gene, respectively. The anidulafungin, micafungin and nikkomycin Z MIC ranges were 0.015-4, 0.03-4 and 2->16 mg/L, respectively. Anidulafungin and micafungin alone exerted weak fungistatic activity against wild-type isolates and the isolate with a mutation in the hot-spot 2 region of but was ineffective against the isolates with a mutation in the hot-spot 1 region. The nikkomycin Z killing curves were always similar to their respective controls. Twenty-two of sixty (36.7%) anidulafungin plus nikkomycin Z and twenty-four of sixty (40%) micafungin plus nikkomycin Z combinations produced at least 100-fold decreases in the CFUs (synergy), with a 41.7% and 20% fungicidal effect, respectively, against wild-type isolates. Antagonism was never observed. Similar results were found with the isolate with a mutation in hot-spot 2 of , but the combinations were ineffective against the two isolates with prominent mutations in hot-spot 1 of . The simultaneous inhibition of β-1,3 glucan and chitin synthases in wild-type isolates produced significantly greater killing rates than either drug alone. Further studies are warranted to verify the clinical efficacy of echinocandin plus nikkomycin Z combinations against echinocandin susceptible isolates.
PubMed: 37242607
DOI: 10.3390/pharmaceutics15051365 -
Microbial Genomics Jul 2023Invasive candida infections are significant infections that may occur in vulnerable patients with high rates of mortality or morbidity. Drug-resistance rates also appear...
Invasive candida infections are significant infections that may occur in vulnerable patients with high rates of mortality or morbidity. Drug-resistance rates also appear to be on the rise which further complicate treatment options and outcomes. The aims of this study were to describe the prevalence, molecular epidemiology, and genetic features of bloodstream isolates in a hospital setting. The resistance mechanisms towards the two most commonly administered antifungals, fluconazole and anidulafungin, were determined. Blood culture isolates between 1 January 2018 and 30 June 2021 positive for spp. were included. Susceptibility testing was performed using Etest. Whole-genome-sequencing was performed using Illumina NovaSeq with bioinformatics analysis performed. A total of 203 isolates were sequenced: 56 . 53 . , 44 . 36 . complex (consisting of and ), six . five . , and three . . A single cluster of azole-resistant and four clusters of isolates were observed, suggesting possible transmission occurring over several years. We found 11.3%, and 52.7 % of and , respectively, clustered with other isolates, suggesting exogenous sources may play a significant role of transmission, particularly for . The clusters spanned over several years suggesting the possibility of environmental reservoirs contributing to the spread. Limited clonality was seen for . Several sequence types appeared to be dominant for however the SNP differences varied widely, indicating absence of sustained transmission.
Topics: Humans; Tertiary Care Centers; Drug Resistance, Fungal; Antifungal Agents; Candidemia; Candida; Genomics
PubMed: 37440287
DOI: 10.1099/mgen.0.001047 -
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 -
Antimicrobial Agents and Chemotherapy Jun 2023Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high...
Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high proportion of C. auris isolates that display antifungal resistance severely limits treatment options. Combination therapies provide a possible strategy by which to enhance antifungal efficacy and prevent the emergence of further resistance. Therefore, we examined drug combinations using antifungals that are already in clinical use or are undergoing clinical trials. Using checkerboard assays, we screened combinations of 5-flucytosine and manogepix (the active form of the novel antifungal drug fosmanogepix) with anidulafungin, amphotericin B, or voriconazole against drug resistant and susceptible C. auris isolates from clades I and III. Fractional inhibitory concentration indices (FICI values) of 0.28 to 0.75 and 0.36 to 1.02 were observed for combinations of anidulafungin with manogepix or 5-flucytosine, respectively, indicating synergistic activity. The high potency of these anidulafungin combinations was confirmed using live-cell microfluidics-assisted imaging of the fungal growth. In summary, combinations of anidulafungin with manogepix or 5-flucytosine show great potential against both resistant and susceptible C. auris isolates.
Topics: Antifungal Agents; Anidulafungin; Flucytosine; Candida auris; Candida; Microbial Sensitivity Tests
PubMed: 37162367
DOI: 10.1128/aac.01645-22