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Japanese Journal of Infectious Diseases May 2022Data on antifungal utilization trends are important for encouraging antifungal stewardship. This study explored the use of antifungal agents for systemic application and...
Data on antifungal utilization trends are important for encouraging antifungal stewardship. This study explored the use of antifungal agents for systemic application and the impact of reimbursement policy changes in Australia. We analyzed national data from the Australian Pharmaceutical Benefits Scheme (PBS) (2005-2016) and determined patterns of use over time and the impact of reimbursement decisions using an interrupted time-series model. From 2005-2016, there was an increase in the use of most antifungals, especially fluconazole, itraconazole, and posaconazole. Ketoconazole was the most commonly dispensed systemic antifungal agent (46.0%) prior to being removed from the PBS list and being replaced by fluconazole (69.8%). The PBS event "Fluconazole and itraconazole restrictions eased" led to the immediate increased use of fluconazole (0.025/1,000 per day), with both the highest rates and numerical increases attributed to obstetricians and gynecologists (1,969%; 1,851 dispensed prescriptions), as well as dermatologists (1,723%; 1,689 dispensed prescriptions) in 2010 and 2016. This is the first Australian national longitudinal estimate of systemic antifungal use. Our findings show an overall increase in the prescription of most antifungals during the investigated period, with reimbursement decisions impacting utilization. These data provide a baseline to inform the development of national antifungal guidelines and policies to encourage more targeted antifungal stewardship.
Topics: Antifungal Agents; Australia; Fluconazole; Itraconazole
PubMed: 34588371
DOI: 10.7883/yoken.JJID.2021.505 -
Clinical Microbiology Reviews Oct 2006Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance... (Review)
Review
Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion.
Topics: Antifungal Agents; Drug Therapy; Genetic Variation; Genome, Human; Humans; Intestinal Absorption; Pharmacogenetics; Polymorphism, Genetic; Treatment Outcome
PubMed: 17041143
DOI: 10.1128/CMR.00059-05 -
PloS One 2021To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This...
To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.
Topics: Amphotericin B; Antifungal Agents; Candidiasis; Drug Resistance, Multiple; Fluconazole; Humans; Microbial Sensitivity Tests; Mycoses; Thiazoles
PubMed: 34735467
DOI: 10.1371/journal.pone.0258465 -
Molecules (Basel, Switzerland) Oct 2023The aim of this study was to investigate the compounds in the hexane extract of (Savi.) Ten. and to determine the antibacterial, antifungal, and antioxidant activities...
The aim of this study was to investigate the compounds in the hexane extract of (Savi.) Ten. and to determine the antibacterial, antifungal, and antioxidant activities of different extracts. The (NGBB 7229) plant was collected from Turkey's Trakya region. Crude extracts were obtained using different solvents. The chemical composition of was determined in hexane extract using gas chromatography mass spectrometry. The antioxidant activities of the extracts were evaluated by Trolox equivalent antioxidant activity (TEAC), ferric-reducing antioxidant power (FRAP), cupric-reducing antioxidant capacity (CUPRAC), the β-carotene bleaching method, and the determination of superoxide anion scavenging activities. The antibacterial activity was tested against , , , , , and , whereas the antifungal activity was tested against , , and by applying microdilution methods. A total of 41 bioactive compounds were identified using the GC-MS library. Terpenoids were found to be dominant (52.89%), and lup-20(29)-en-3-yl-acetate and lupeol were the most abundant terpenoids. The highest total flavonoid content (25.73 mg catechin/g) and antioxidant capacity were found in the methanolic extract. The highest antibacterial activity was detected against in the ethyl acetate extract, and the highest antifungal activity was found against and in the hexane extract. The observed antioxidant characteristics of the extracts could be attributed to the presence of flavonoids. The high antifungal activity of the hexane extract against all fungal strains can be attributed to its constituents, i.e., terpenoids. This study discloses the potential antioxidant and antimicrobial activities, including some bioactive components, of and implies that holds possible applications in the food and pharmaceutical industries as an antioxidant, antibacterial, and antifungal agent.
Topics: Antioxidants; Antifungal Agents; Cirsium; Hexanes; Plant Extracts; Anti-Infective Agents; Anti-Bacterial Agents; Flavonoids; Terpenes; Candida albicans
PubMed: 37894654
DOI: 10.3390/molecules28207177 -
European Journal of Pharmaceutical... Aug 2021PC945 is a novel antifungal agent, optimised for inhaled treatment. In this study, the relationship between antifungal effects of PC945 and its exposure in the lungs was...
Relationship between anti-fungal effects and lung exposure of PC945, a novel inhaled antifungal agent, in Aspergillus fumigatus infected mice: Pulmonary PK-PD analysis of anti-fungal PC945.
PC945 is a novel antifungal agent, optimised for inhaled treatment. In this study, the relationship between antifungal effects of PC945 and its exposure in the lungs was investigated in Aspergillus fumigatus intranasally infected, temporarily neutropenic mice. Mice were given prophylactic PC945 intranasally once daily (0.56 µg/mouse) on either Day -7 to 0 (8 doses) or Day -1 to 0 (2 doses). Lung tissue, plasma and bronchoalveolar lavage (BAL) fluid were collected 24 or 72 h post A. fumigatus inoculation for biomarker and pharmacokinetic analyses. BAL cell pellets and supernatants were prepared separately by centrifugation. 8 prophylactic doses of PC945 were found to demonstrate significantly stronger antifungal effects (lung fungal burden and galactomannan (GM) in BAL and plasma) than prophylaxis with 2 doses. PC945 concentrations were below the limit of detection in plasma but readily measured in lung extracts. The concentrations were much higher after extended prophylaxis (709 and 312 ng/g of lung) than short prophylaxis (301 and 195 ng/g of lung) at 24 and 72 h post last dose, respectively, suggesting PC945 accumulation in whole lung after repeat dosing although it was likely to be a mixture of dissolved and undissolved PC945, meaning that the data should be interpreted with caution. Interestingly, low concentrations of PC945 were detected in BAL supernatant (6.6 and 1.9 ng/ml) whereas high levels of PC945 were measured in BAL cell pellets (626 and 406 ng/ml) at 24 and 72 h post last dose, respectively, in extended prophylaxis. In addition, the PC945 concentrations in BAL cells showed a statistically significant correlation with measured anti-fungal activities. These observations will be pursued, and it is intended that BAL cell concentrations of PC945 be measured in future clinical studies rather than standard measurement in BAL itself. Thus, PC945's profile makes it an attractive potential prophylactic agent for the prevention of pulmonary fungal infections.
Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Lung; Mannans; Mice
PubMed: 34015430
DOI: 10.1016/j.ejps.2021.105878 -
Current Medicinal Chemistry 2009There is an urgent need for new antifungal agents that are both effective and non-toxic in the therapy of systemic mycoses. The model nematode Caenorhabditis elegans has... (Review)
Review
There is an urgent need for new antifungal agents that are both effective and non-toxic in the therapy of systemic mycoses. The model nematode Caenorhabditis elegans has been used both to elucidate evolutionarily conserved components of host-pathogen interactions and to screen large chemical libraries for novel antimicrobial compounds. Here we review the use of C. elegans models in drug discovery and discuss caffeic acid phenethyl ester, a novel antifungal agent identified using an in vivo screening system. C. elegans bioassays allow high-throughput screens of chemical libraries in vivo. This whole-animal system may enable the identification of compounds that modulate immune responses or affect fungal virulence factors that are only expressed during infection. In addition, compounds can be simultaneously screened for antifungal efficacy and toxicity, which may overcome one of the main obstacles in current antimicrobial discovery. A pilot screen for antifungal compounds using this novel C. elegans system identified 15 compounds that prolonged survival of nematodes infected with the medically important human pathogen Candida albicans. One of these compounds, caffeic acid phenethyl ester (CAPE), was an effective antifungal agent in a murine model of systemic candidiasis and had in vitro activity against several fungal species. Interestingly, CAPE is a potent immunomodulator in mammals with several distinct mechanisms of action. The identification of CAPE in a C. elegans screen supports the hypothesis that this model can identify compounds with both antifungal and host immunomodulatory activity.
Topics: Animals; Antifungal Agents; Caenorhabditis elegans; Candida albicans; Drug Discovery; Models, Chemical
PubMed: 19442135
DOI: 10.2174/092986709788186237 -
European Journal of Medical Research Apr 2011Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity... (Review)
Review
Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity of the fungal cell wall. Currently there are three available agents: caspofungin, micafungin and anidulafungin. While the individual echinocandin antifungals have a different spectrum of licensed indications, basically all of them are available for the treatment of candidemia and invasive candidiasis. Antifungal treatment modalities basically include in therapy for suspected or proven infection and prophylaxis. All three drugs are comparatively expensive. Therefore a systematic review of the literature was performed to investigate the following aspects: * General aspects of cost-effectiveness in the treatment of invasive fungal infections * Cost-effectiveness of the treatment with the above-mentioned antifungals * Cost-effectiveness in two settings: therapy and prophylaxis - Early initiation of antifungal therapy, adjustment after availability of microbiological results, duration of therapy, success and occurrence of severe complications (e.g. renal failure) are the most important cost drivers in antifungal therapy. - Considering the specific antifungals, for caspofungin the best evidence for cost-effectiveness is found in treatment of invasive candidiasis and in empiric therapy of suspected infections. Favourable economic data are available for micafungin as a cost-effective alternative to LAmB for prophylaxis in patients with hematopoietic stem cell transplantation (HSCT). For anidulafungin, cost-effectiveness was demostrated in a pharmacoeconomic model. Net savings - yet not significant - were observed in a retrospective chart review of 234 patients. Generally, however, most analyses are still based on pharmacoeconomic modelling rather than direct analysis of trial data or real-life clinical populations. - As an overall conclusion, using caspofungin, micafungin, or anidulafungin is not more expensive than using other established therapies. Micafungin has proven to be cost-effective in prophylaxis if the local fungal epidemiology indicates a high level of resistance to fluconazole. Switch strategies involving early initiation of broadly active therapy with switch to cheaper alternatives according to microbiology results and clinical status and early initiation of an appropriate therapy have been proven to be cost-efficient independent of the antifungal agent.
Topics: Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Echinocandins; Humans; Lipopeptides; MEDLINE; Micafungin
PubMed: 21486732
DOI: 10.1186/2047-783x-16-4-180 -
Molecules (Basel, Switzerland) Apr 2023The loading of drugs or medicinally active compounds has recently been performed using metal-organic frameworks (MOFs), which are thought to be a new type of porous...
The loading of drugs or medicinally active compounds has recently been performed using metal-organic frameworks (MOFs), which are thought to be a new type of porous material in which organic ligands and metal ions can self-assemble to form a network structure. The quercetin (QRC) loading and biofilm application on a cyclodextrin-based metal-organic framework via a solvent diffusion approach is successfully accomplished in the current study. The antibacterial plant flavonoid QRC is loaded onto β-CD-K MOFs to create the composite containing inclusion complexes (ICs) and denoted as QRC:β-CD-K MOFs. The shifting in the chemical shift values of QRC in the MOFs may be the reason for the interaction of QRC with the β-CD-K MOFs. The binding energies and relative contents of MOFs are considerably changed after the formation of QRC:β-CD-K MOFs, suggesting that the interactions took place during the loading of QRC. Confocal laser scanning microscopy (CLSM) showed a reduction in the formation of biofilm. The results of the cell aggregation and hyphal growth are consistent with the antibiofilm activity that is found in the treatment group. Therefore, QRC:β-CD-K MOFs had no effect on the growth of planktonic cells while inhibiting the development of hyphae and biofilm in DAY185. This study creates new opportunities for supramolecular β-CD-based MOF development for use in biological research and pharmaceutical production.
Topics: Metal-Organic Frameworks; Antifungal Agents; Quercetin; beta-Cyclodextrins; Biofilms
PubMed: 37175077
DOI: 10.3390/molecules28093667 -
Plant Communications Feb 2024Rice blast is a devastating disease worldwide, threatening rice production and food security. The blast fungus Magnaporthe oryzae invades the host via the appressorium,...
Rice blast is a devastating disease worldwide, threatening rice production and food security. The blast fungus Magnaporthe oryzae invades the host via the appressorium, a specialized pressure-generating structure that generates enormous turgor pressure to penetrate the host cuticle. However, owing to ongoing evolution of fungicide resistance, it is vitally important to identify new targets and fungicides. Here, we show that Trs85, a subunit of the transport protein particle III complex, is essential for appressorium-mediated infection in M. oryzae. We explain how Trs85 regulates autophagy through Ypt1 (a small guanosine triphosphatase protein) in M. oryzae. We then identify a key conserved amphipathic α helix within Trs85 that is associated with pathogenicity of M. oryzae. Through computer-aided screening, we identify a lead compound, SP-141, that affects autophagy and the Trs85-Ypt1 interaction. SP-141 demonstrates a substantial capacity to effectively inhibit infection caused by the rice blast fungus while also exhibiting wide-ranging potential as an antifungal agent with broad-spectrum activity. Taken together, our data show that Trs85 is a potential new target and that SP-141 has potential for the control of rice blast. Our findings thus provide a novel strategy that may help in the fight against rice blast.
Topics: Antifungal Agents; Magnaporthe; Fungal Proteins; Ascomycota; Indoles; Pyridines
PubMed: 37771153
DOI: 10.1016/j.xplc.2023.100724 -
Microbiology Spectrum Jun 2023Botrytis cinerea, the causal agent of gray mold, is an important plant pathogen causing preharvest and postharvest diseases. Due to the extensive use of commercial...
Botrytis cinerea, the causal agent of gray mold, is an important plant pathogen causing preharvest and postharvest diseases. Due to the extensive use of commercial fungicides, fungicide-resistant strains have emerged. Natural compounds with antifungal properties are widely present in various kinds of organisms. Perillaldehyde (PA), derived from the plant species Perilla frutescens, is generally recognized as a potent antimicrobial substance and to be safe to humans and the environment. In this study, we demonstrated that PA could significantly inhibit the mycelial growth of B. cinerea and reduced its pathogenicity on tomato leaves. We also found that PA had a significant protective effect on tomato, grape, and strawberry. The antifungal mechanism of PA was investigated by measuring the reactive oxygen species (ROS) accumulation, the intracellular Ca level, the mitochondrial membrane potential, DNA fragmentation, and phosphatidylserine exposure. Further analyses revealed that PA promoted protein ubiquitination and induced autophagic activities and then triggered protein degradation. When the two metacaspase genes, and , were knocked out from , all mutants did not exhibit reduced sensitivity to PA. These findings demonstrated that PA could induce metacaspase-independent apoptosis in . Based on our results, we proposed that PA could be used as an effective control agent for gray mold management. Botrytis cinerea causes gray mold disease, is considered one of the most important dangerous pathogens worldwide, and leads to severe economic losses worldwide. Due to the lack of resistant varieties of , gray mold control has mainly relied on application of synthetic fungicides. However, long-term and extensive use of synthetic fungicides has increased fungicide resistance in and is harmful to humans and the environment. In this study, we found that perillaldehyde has a significant protective effect on tomato, grape, and strawberry. We further characterized the antifungal mechanism of PA on . Our results indicated that PA induced apoptosis that was independent of metacaspase function.
Topics: Humans; Antifungal Agents; Fungicides, Industrial; Plant Diseases; Apoptosis; Solanum lycopersicum
PubMed: 37191530
DOI: 10.1128/spectrum.00526-23