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Vahedi-Shahandashti, Roya, and Cornelia Lass-Flörl. "Novel Antifungal Agents and Their Activity against Aspergillus Species." Journal of Fungi 6, no. 4 (October 9, 2020): 213. http://dx.doi.org/10.3390/jof6040213.
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There is a need for new antifungal agents, mainly due to increased incidence of invasive fungal infections (IFI), high frequency of associated morbidity and mortality and limitations of the current antifungal agents (e.g., toxicity, drug–drug interactions, and resistance). The clinically available antifungals for IFI are restricted to four main classes: polyenes, flucytosine, triazoles, and echinocandins. Several antifungals are hampered by multiple resistance mechanisms being present in fungi. Consequently, novel antifungal agents with new targets and modified chemical structures are required to combat fungal infections. This review will describe novel antifungals, with a focus on the Aspergillus species.
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Yoshida, Minoru. "Development of a Method of Measuring β-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections." International Journal of Molecular Sciences 22, no. 17 (August 27, 2021): 9265. http://dx.doi.org/10.3390/ijms22179265.
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Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. β-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia.
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Robenshtok, Eyal, Anat Gafter-Gvili, Elad Goldberg, Miriam Weinberger, Moshe Yeshurun, Leonard Leibovici, and Mical Paul. "Antifungal Prophylaxis in Cancer Patients After Chemotherapy or Hematopoietic Stem-Cell Transplantation: Systematic Review and Meta-Analysis." Journal of Clinical Oncology 25, no. 34 (December 1, 2007): 5471–89. http://dx.doi.org/10.1200/jco.2007.12.3851.
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Purpose To evaluate the effect of antifungal prophylaxis on all-cause mortality as primary outcome, invasive fungal infections (IFIs), and adverse events. Many studies have evaluated the role of antifungal prophylaxis in cancer patients, with inconsistent conclusions. Methods We performed a systematic review and meta-analysis of randomized, controlled trials comparing systemic antifungals with placebo, no intervention, or other antifungal agents for prophylaxis in cancer patients after chemotherapy. The Cochrane Library, MEDLINE, conference proceedings, and references were searched. Two reviewers independently appraised the quality of trials and extracted data. Results Sixty-four trials met inclusion criteria. Antifungal prophylaxis decreased all-cause mortality significantly at end of follow-up compared with placebo, no treatment, or nonsystemic antifungals (relative risk [RR], 0.84; 95% CI, 0.74 to 0.95). In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFI. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFI, whereas the difference in mortality was only borderline significant (RR, 0.88; 95% CI, 0.74 to 1.06). Prophylaxis with itraconazole suspension reduced documented IFI when compared with fluconazole, with no difference in survival, and at the cost of more adverse events. On the basis of two studies, posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFI when compared with fluconazole. Conclusion Antifungal prophylaxis decreases all-cause mortality significantly in patients after chemotherapy. Antifungal prophylaxis should be administered to patients undergoing allogeneic HSCT, and should probably be administered to high-risk acute leukemia patients.
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Shalini, Kumari, Nitin Kumar, Sushma Drabu, and Pramod Kumar Sharma. "Advances in synthetic approach to and antifungal activity of triazoles." Beilstein Journal of Organic Chemistry 7 (May 25, 2011): 668–77. http://dx.doi.org/10.3762/bjoc.7.79.
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Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded.
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Bugli, Francesca, Brunella Posteraro, Massimiliano Papi, Riccardo Torelli, Alessandro Maiorana, Francesco Paroni Sterbini, Patrizia Posteraro, Maurizio Sanguinetti, and Marco De Spirito. "In VitroInteraction between Alginate Lyase and Amphotericin B against Aspergillus fumigatus Biofilm Determined by Different Methods." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 21, 2012): 1275–82. http://dx.doi.org/10.1128/aac.01875-12.
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ABSTRACTAspergillus fumigatusbiofilms represent a problematic clinical entity, especially because of their recalcitrance to antifungal drugs, which poses a number of therapeutic implications for invasive aspergillosis, the most difficult-to-treatAspergillus-related disease. While the antibiofilm activities of amphotericin B (AMB) deoxycholate and its lipid formulations (e.g., liposomal AMB [LAMB]) are well documented, the effectiveness of these drugs in combination with nonantifungal agents is poorly understood. In the present study,in vitrointeractions between polyene antifungals (AMB and LAMB) and alginate lyase (AlgL), an enzyme degrading the polysaccharides produced as extracellular polymeric substances (EPSs) within the biofilm matrix, againstA. fumigatusbiofilms were evaluated by using the checkerboard microdilution and the time-kill assays. Furthermore, atomic force microscopy (AFM) was used to image and quantify the effects of AlgL-antifungal combinations on biofilm-growing hyphal cells. On the basis of fractional inhibitory concentration index values, synergy was found between both AMB formulations and AlgL, and this finding was also confirmed by the time-kill test. Finally, AFM analysis showed that whenA. fumigatusbiofilms were treated with AlgL or polyene alone, as well as with their combination, both a reduction of hyphal thicknesses and an increase of adhesive forces were observed compared to the findings for untreated controls, probably owing to the different action by the enzyme or the antifungal compounds. Interestingly, marked physical changes were noticed inA. fumigatusbiofilms exposed to the AlgL-antifungal combinations compared with the physical characteristics detected after exposure to the antifungals alone, indicating that AlgL may enhance the antibiofilm activity of both AMB and LAMB, perhaps by disrupting the hypha-embedding EPSs and thus facilitating the drugs to reach biofilm cells. Taken together, our results suggest that a combination of AlgL and a polyene antifungal may prove to be a new therapeutic strategy for invasive aspergillosis, while reinforcing the EPS as a valuable antibiofilm drug target.
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Edwards, Jessica A., Megan M. Kemski, and Chad A. Rappleye. "Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum." Antimicrobial Agents and Chemotherapy 57, no. 9 (July 1, 2013): 4349–59. http://dx.doi.org/10.1128/aac.00459-13.
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ABSTRACTAs eukaryotes, fungi possess relatively few molecules sufficiently unique from mammalian cell components to be used as drug targets. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g.,Histoplasma) are of particular concern, as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoringHistoplasmagrowth and employed it in a phenotypic screen of 3,600 commercially available compounds. Seven hit compounds that inhibitedHistoplasmayeast growth were identified. Compound 41F5 has fungistatic activity againstHistoplasmayeast at micromolar concentrations, with a 50% inhibitory concentration (IC50) of 0.87 μM, and has the greatest selectivity for yeast (at least 62-fold) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5-position. 41F5 inhibitsHistoplasmagrowth in liquid culture and similarly inhibits yeast cells within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells fromHistoplasma-induced macrophage death, making this aminothiazole hit compound an excellent candidate for development as an antifungal forHistoplasmainfections.
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Long, L., C. Hager, and M. Ghannoum. "Evaluation of the Efficacy of ME1111 in the Topical Treatment of Dermatophytosis in a Guinea Pig Model." Antimicrobial Agents and Chemotherapy 60, no. 4 (February 1, 2016): 2343–45. http://dx.doi.org/10.1128/aac.03073-15.
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ABSTRACTThe treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, thein vivoefficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused byTrichophyton mentagrophytesusing a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with aPvalue of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding.
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Soulaimani, Bouchra, Elena Varoni, Marcello Iriti, Nour-Eddine Mezrioui, Lahcen Hassani, and Abdelaziz Abbad. "Synergistic Anticandidal Effects of Six Essential Oils in Combination with Fluconazole or Amphotericin B against Four Clinically Isolated Candida Strains." Antibiotics 10, no. 9 (August 27, 2021): 1049. http://dx.doi.org/10.3390/antibiotics10091049.
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The development of opportunistic pathogenic Candida strains insensitive to several classes of antifungals has emerged as a major health care problem during the last years. Combinational therapy of natural products (e.g., essential oils, EOs) with conventional antifungals has been suggested as a promising alternative to overcome this medical problem. The present study investigates the potential antifungal activity of EOs extracted from some selected medicinal plants, alone and in combination with two common conventional antifungals (fluconazole and amphotericin B) against four clinical Candida isolates. MIC assays indicated that EOs induced strong anticandidal activities with MIC values ranging from 0.162 to 4.950 mg/mL. The combination of amphotericin B with Thymus leptobotrys, Origanum compactum and Artemisia herba alba EOs provided a synergistic effect against C. krusei only, with MIC gain of four-fold, and additive effect against remaining strains (MIC gain = two-fold). Interesting synergistic interactions were observed by combining all studied EOs with fluconazole, with reduction rates of their MICs ranging from 16 to 512-fold. This synergistic effect was very pronounced with the combination of T. leptobotrys EO and fluconazole. These findings indicate that studied EOs can be used as anti-candidals in combination with antifungals, particularly fluconazole, to counteract the emergence of resistant Candida spp.
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Silva, Laura Nunes, Thaís Pereira de Mello, Lívia de Souza Ramos, Marta Helena Branquinha, and André Luis Souza dos Santos. "New and Promising Chemotherapeutics for Emerging Infections Involving Drug-resistant Non-albicans Candida Species." Current Topics in Medicinal Chemistry 19, no. 28 (December 19, 2019): 2527–53. http://dx.doi.org/10.2174/1568026619666191025152412.
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Fungal infections are a veritable public health problem worldwide. The increasing number of patient populations at risk (e.g. transplanted individuals, cancer patients, and HIV-infected people), as well as the use of antifungal agents for prophylaxis in medicine, have favored the emergence of previously rare or newly identified fungal species. Indeed, novel antifungal resistance patterns have been observed, including environmental sources and the emergence of simultaneous resistance to different antifungal classes, especially in Candida spp., which are known for the multidrug-resistance (MDR) profile. In order to circumvent this alarming scenario, the international researchers’ community is engaged in discovering new, potent, and promising compounds to be used in a near future to treat resistant fungal infections in hospital settings on a global scale. In this context, many compounds with antifungal action from both natural and synthetic sources are currently under clinical development, including those that target either ergosterol or β(1,3)-D-glucan, presenting clear evidence of pharmacologic/pharmacokinetic advantages over currently available drugs against these two well-known fungal target structures. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598, the echinocandin CD101, and the glucan synthase inhibitor SCY-078. In this review, we compiled the most recent antifungal compounds that are currently in clinical trials of development and described the potential outcomes against emerging and rare Candida species, with a focus on C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. haemulonii, and C. rugosa. In addition to possibly overcoming the limitations of currently available antifungals, new investigational chemical agents that can enhance the classic antifungal activity, thereby reversing previously resistant phenotypes, were also highlighted. While novel and increasingly MDR non-albicans Candida species continue to emerge worldwide, novel strategies for rapid identification and treatment are needed to combat these life-threatening opportunistic fungal infections.
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T., Son Nguyen, Hoa M. Nguyen, Anh H. Nguyen, Tan D. Nguyen, and Binh T. T. Vo. "ID: 1046 Antifungal prophylaxis in hematopoietic stem cell transplantation recipients: drug use evaluation at Vietnam National Institute of Hemotology and Blood transfusion." Biomedical Research and Therapy 4, S (September 5, 2017): 126. http://dx.doi.org/10.15419/bmrat.v4is.322.
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*For correspondence:
tungson94@gmail.com
Competing interests: The authors declare that no competing interests exist.
Received: 2017-07-13
Accepted: 2017-08-04
Published: 2017-09-05
Copyright The Author(s) 2017. This article is published with open access by BioMedPress (BMP).
This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Background: Hematopoietic stem cell transplantation (HSCT) recipients were known to be in high risk of fungal infection. However, not all HSCT patients need antifungal prophylaxis. The aim of this study was to describe the characteristics of the use of antifungal prophylaxis in hematopoietic stem cell transplantation recipients and to evaluate the appropriateness of use.
Methods: In this observational prospective study, adult hematopoietic stem cell transplantation recipients without using antifungal treatment were recruited from start of stem cell transfusion in Vietnam National Institute of Hematology and Blood Transfusion (from April to December 2016) to end of antifungal prophylaxis or start of antifungal treatment. Appropriateness was defined based on National Comprehensive Cancer Network (NCCN) guidelines. Clinically significant Drug-drug interactions related to antifungals were defined based on Hansten and Horn’s Drug interaction and management 2013.
Results: 38 patients (mean age: 35.7 ± 12.0; 57.9% male) were admitted, included 21 autologous and 17 allogeneic HSCT recipients. After HSCT, 3 deaths, 1 to ICU, 1 IFI. Azoles prophylaxis was given to 100% of patients with median 17.5 days (13 - 47.5). Fluconazole was the most used antifungal agents, in 94.7% of patients and 74.5% of episodes. 10 patients had been changed antifungal agents. Indication was appropriate in 44.7%, 0% in autologous and 100% in allogeneic group. In patients with appropriate indication, choice of antifungal agents was 100% appropriate. 100% of patients used inappropriate dosage, mostly lower than recommeded dosage with azoles. 12.7% had appropriate prophylactic time. Potential drug-drug interactions were identified in 92.1% of patients. Most frequent interactions involved azoles-diazepam (80.4% of episodes) and azoles-immunosuppressive drugs (49% of episodes).
Conclusion: Our evaluation revealed a high proportion of inappropriate of antifungal prophylaxis. An antifungal stewardship programme is needed to strengthen rational use of antifungal in this specific circumstance.
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Van Arnam, Ethan B., Antonio C. Ruzzini, Clarissa S. Sit, Heidi Horn, Adrián A. Pinto-Tomás, Cameron R. Currie, and Jon Clardy. "Selvamicin, an atypical antifungal polyene from two alternative genomic contexts." Proceedings of the National Academy of Sciences 113, no. 46 (November 1, 2016): 12940–45. http://dx.doi.org/10.1073/pnas.1613285113.
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The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A1 and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin’s shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin’s biosynthesis including a subcluster of genes consistent with selvamicin’s 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.
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Alverson, Janet. "Efficacy of Antifungal Agents to Control Aspergillus niger Contamination in an Artificial Diet for Lygus hesperus Knight (Heteroptera: Miridae)." Journal of Entomological Science 38, no. 2 (April 1, 2003): 278–85. http://dx.doi.org/10.18474/0749-8004-38.2.278.
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The ability of four antifungal agents to suppress growth of Aspergillus niger (USDA, ARS Robert T. Gast Rearing Laboratory, Mississippi State, MS isolate) in an artificial diet for Lygus hesperus Knight (Heteroptera: Miridae) was tested by inoculating a standard number of conidial spores into artificial diet with different antifungal agents added and determining the amount of ensuing microbial growth. The effects on biological fitness of L. hesperus also were measured. Measured characteristics of biological fitness included total number of surviving adults, mean biomass (dry weight) accumulated per cage over the total treatment period, egg production, time to adult emergence, and time to the beginning of egg laying. Benzoic acid, high concentrations of formalin, and a high concentration of sorbic acid suppressed the growth of A. niger. Propionic acid and low concentrations of sorbic acid and formalin were less effective at suppressing A. niger growth. Biological fitness was negatively affected in insects reared on diets containing high levels of A. niger growth and in diets with high concentrations of formalin. This study demonstrates how the antifungals that are added to the artificial diet of L. hesperus to control contamination by A. niger must be chosen carefully with consideration not only of their effectiveness at controlling contamination, but also to the tolerance level of the insect to the chemical compound.
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Sardar, Asjad, Bijin Thajudeen, and Pradeep V. Kadambi. "Histoplasma Peritonitis: An Extremely Rare Complication of Peritoneal Dialysis." Case Reports in Nephrology 2018 (2018): 1–3. http://dx.doi.org/10.1155/2018/8015230.
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Bacterial peritonitis is a common complication of peritoneal dialysis, but fungal peritonitis is unusual and is mostly due to Candida species. Peritonitis due to Histoplasma capsulatum is rare and we report one such case. A 63-year-old female presented with progressively worsening abdominal pain, fever, and altered mental status. She had end-stage renal disease and had been on peritoneal dialysis for 4 years. She had abdominal tenderness without rebound or guarding. Laboratory studies and CT of abdomen were significant for leukocytosis and peritoneal membrane thickening, respectively. Peritoneal dialysis fluid study was consistent with peritonitis and culture of the fluid grew Histoplasma capsulatum. Treatment recommendations include removal of catheter and initiation of antifungal therapy. With the availability of newer antifungals, medical management without removal of PD catheter is possible, but at the same time if there is no response to treatment within a week, PD catheter should be removed promptly.
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Galsurker, Ortal, Sonia Diskin, Danielle Duanis-Assaf, Adi Doron-Faigenboim, Dalia Maurer, Oleg Feygenberg, and Noam Alkan. "Harvesting Mango Fruit with a Short Stem-End Altered Endophytic Microbiome and Reduce Stem-End Rot." Microorganisms 8, no. 4 (April 13, 2020): 558. http://dx.doi.org/10.3390/microorganisms8040558.
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Stem-end rot (SER) is a serious postharvest disease of mango fruit grown in semi-dry area. Pathogenic and non-pathogenic microorganisms endophytically colonize fruit stem-end. As fruit ripens, some pathogenic fungi switch from endophytic colonization to necrotrophic stage and cause SER. Various pre/post-treatments may alter the stem-end community and modify SER incidence. This study investigates the effects of harvesting mango with or without short stem-end on fruit antifungal and antioxidant activities, the endophytic microbiome, and SER during fruit storage. Our results show that harvesting mango with short stem significantly reduced SER during storage. At harvest, fruit harvested with or without stem exhibit a similar microorganisms community profile. However, after storage and shelf life, the community of fruit without stem shifted toward more SER-causing-pathogens, such as Lasiodiplodia, Dothiorella, and Alternaria, and separated from the community of fruit with stem. This change correlated to the high antifungal activity of stem extract that strongly inhibited both germination and growth of Lasiodiplodia theobromae and Alternaria alternata. Additionally, fruit that was harvested with stem displayed more antioxidant activity and less ROS. Altogether, these findings indicate that harvesting mango with short stem leads to higher antifungal and antioxidant activity, retaining a healthier microbial community and leading to reduced postharvest SER.
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Mathieu, Kra Adou Koffi, SIAKA Sohro, Ahon Gnamien Marcel, KASSI Amian Brise Benjamin, OUATTARA Sitapha, AW Sadat, COULIBALY Adama, SORO Yaya, and DJAMAN Allico Joseph. "Antifungal activity of Terminalia superba (combretaceae)." Journal of Experimental Biology and Agricultural Sciences 3, no. 2 (April 25, 2015): 162–73. http://dx.doi.org/10.18006/2015.3(2).162.173.
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Llop, C., I. Pujol, C. Aguilar, J. Sala, D. Riba, and J. Guarro. "Comparison of Three Methods of Determining MICs for Filamentous Fungi Using Different End Point Criteria and Incubation Periods." Antimicrobial Agents and Chemotherapy 44, no. 2 (February 1, 2000): 239–42. http://dx.doi.org/10.1128/aac.44.2.239-242.2000.
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ABSTRACT Three different methods were used to determine the in vitro activities of amphotericin B, ketoconazole, itraconazole, and flucytosine against 30 isolates of different genera of filamentous fungi. MICs were determined visually, with or without agitation, and spectrophotometrically by using a broth microdilution method. For amphotericin B, there was one end point reading criterion (the minimum concentration of antifungal that inhibited 100% of growth), but for azoles and flucytosine there were two (the minimum concentrations that inhibited 50 and 75% of fungal growth, respectively) after 48 and 72 h of incubation. All tests were performed in triplicate. An intraclass correlation coefficient (ICC) was used to evaluate the reproducibility of each of the methods and the correlation among them. The reproducibility of the three methods was very high (ICC of 0.808 to 0.992), particularly in the case of azoles and flucytosine. In general, the degree of reproducibility was highest for azoles and amphotericin B after 72 h of incubation and for flucytosine after 48 h of incubation. The degree of correlation among the three methods was very high (ICC of >0.98) with all of the antifungals under all the conditions tested. The end point reading criteria and the time of incubation affected neither the reproducibility of the methods nor their correlation, and their effect on MICs was statistically significant.
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Meletiadis, Joseph, Stephen Chanock, and Thomas J. Walsh. "Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy." Clinical Microbiology Reviews 19, no. 4 (October 2006): 763–87. http://dx.doi.org/10.1128/cmr.00059-05.
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SUMMARY 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.
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Huang, Xiaojun, Fengrong Wang, Yuhong Chen, Ting Liu, Jianxiang Wang, Jianda Hu, Jie Jin, et al. "A Multicenter, Open-Label Study of Posaconazole Oral Suspension in Treatment of Patients with Invasive Fungal Infection Refractory to or Intolerant of First-Line Therapy,." Blood 118, no. 21 (November 18, 2011): 3241. http://dx.doi.org/10.1182/blood.v118.21.3241.3241.
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Abstract Abstract 3241 Background Invasive fungal infection represents one major health threat for patients with a compromised immune system. Methods We performed a multicenter, open-label clinical study of posaconazole oral suspension in the treatment of 63 patients with invasive fungal infection that was refractory to or intolerant of first-line therapy. The primary efficacy end point was the cumulative response rate at the end of posaconazole treatment. The safety end points were adverse events (AEs), laboratory test results, and vital sign measurements, as well as patients' rate of withdrawal because of AEs or laboratory abnormalities. Results Of the 63 patients enrolled in the study, 62 (98.4%) were treated with study drug and included in the safety set. From those 62 patients, 59 patients entered the full analysis set for efficacy data assessment. A total of 47 patients were included in the per-protocol set. The cumulative clinical response rates at weeks 4, 8, and 12 of treatment were 69.49% (41/59, 95% confidence interval [CI]: 56.13–80.81), 62.71% (37/59, 95% CI: 49.15–74.96), and 64.41% (38/59, 95% CI: 50.87–76.45), respectively. Cumulative fungal pathogens eradication rates at week 4, week 8, and the end of treatment (week 12) were 47.06% (95% CI: 22.98–72.19), 47.06% (95% CI: 22.98–72.19), and 52.94% (95% CI: 27.81–77.02), respectively. At the end of treatment (week 12), 2 patients had died; the cumulative survival rate was 96.61% (95% CI: 88.29–99.59). The incidences of AEs, adverse reactions, and SAEs were 79.0%, 32.3%, and 8.1%, respectively. None of the serious adverse reactions were related to the study drug. Conclusions Posaconazole is effective in treating patients with refractory invasive fungal infection. As a novel broad-spectrum triazole antifungal with a good long-term safety profile, posaconazole can be used to treat patients with fungal infection relapse after antifungal treatment, patients with fungal infection resistant to routine antifungal treatment, patients with fungal infection intolerant of routine antifungal treatment due to side effects, and patients with organ dysfunction (e.g., renal dysfunction). (ClinicalTrials.gov number, NCT00811642) Disclosures: No relevant conflicts of interest to declare.
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Stergiopoulou, Theodouli, Joseph Meletiadis, Tin Sein, Paraskevi Papaioannidou, Ioannis Tsiouris, Emmanuel Roilides, and Thomas J. Walsh. "Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus." Antimicrobial Agents and Chemotherapy 52, no. 6 (February 25, 2008): 2196–204. http://dx.doi.org/10.1128/aac.00735-07.
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ABSTRACT Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 μg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis.
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Donnelly, J. Peter, and Johan Maertens. "The end of the road for empirical antifungal treatment?" Lancet Infectious Diseases 13, no. 6 (June 2013): 470–72. http://dx.doi.org/10.1016/s1473-3099(13)70112-9.
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Gupta, Aditya K., Jennifer E. Ryder, and Alayne R. Skinner. "Treatment of Onychomycosis: Pros and Cons of Antifungal Agents." Journal of Cutaneous Medicine and Surgery 8, no. 1 (January 2004): 25–30. http://dx.doi.org/10.1177/120347540400800107.
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Background: Antifungal agents are beneficial in the treatment of onychomycosis in the general population, as well as in children, the elderly, and immunocompromised individuals. Special patient populations can be more difficult to treat due to such factors as drug interactions with concomitant medications, adverse events, and poor compliance. In addition, there is limited information about the use of antifungal agents in special populations, e.g., children. Objective: The pros and cons of oral and topical antifungal agents are discussed, with focus on special patient populations. Methods: We searched MedLine (1966 to April 2003) for clinical studies evaluating the efficacy of oral and topical antifungal agents to treat onychomycosis. The key words used in conjunction with “onychomycosis” include: “terbinafine,” “itraconazole,” “fluconazole,” “amorolfine nail lacquer,” “ciclopirox nail lacquer,” “HIV,” “transplant patients,” “diabetes,” “children,” and “elderly.” Studies were excluded if published in a language other than English. Results: Studies have shown that antifungal agents can be of benefit in treating the elderly, children, and immunocompromised individuals (e.g., transplant patients, Down's patients, HIV patients, and diabetics) with onychomycosis. Conclusion: The treatment modality of onychomycosis in special patient populations should take into account the clinical presentation of the onychomycosis, the causative organism, patient and physician preference, the concomitant medications that the patient is on, and the potential for adverse events for that patient if antifungal therapy is undertaken.
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Busca, Alessandro, Anna Candoni, Livio Pagano, Francesco Scaglione, and Claudio Viscoli. "Prophylaxis and treatment of invasive fungal infections in hematological patients." Reviews in Health Care 3, no. 1S (October 29, 2012): 27. http://dx.doi.org/10.7175/rhc.43031s27-40.
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The evidence from the literature strongly support antifungal prophylaxis in high risk haematological patients, such as patients with AML during remission induction chemotherapy and alloHSCT patients. Current antifungal prophylaxis guidelines for high risk patients recommend azoles (fluconazole, posaconazole, voriconazole) and echinocandins (micafungin) with the strongest level of evidence. In terms of treatment, the choice between empiric therapy (or fever driven) and pre-emptive therapy (or diagnostic driven) is still debated. Not a single therapeutic strategy is appropriate in every patients, in particular empirical antifungal therapy may be recommended in patients at very high risk, while a pre-emptive approach may be advised for those at standard risk. In order to exploit the synergistic and/or additive effect of two antifungal drugs it’s possible to combine two agents that work with different mechanisms of action (e.g. echinocandins + azoles or polyenes). Once the treatment has been initiated we should consider the therapeutic drug monitoring (TDM) of the drugs, especially when the pharmacokinetic variability is high and the dose-concentration effect relationships is not predictable (e.g. for itraconazole, voriconazole and posaconazole).
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Busca, Alessandro, Anna Candoni, Livio Pagano, Francesco Scaglione, and Claudio Viscoli. "Prophylaxis and treatment of invasive fungal infections in hematological patients." Reviews in Health Care 3, no. 1S (October 29, 2012): 27–40. http://dx.doi.org/10.7175/rhc.v3i1s.430.
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The evidence from the literature strongly support antifungal prophylaxis in high risk haematological patients, such as patients with AML during remission induction chemotherapy and alloHSCT patients. Current antifungal prophylaxis guidelines for high risk patients recommend azoles (fluconazole, posaconazole, voriconazole) and echinocandins (micafungin) with the strongest level of evidence. In terms of treatment, the choice between empiric therapy (or fever driven) and pre-emptive therapy (or diagnostic driven) is still debated. Not a single therapeutic strategy is appropriate in every patients, in particular empirical antifungal therapy may be recommended in patients at very high risk, while a pre-emptive approach may be advised for those at standard risk. In order to exploit the synergistic and/or additive effect of two antifungal drugs it’s possible to combine two agents that work with different mechanisms of action (e.g. echinocandins + azoles or polyenes). Once the treatment has been initiated we should consider the therapeutic drug monitoring (TDM) of the drugs, especially when the pharmacokinetic variability is high and the dose-concentration effect relationships is not predictable (e.g. for itraconazole, voriconazole and posaconazole).
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Váradi, Györgyi, Gábor Tóth, and Gyula Batta. "Structure and Synthesis of Antifungal Disulfide β-Strand Proteins from Filamentous Fungi." Microorganisms 7, no. 1 (December 27, 2018): 5. http://dx.doi.org/10.3390/microorganisms7010005.
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The discovery and understanding of the mode of action of new antimicrobial agents is extremely urgent, since fungal infections cause 1.5 million deaths annually. Antifungal peptides and proteins represent a significant group of compounds that are able to kill pathogenic fungi. Based on phylogenetic analyses the ascomycetous, cysteine-rich antifungal proteins can be divided into three different groups: Penicillium chrysogenum antifungal protein (PAF), Neosartorya fischeri antifungal protein 2 (NFAP2) and “bubble-proteins” (BP) produced, for example, by P. brevicompactum. They all dominantly have β-strand secondary structures that are stabilized by several disulfide bonds. The PAF group (AFP antifungal protein from Aspergillus giganteus, PAF and PAFB from P. chrysogenum, Neosartorya fischeri antifungal protein (NFAP)) is the best characterized with their common β-barrel tertiary structure. These proteins and variants can efficiently be obtained either from fungi production or by recombinant expression. However, chemical synthesis may be a complementary aid for preparing unusual modifications, e.g., the incorporation of non-coded amino acids, fluorophores, or even unnatural disulfide bonds. Synthetic variants up to ca. 6–7 kDa can also be put to good use for corroborating structure determination. A short overview of the structural peculiarities of antifungal β-strand disulfide bridged proteins will be given. Here, we describe the structural propensities of some known antifungal proteins from filamentous fungi which can also be prepared with modern synthetic chemistry methods.
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DALIE, D. K. D., A. M. DESCHAMPS, V. ATANASOVA-PENICHON, and F. RICHARD-FORGET. "Potential of Pediococcus pentosaceus (L006) Isolated from Maize Leaf To Suppress Fumonisin-Producing Fungal Growth." Journal of Food Protection 73, no. 6 (June 1, 2010): 1129–37. http://dx.doi.org/10.4315/0362-028x-73.6.1129.
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The present study was aimed at characterizing the ability of lactic acid bacteria isolated from maize to repress the growth of fumonisin-producing fungi. A total of 67 isolates were screened for their antifungal activity against Fusarium proliferatum and Fusarium verticillioides by using the overlay method. The most efficient antifungal isolate was identified as Pediococcus pentosaceus (L006), on the basis of physiological and biochemical characterization and 16S rRNA gene sequencing. Production of the antifungal metabolite by this isolate commenced at the end of the growth exponential phase (8 h) and reached a maximum level after a long period of incubation (120 h). The antifungal metabolites produced were shown to be heat stable, resistant to proteolytic enzyme treatments, and pH dependent. The exact chemical nature of these substances remains to be clarified.
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Brayman, Timothy G., and John W. Wilks. "Sensitive Assay for Antifungal Activity of Glucan Synthase Inhibitors That Uses Germ Tube Formation in Candida albicans as an End Point." Antimicrobial Agents and Chemotherapy 47, no. 10 (October 2003): 3305–10. http://dx.doi.org/10.1128/aac.47.10.3305-3310.2003.
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ABSTRACT We implemented a simple, sensitive, objective, and rapid cellular assay to reveal the antifungal activity of a novel class of glucan synthase inhibitors. The assay, especially useful for early drug discovery, measures the transformation of Candida albicans from the yeast form to the hyphal form. Test compounds were ranked by potency (50% inhibitory concentration) and efficacy (percent inhibition of germ tube formation); the intra-assay coefficients of variation for these parameters were 17 and 5%, respectively. The germ tube formation assay proved useful for the early-stage antifungal characterization of a novel class of glucan synthase inhibitors discovered at Pharmacia. Drug concentrations required in this assay to inhibit germ tube formation were lower for 90% of the novel compounds than the concentrations required to determine MICs. The method may have utility for other mechanistic classes of antifungal compounds during the hit-to-lead transition of drug discovery.
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Dumitru, Raluca, Jacob M. Hornby, and Kenneth W. Nickerson. "Defined Anaerobic Growth Medium for Studying Candida albicans Basic Biology and Resistance to Eight Antifungal Drugs." Antimicrobial Agents and Chemotherapy 48, no. 7 (July 2004): 2350–54. http://dx.doi.org/10.1128/aac.48.7.2350-2354.2004.
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ABSTRACT The polymorphic fungus Candida albicans is one of the most versatile opportunistic pathogens in humans. Many organs of the human body are potential targets for infection by this pathogen, but infection is commonly localized in the gastrointestinal tract, an environment providing anaerobic growth conditions. We describe a chemically defined anaerobic growth medium for four strains of Candida albicans (A72, SC5314, MEN, and 10261). It is a defined liquid glucose-phosphate-proline growth medium supplemented with oleic acid, nicotinic acid, and ammonium chloride. The cells did not require or respond to added ergosterol. Oleic acid and nicotinic acid are growth factors which are required only for the anaerobic growth of C. albicans. An important technical feature of this study was the use of anaerobically grown inocula to study anaerobic growth. Anaerobically, the cells grew exclusively as mycelia at 25, 30, and 37°C. The doubling time at 30°C was ca. 20 h. The cells did not produce farnesol and did not respond to exogenous farnesol, and they were resistant to the highest tested levels of amphotericin B and four of the azole antifungals. We suggest that the anaerobic growth of C. albicans may contribute to the trailing end point phenomenon and the resistance of C. albicans biofilms to antifungal drugs.
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Cochrane, James R., Dong Hee Yoon, Christopher S. P. McErlean, and Katrina A. Jolliffe. "A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues." Beilstein Journal of Organic Chemistry 8 (August 21, 2012): 1344–51. http://dx.doi.org/10.3762/bjoc.8.154.
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The cyclic peptide core of the antifungal and antibiotic cyclic depsipeptide LI-F04a was synthesised by using a modified Yamaguchi macrolactonization approach. Alternative methods of macrolactonization (e.g., Corey–Nicolaou) resulted in significant epimerization of the C-terminal amino acid during the cyclization reaction. The D-stereochemistry of the alanine residue in the naturally occurring cyclic peptide may be required for the antifungal activity of this natural product.
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Kiran, Ismail, Semra Ilhan, Tamer Akar, Lacine Tur, and Erdinc Erol. "Synthesis and Evaluation of Demethoxyviridin Derivatives as Potential Antimicrobials." Zeitschrift für Naturforschung C 60, no. 9-10 (October 1, 2005): 686–92. http://dx.doi.org/10.1515/znc-2005-9-1005.
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Abstract The in vitro antibacterial and antifungal activities of demethoxyviridin and some synthetic analogues were evaluated by the agar diffusion method. The minimum inhibitory concentrations (MIC) of the active compounds were also determined by the agar dilution method. Demethoxyviridin (1) showed moderate antibacterial activity against most of the strains tested. 1α-Hydroxydemethoxyviridin (3) showed antibacterial activity and the most potent in vitro antifungal activity with MIC of 20 μg/ml (0.062 mm) against Aspergillus niger, A. fumigatus, A. flavus, A. parasiticus, Fusarium solani, F. graminarum, Geotrichum candidum whereas 5′-methylfuro-(4′,3′,2′-4,5,6)androst-5-ene-3,17-dione (7) exhibited very weak antifungal activity against Candida albicans only.
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Nizami, Sobia, Ioannis Zacharioudakis, Maria E. Aguero-Rosenfeld, and Henry J. Neumann. "250. Comparison of T2Candida Assay with Blood Culture, Candida Sepsis Score and Serum β-d-glucan in Diagnosis of Candidemia." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S140—S141. http://dx.doi.org/10.1093/ofid/ofz360.325.
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Abstract Background Although blood cultures are the clinical diagnostic standard for candidemia, their delay in results and low sensitivity has lead to increasing the use of alternate tests and diagnostic algorithms. The T2Candida magnetic resonance assay (T2C) results in a few hours, but concomitant cultures are also needed. We compared results from the T2C with β-d-glucan (BDG), blood cultures (BCx) and the Candida Sepsis Score (CSc) in diagnosis and management of candidemia. Methods This retrospective observational study included patients from July 2017 to December 2018 who had a T2C as well as BCx. Positive (+) and negative (–) results of BCx and BDG within 24 hours (24 h) of T2C were recorded, with clinical data to determine CSc at the time of T2C (recent surgery, severe sepsis, parenteral nutrition, multifocal candida colonization). Results There were 648 T2Cs done over the study period. Only the first +T2C for patients with multiple T2Cs on admission was included. There were 41 patients with +T2, in which 31 had a 24hBCx. Two patients were of pediatric age. There were 7 neutropenic, 1 post-transplant, and 27 intensive care (ICU) patients. Reasons for ordering T2C included sepsis and persistent fevers. In 18 (44%) patients, antifungals were given prior to the T2C. Eight among 31 24hBCx were positive for concordant Candida spp. (26%). Six of these 8 patients were on antifungal therapy when T2C was sent. Seventeen patients had a 24hBDG, with 7 positive (41%). Overall mean CSc in 27 ICU patients with +T2C was 2.2 ± 0.8, and 40% of adult non-neutropenic ICU patients had a CSc of 3 or above. A central line was present in 26 patients, and was removed in 16 after +T2. In 213 patients with −T2C who had 24hBCx, only 1 BCx was positive, from a PICC line in a 2-year-old patient. Seven of the 41 patients with +T2C were treated for deep-seated candidiasis with 6 weeks antifungal therapy or longer; others received 1 to 4 weeks. Thirteen patients died while on antifungal therapy. Conclusion T2Candida was used for diagnosis and management of candidemia in patients who had concomitant blood culture positive in 26%, β-d-glucan positive in 41%, and ICU Candida sepsis score 3 or above in 40% patients. It did not miss candidemia in adults, compared with blood culture within 24 hours. Positive T2Candida helped expedite source control e.g line removal. Disclosures All authors: No reported disclosures.
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Rossetto, André Luiz, Rosana Cé Bella Cruz, and Vidal Haddad Junior. "DOUBLE-BLIND STUDY WITH TOPICAL ISOCONAZOLE AND TERBINAFINE FOR THE TREATMENT OF ONE PATIENT WITH BILATERAL Tinea nigra plantaris AND SUGGESTIONS FOR NEW DIFFERENTIAL DIAGNOSIS." Revista do Instituto de Medicina Tropical de São Paulo 55, no. 2 (April 2013): 125–28. http://dx.doi.org/10.1590/s0036-46652013000200011.
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The authors report a case of bilateral Tinea nigra plantaris treated through a double-blind study with the topical antifungal agents Isoconazole and Terbinafine. The objective of the study was to clinically compare the efficacy of these two topical antifungal agents on days 10, 20 and 30 of the treatment. No significant clinical differences were found, as all the plantar lesions regressed completely by the end of the treatment. Our conclusion was that in the case reported, the topical antifungal agents Isoconazole and Terbinafine demonstrated identical efficacy as a clinical cure. We also suggest the inclusion of injuries caused by arthropods of the Diplopoda Class in the differential diagnosis of Tinea nigra plantaris, due to the persistent acral hyperpigmentation.
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Nowaczyk, Alicja, and Bożena Modzelewska-Banachiewicz. "QSAR studies of a number of triazole antifungal alcohols." Open Chemistry 8, no. 2 (April 1, 2010): 440–47. http://dx.doi.org/10.2478/s11532-009-0143-7.
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AbstractThe activity of fungicide agents containing a quinazolinone ring was described using the quantitative structure-activity relationship (QSAR) model by applying it to data taken from literature. The title compounds exhibit two important types of activity against certain fungal pathogens, i.e. activity against yeast and activity against filamentous fungi. A correlation between both antifungal activities (e.g. FA(yst) and FA(ff)) and physicochemical parameters such as the logarithm of the n-octanol/water partition coefficient (log P), the polarizability (P), the global minimum energy (TE), the energy difference between the frontier molecular orbital (DELH) and the molar refractivity (MR), was established using multiple linear regression. The molecular descriptors of the antifungal agents were obtained by quantum chemical calculations combined with molecular modeling calculations. Statistical analysis shows that the antifungal activity depends mainly on the calculated partition coefficients, log P, of the compounds. Bi-parametric models reveal that antifungal activity relates linearly to log P and P.
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Harousseau, J. L., A. W. Dekker, A. Stamatoullas-Bastard, A. Fassas, W. Linkesch, J. Gouveia, R. De Bock, et al. "Itraconazole Oral Solution for Primary Prophylaxis of Fungal Infections in Patients with Hematological Malignancy and Profound Neutropenia: a Randomized, Double-Blind, Double-Placebo, Multicenter Trial Comparing Itraconazole and Amphotericin B." Antimicrobial Agents and Chemotherapy 44, no. 7 (July 1, 2000): 1887–93. http://dx.doi.org/10.1128/aac.44.7.1887-1893.2000.
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ABSTRACT Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 × 109 neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%];P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.
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Liu, Yu, George Tortora, Maria E. Ryan, Hsi-Ming Lee, and Lorne M. Golub. "Potato Dextrose Agar Antifungal Susceptibility Testing for Yeasts and Molds: Evaluation of Phosphate Effect on Antifungal Activity of CMT-3." Antimicrobial Agents and Chemotherapy 46, no. 5 (May 2002): 1455–61. http://dx.doi.org/10.1128/aac.46.5.1455-1461.2002.
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ABSTRACT The broth macrodilution method (BMM) for antifungal susceptibility testing, approved by the National Committee for Clinical Laboratory Standards (NCCLS), was found to have deficiencies in testing of the antifungal activity of a new type of antifungal agent, a nonantibacterial chemically modified tetracycline (CMT-3). The high content of phosphate in the medium was found to greatly increase the MICs of CMT-3. To avoid the interference of phosphate in the test, a new method using potato dextrose agar (PDA) as a culture medium was developed. Eight strains of fungi, including five American Type Culture Collection strains and three clinical isolates, were used to determine the MICs of amphotericin B and itraconazole with both the BMM and the PDA methods. The MICs of the two antifungal agents determined with the PDA method showed 99% agreement with those determined with the BMM method within 1 log2 dilution. Similarly, the overall reproducibility of the MICs with the PDA method was above 97%. Three other antifungal agents, fluconazole, ketoconazole, and CMT-3, were also tested in parallel against yeasts and molds with both the BMM and the PDA methods. The MICs of fluconazole and ketoconazole determined with the PDA method showed 100% agreement within 1 log2 dilution of those obtained with the BMM method. However, the MICs of CMT-3 determined with the BMM method were as high as 128 times those determined with the PDA method. The effect of phosphate on the antifungal activity of CMT-3 was evaluated by adding Na2HPO4 to PDA in the new method. It was found that the MIC of CMT-3 against a Penicillium sp. increased from 0.5 μg/ml (control) to 2.0 μg/ml when the added phosphate was used at a concentration of 0.8 mg/ml, indicating a strong interference of Na2HPO4 with the antifungal activity of CMT-3. Except for fluconazole, all the other antifungal agents demonstrated clear end points among the yeasts and molds tested. Nevertheless, with its high reproducibility, good agreement with NCCLS proposed MIC ranges, and lack of interference of phosphate, the PDA method shows promise as a useful assay for antifungal susceptibility testing and screening for new antifungal agents, especially for drugs that may be affected by high (supraphysiologic) phosphate concentrations.
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Huber, Anna, Hannah Lerchster, and Florentine Marx. "Nutrient Excess Triggers the Expression of the Penicillium chrysogenum Antifungal Protein PAFB." Microorganisms 7, no. 12 (December 4, 2019): 654. http://dx.doi.org/10.3390/microorganisms7120654.
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Nutrient limitation and nonfavorable growth conditions have been suggested to be major triggers for the expression of small, cysteine-rich antimicrobial proteins (AMPs) of fungal origin, e.g., the Penicillium chrysogenum antifungal protein (PAF), the Aspergillus giganteus antifungal protein (AFP), the Aspergillus niger antifungal protein (AnAFP). Therefore, these AMPs have been considered to be fungal secondary metabolite products. In contrast, the present study revealed that the expression of the PAF-related AMP P. chrysogenum antifungal protein B (PAFB) is strongly induced under nutrient excess during the logarithmic growth phase, whereas PAFB remained under the detection level in the supernatant of cultures grown under nutrient limitation. The efficiency of the pafB-promoter to induce PAFB expression was compared with that of two P. chrysogenum promoters that are well established for recombinant protein production: the paf-promoter and the xylose-inducible promoter of the xylanase gene, xylP. The inducibility of the pafB-promoter was superior to that of the xylP-promoter yielding comparable PAFB amounts as under the regulation of the paf-promoter. We conclude that (i) differences in the expression regulation of AMPs suggest distinct functional roles in the producer beyond their antifungal activity; and (ii) the pafB-promoter is a promising tool for recombinant protein production in P. chrysogenum, as it guarantees strong gene expression with the advantage of inducibility.
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Marr, Kieren A., Tige R. Rustad, John H. Rex, and Theodore C. White. "The Trailing End Point Phenotype in Antifungal Susceptibility Testing Is pH Dependent." Antimicrobial Agents and Chemotherapy 43, no. 6 (June 1, 1999): 1383–86. http://dx.doi.org/10.1128/aac.43.6.1383.
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ABSTRACT The interpretation of end points in azole antifungal drug susceptibility testing is problematic, in part due to incomplete growth inhibition of Candida species. Such trailing growth can cause the MICs of fluconazole for some isolates to be low (<1 μg/ml) after 24 h of growth but much higher (>64 μg/ml) after 48 h. Isolates having this type of growth have been described as having a low-high phenotype. Although these isolates would be considered resistant by current National Committee of Clinical Laboratory Standards definitions, growing evidence suggests that they are susceptible in vivo. To further characterize these isolates in vitro, microdilution susceptibility testing comparing the complex defined medium RPMI 1640 to a defined minimal medium (yeast nitrogen broth) was performed. Isolates having trailing growth in MOPS (morpholinepropanesulfonic acid)-buffered RPMI 1640 (pH 7.0) were found to have clear end points in the minimal medium at its native pH of 4.5. The pH of the medium influenced the low-high phenotype, as these same isolates trailed in minimal medium adjusted to a pH of ≥6.0 but did not trail in RPMI 1640 adjusted to a pH of ≤5.0. This pH effect was independent of the medium buffering capacity, as trailing was decreased in both minimal medium and RPMI 1640 (pH 4.5) buffered in citrate. Adjustment in the pH of MOPS-buffered RPMI 1640 reduced trailing in multiple strains of Candida albicans without affecting the MICs for isolates having known susceptible (low-low) and resistant (high-high) phenotypes. Adjustment of the medium pH could be considered to eliminate trailing in azole drug susceptibility testing.
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Policar, T., J. Smyth, M. Flanigan, A. Kouba, and P. Kozák. "Sodium chloride as effective antifungal treatment for artificial egg incubation inAustropotamobius pallipes." Knowledge and Management of Aquatic Ecosystems, no. 401 (2011): 13. http://dx.doi.org/10.1051/kmae/2011027.
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Chen, Yi-Chan, Ting-Shuo Huang, Yu-Chao Wang, Chih-Hsien Cheng, Chen-Fang Lee, Ting-Jun Wu, Hong-Shiue Chou, Kun-Ming Chan, Wei-Chen Lee, and Ruey-Shyang Soong. "Effect of Prophylactic Antifungal Protocols on the Prognosis of Liver Transplantation: A Propensity Score Matching and Multistate Model Approach." BioMed Research International 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/6212503.
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Background. Whether routine antifungal prophylaxis decreases posttransplantation fungal infections in patients receiving orthotopic liver transplantation (OLT) remains unclear. This study aimed to determine the effectiveness of antifungal prophylaxis for patients receiving OLT.Patients and Methods. This is a retrospective analysis of a database at Chang Gung Memorial Hospital. We have been administering routine antibiotic and prophylactic antifungal regimens to recipients with high model for end-stage liver disease scores (>20) since 2009. After propensity score matching, 402 patients were enrolled. We conducted a multistate model to analyze the cumulative hazards, probability of fungal infections, and risk factors.Results. The cumulative hazards and transition probability of “transplantation to fungal infection” were lower in the prophylaxis group. The incidence rate of fungal infection after OLT decreased from 18.9% to 11.4% (p=0.052); overall mortality improved from 40.8% to 23.4% (p<0.001). In the “transplantation to fungal infection” transition, prophylaxis was significantly associated with reduced hazards for fungal infection (hazard ratio: 0.57, 95% confidence interval: 0.34–0.96,p=0.033). Massive ascites, cadaver transplantation, and older age were significantly associated with higher risks for mortality.Conclusion. Prophylactic antifungal regimens in high-risk recipients might decrease the incidence of posttransplant fungal infections.
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Dannaoui, Eric, and Ana Espinel-Ingroff. "Antifungal Susceptibly Testing by Concentration Gradient Strip Etest Method for Fungal Isolates: A Review." Journal of Fungi 5, no. 4 (November 22, 2019): 108. http://dx.doi.org/10.3390/jof5040108.
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Antifungal susceptibility testing is an important tool for managing patients with invasive fungal infections, as well as for epidemiological surveillance of emerging resistance. For routine testing in clinical microbiology laboratories, ready-to-use commercial methods are more practical than homemade reference techniques. Among commercially available methods, the concentration gradient Etest strip technique is widely used. It combines an agar-based diffusion method with a dilution method that determinates a minimal inhibitory concentration (MIC) in µg/mL. Many studies have evaluated the agreement between the gradient strip method and the reference methods for both yeasts and filamentous fungi. This agreement has been variable depending on the antifungal, the species, and the incubation time. It has also been shown that the gradient strip method could be a valuable alternative for detection of emerging resistance (non-wild-type isolates) as Etest epidemiological cutoff values have been recently defined for several drug-species combinations. Furthermore, the Etest could be useful for direct antifungal susceptibility testing on blood samples and basic research studies (e.g., the evaluation of the in vitro activity of antifungal combinations). This review summarizes the available data on the performance and potential use of the gradient strip method.
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Neyra, Karyna, and Kyle Brizendine. "Invasive Mold Infections (IMI) among Liver Transplant Recipients (LTR): Is It Time to Reconsider the Risk Factors that Determine Antifungal Prophylaxis?" Open Forum Infectious Diseases 4, suppl_1 (2017): S78. http://dx.doi.org/10.1093/ofid/ofx163.017.
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Abstract Background IMI have high mortality among LTR. Prevention is critical. Data supporting guideline-recommended three-tiered approach to antifungal prophylaxis based on risk for IMI are lacking. Methods Retrospective study of 534 adult LTR at the Cleveland Clinic (CCF) August 2010–December 2014. We analyzed the association between IMI and risk factors: retransplantation, hemodialysis, reoperation, and fulminant hepatic failure. Model of end-stage liver disease (MELD) was evaluated as novel risk factor. We compared the incidence of IMI among three subgroups: no antifungal prophylaxis, prophylaxis against yeast alone, and prophylaxis against yeast and mold. Results Mean age was 56 ± 11 years. 68% were male (n = 364). The most common underlying diseases were hepatitis C virus (32%), hepatocellular carcinoma (28%), alcoholic cirrhosis (19%), and nonalcoholic steatohepatitis (19%). The overall incidence of IMI was 0.9% (n = 5). The incidence of IMI among LTR with (n = 128) and without (n = 406) risk factors was 0.78 and 0.98%, respectively (see Figure). Table 1 details the risk factors and outcomes by subgroups. Only one patient with IMI had a risk factor for mold (reoperation). The other four had none. Incidence of IMI among LTR who did not receive antifungal prophylaxis was 1 and 0% in those who received yeast or mold prophylaxis. There was no association between MELD and IMI. Conclusion Risk factors and MELD did not predict IMI. Because risks are used to recommend mold-active prophylaxis, antifungal agent overuse may be a concern. Additional studies are needed to reconsider risk factors so that transplant providers may target antifungal agents appropriately, practice antifungal stewardship and improve outcomes. Disclosures All authors: No reported disclosures.
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Mane, Pratibha M., and Y. Hyma Pratyusha. "Oral candidiasis: Species identification and their antifungal susceptibility pattern in cancer patients receiving radiation therapy." Journal of Radiotherapy in Practice 12, no. 2 (February 13, 2012): 100–104. http://dx.doi.org/10.1017/s1460396911000446.
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AbstractIntroduction:Radiotherapy-induced hyposalivation encourages oralCandidacolonization that often leads to oral/pharyngeal candidiasis. The objective of this study was to identify theCandidaspecies in lesions of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck cancers and to find out antifungal susceptibility pattern.Material and methods:Swabs were collected from 60 patients who developed lesions suggestive of oral candidiasis at the end of 1st week of radiation therapy. Antifungal susceptibility of each of the isolated species was done using disc diffusion method following CLSI guidelines.Results: Candidawas isolated in 13 cases.C.albicans(7) was the most predominant species; a small number of other species have also been identified. Few strains (3) ofCandidashowed variable resistance to the commonly used antifungal drugs.Discussion:The colonization ofCandidamay lead to development of infections with drug-resistant strains, and hence the patients receiving radiation for head and neck cancers should undergo microbiological study for oral candidiasis.
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Stefańska, Joanna, Anna Bielenica, Marta Struga, Stafan Tyski, Jerzy Kossakowski, Roberta Loddo, Cristina Ibba, David Collu, Esther Marongiu, and Paolo Colla. "Biological evaluation of 10-(diphenylmethylene)- 4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives." Open Life Sciences 4, no. 3 (September 1, 2009): 362–68. http://dx.doi.org/10.2478/s11535-009-0015-3.
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AbstractAntibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC’s for the most active agents were determined. Title compounds were also evaluated in vitro against representatives of different virus classes. Most of the tested compounds exhibit activity against CVB-2 virus.
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Gale, Andrew N., Rima M. Sakhawala, Anton Levitan, Roded Sharan, Judith Berman, Winston Timp, and Kyle W. Cunningham. "Identification of Essential Genes and Fluconazole Susceptibility Genes in Candida glabrata by Profiling Hermes Transposon Insertions." G3: Genes|Genomes|Genetics 10, no. 10 (August 20, 2020): 3859–70. http://dx.doi.org/10.1534/g3.120.401595.
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Within the budding yeasts, the opportunistic pathogen Candida glabrata and other members of the Nakaseomyces clade have developed virulence traits independently from C. albicans and C. auris. To begin exploring the genetic basis of C. glabrata virulence and its innate resistance to antifungals, we launched the Hermes transposon from a plasmid and sequenced more than 500,000 different semi-random insertions throughout the genome. With machine learning, we identified 1278 protein-encoding genes (25% of total) that could not tolerate transposon insertions and are likely essential for C. glabrata fitness in vitro. Interestingly, genes involved in mRNA splicing were less likely to be essential in C. glabrata than their orthologs in S. cerevisiae, whereas the opposite is true for genes involved in kinetochore function and chromosome segregation. When a pool of insertion mutants was challenged with the first-line antifungal fluconazole, insertions in several known resistance genes (e.g., PDR1, CDR1, PDR16, PDR17, UPC2A, DAP1, STV1) and 15 additional genes (including KGD1, KGD2, YHR045W) became hypersensitive to fluconazole. Insertions in 200 other genes conferred significant resistance to fluconazole, two-thirds of which function in mitochondria and likely down-regulate Pdr1 expression or function. Knockout mutants of KGD2 and IDH2, which consume and generate alpha-ketoglutarate in mitochondria, exhibited increased and decreased resistance to fluconazole through a process that depended on Pdr1. These findings establish the utility of transposon insertion profiling in forward genetic investigations of this important pathogen of humans.
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Gutmann, Dennis, Jan Felix Kersten, Philippe Schafhausen, Tim H. Brummendorf, Martin Trepel, Carsten Bokemeyer, and Jens Panse. "Empirical Vs. Prophylactic Antifungal Strategies: Comparison of Effectiveness In High Risk AML Patients at a Tertiary Cancer Center." Blood 116, no. 21 (November 19, 2010): 1729. http://dx.doi.org/10.1182/blood.v116.21.1729.1729.
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Abstract Abstract 1729 Objectives: Invasive fungal infections (IFI) remain a major threat for patients with acute myelogenious leukemia (AML). Since the publication of two landmark studies, which demonstrated a reduction in morbidity and mortality from IFI in high risk patients through prophylaxis with posaconazole, guidelines have recommend routine prophylaxis with posaconazole during induction chemotherapy. However, prompt empirical or pre-emptive therapy strategies are still commonly used alternatives. Real life data about posaconazole prophylaxis are scarce and potential overtreatment, increasing costs and development of resistant fungi are of concern. We therefore compared effectiveness of empirical and prophylactic antifungal strategies at a tertiary cancer center during a phase of intensive building (re-) construction Methods: 104 patients (pts.) with AML treated between January 2005 and February 2009 were retrospectively evaluated. Each induction chemotherapy or consolidation therapy with neutropenia >=10 days was counted as an episode (n=222). Patients were stratified according to their antifungal approach: primary prophylaxis (n=35, 51 episodes; group 1), empirical therapy (n=63, 111 indices; group 2), secondary prophylaxis (n=41, 60 episodes; group 3, which comprised of patients from groups 1 and 2). Group 1 received posaconazole 3 × 200 mg p.o.; group 2 received topical polyene prophylaxis and empirical treatment with voriconazole or fluconazole. Patients in group 3 received either voriconazole, posaconazole, fluconazole or intraconazole. Results: Demographics, AML subtypes, co-morbidities and neutropenic days (median = 13) were comparable in all three groups; no patient received G-CSF support. Logistic regression analysis revealed days of neutropenia, performance status, use of antibiotics and secondary AML as risk factors for development of IFI, while primary prophylaxis reduced the risk for possible/probable/proven IFI by 86,7% compared to empirical therapy (p=0.001). Incidences of probable/proven IFI were 3% in group 1, 29% in group 2 and 7% in group 3 (p=0.001) and 17%, 69% and 37% (p<0.001) when possible IFIs were included. Mortality during observation period was similar (4%, 6,4%, 7%, NS). Also similar were isolated pathogens, additional antifungals, change of antibiotics, days at intensive care unit (ICU). Bacterial infections were similiar in all groups except for pneumonia and GI-tract infections being significantly higher in pts with empirical antifungal therapy. Side effects were also slightly higher in this group (8% vs 2% and 5%, NS). Days of hospitalization, antifungal, antibiotic, and antiviral costs were comparable, while imaging costs were significantly higher in group 2 (p=0.006). Conclusion: Posaconazole prophylaxis significantly reduces incidences of IFI in high risk AML patients and leads to a reduction of costs for imaging studies, with a minimal overall reduction of costs for inpatients. Additionally, infectious complications such as pneumonia and GI-tract infections are also reduced, while mortality rates, days of hospitalization, anti-infective use or duration are not reduced. Accordingly, in areas/surroundings with high rates of fungal infections (e.g. due to intensive building (re-)construction), primary prophylaxis with posaconazole is recommended. Disclosures: Brummendorf: Pfizer: Membership on an entity's Board of Directors or advisory committees. Panse:Gilead: Honoraria; Schering-Plough: Honoraria; MSD: Travel Grant.
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Martin, Žabka, and Pavela Roman. "Effectiveness of environmentally safe food additives and food supplements in an in vitro growth inhibition of significant Fusarium, Aspergillus and Penicillium species." Plant Protection Science 54, No. 3 (May 15, 2018): 163–73. http://dx.doi.org/10.17221/86/2017-pps.
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We tested 38 legislatively recognised substances such as food additives and supplements for antifungal efficacy, with the aim of providing an alternative to synthetic conventional fungicides. These compounds were tested against 9 significant pathogenic fungal species belonging to the significant genera Fusarium, Penicillium, and Aspergillus. Of these compounds, 6 are proposed as potential candidates to provide a complementary alternative to conventional fungicides. Natamycin provided extreme efficacy expressed as MIC50 (5–31 µg/ml), followed by BHA and then BHT, CaNa2EDTA, PABA, and chitosan expressed as MIC50 (0.7–1.9 mg/ml). Safety and antifungal activity were discussed in terms of the mode of action and molecular structure, as well as in terms of potential practical use and legislative requirements for the introduction into practice. We presume that food additives and food supplements are definitely a great source of antifungal compounds. In developed areas of the world (e.g. in the EU), they could represent legislatively recognised compounds, so-called basic substances.
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Velasco-de Andrés, María, Cristina Català, Sergi Casadó-Llombart, Mario Martínez-Florensa, Inês Simões, Joaquín García-Luna, Gustavo Mourglia-Ettlin, Óscar Zaragoza, Esther Carreras, and Francisco Lozano. "The Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal Infection." Antimicrobial Agents and Chemotherapy 65, no. 1 (October 12, 2020): e01103-20. http://dx.doi.org/10.1128/aac.01103-20.
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ABSTRACTInvasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern recognition receptors (e.g., Toll-like receptors, C-type lectins, or scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a nonredundant component of the antifungal host immune response that binds to fungal β-glucans. Antifungal properties of the soluble ectodomain of human CD5 (shCD5) were assessed in vivo in experimental models of systemic fungal infection induced by pathogenic species (Candida albicans and Cryptococcus neoformans). In vitro mechanistic studies were performed by means of fungus-spleen cell cocultures. shCD5-induced survival of lethally infected mice was dose and time dependent and concomitant with reduced fungal load and increased leukocyte infiltration in the primary target organ. Additive effects were observed in vivo after shCD5 was combined with suboptimal doses of fluconazole. Ex vivo addition of shCD5 to fungus-spleen cell cocultures increased the release of proinflammatory cytokines involved in antifungal defense (tumor necrosis factor alpha and gamma interferon) and reduced the number of viable C. albicans organisms. The results prompt further exploration of the adjunctive therapeutic potential of shCD5 in severe invasive fungal diseases.
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Ajdidi, Ahmad, Gerard Sheehan, and Kevin Kavanagh. "Exposure of Aspergillus fumigatus to Atorvastatin Leads to Altered Membrane Permeability and Induction of an Oxidative Stress Response." Journal of Fungi 6, no. 2 (March 26, 2020): 42. http://dx.doi.org/10.3390/jof6020042.
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Aspergillus fumigatus is a serious cause of disease in immune-deficient patients and in those with pulmonary malfunction (e.g., cystic fibrosis (CF), asthma). Atorvastatin is a member of the statin drug family, which are the main therapeutic agents used to decrease high serum cholesterol levels by inhibiting (HMG-CoA) reductase enzyme. The aim of the work presented here was to analyse the antifungal activity of atorvastatin and assess its effect on the virulence of A. fumigatus. Atorvastatin demonstrated strong antifungal activity and reduced the growth and viability of A. fumigatus. Exposure of A. fumigatus to atorvastatin led to a reduction in ergosterol content and increased membrane permeability, as evidenced by the release of protein, amino acids and gliotoxin. Proteomic analysis revealed an increased abundance of proteins associated with an oxidative stress response, such as the glutathione s-transferase family protein (+8.43-fold), heat shock protein Hsp30/Hsp42 (+2.02-fold) and 5-demethoxyubiquinone hydroxylase, mitochondrial (+1.73-fold), as well as secondary metabolites such as isocyanide synthase A icsA (+8.52-fold) and non-ribosomal peptide synthetase fmpE (+3.06-fold). The results presented here indicate that atorvastatin has strong antifungal properties and may have potential application in the treatment of A. fumigatus infections alone or in combination with existing antifungal agents.
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Reza, Mohammad Irshad, Divya Goel, Rahul Kumar Gupta, and Musarrat Hussain Warsi. "FORMULATION OF KETOCONAZOLE LOADED NANO DISPERSIVE GEL USING SWOLLEN MICELLES TECHNIQUE AND ITS IN VITRO CHARACTERIZATION." International Journal of Pharmacy and Pharmaceutical Sciences 10, no. 3 (March 1, 2018): 162. http://dx.doi.org/10.22159/ijpps.2018v10i3.24552.
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Objective: The objective of the present work was to formulate and characterize nano dispersive gel (NDG) for topical delivery of water-insoluble antifungal agent ketoconazole in order to enhance its solubility, penetration through the skin and antifungal activity.Methods: Nano dispersion of the drug was first prepared by swollen micelles technique (SMT) using tween 80 and chloroform which is then incorporated into the gel using carbopol 934. Ten formulations of ketoconazole loaded NDG was prepared and characterized for different physicochemical parameters like homogeneity, pH, spreadability, extrudability, practical yield, drug content, in vitro drug release, ex vivo permeation study, and biological parameter antifungal activity.Results: The formulated topical preparation exhibit pH in the range of 6.5 to 7.4, and unveiled excellent homogeneity, spreadability and extrudability. Out of 10 formulations, formulation F4 showed maximum drug content of 95.56±1.13% and practical yield of 97.23±0.51%. The in vitro drug release studies were performed using pH 7.4 phosphate buffer. Formulation F4 showed best in vitro drug release 96.52±0.52% at the end of 24 h of study. Ex vivo permeation study of formulation F4 carried out using franz diffusion cell, also manifested good permeation and flux of drug across the chicken skin. Antifungal activity test of formulation F4 was carried out by the cup plate method using Aspergillus niger strain against marketed ketoconazole unveiled higher antifungal activity than marketed one.Conclusion: The study confirmed formulation F4 to be an optimized and promising formulation for the effective treatment of topical fungal infections with enhanced solubility and penetration through the skin.
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Kumar, Ajay, Kalyani Deshmukh, and Mahendra Singh Deora. "The role of topical tacrolimus in adherence to antifungal therapy in recalcitrant tinea incognito: a preliminary non randomised controlled study." International Journal of Research in Dermatology 5, no. 1 (January 25, 2019): 183. http://dx.doi.org/10.18203/issn.2455-4529.intjresdermatol20190242.
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<p class="abstract"><strong>Background:</strong> The dropout of outpatients on antifungal therapy for recalcitrant tinea incognito is attributable to the flare on withdrawal of topical corticosteroids and the virulence of pathogens. The objective of the study was to evaluate the role of topical tacrolimus in adherence to antifungal therapy in recalcitrant tinea incognito.</p><p class="abstract"><strong>Methods:</strong> 28 cases of topical corticosteroid induced tinea incognito of more than 6 months duration were enrolled and topical and systemic antifungal therapy instituted for 8 weeks. Topical tacrolimus was also instituted in the test cohort. The end point for resolution was the absence of raised margins, erythema, induration and scaling.<strong></strong></p><p class="abstract"><strong>Results:</strong> 17 patients were male while 11 were female and their age ranged from 16-45 years (mean 26.5). Two patients were from upper-middle; 5 from lower-middle and 21 from upper-lower socioeconomic class. Their occupations included shop assistants, security guards, drivers and labourers and the duration of illness ranged from 7-36 months. Topical corticosteroids were obtained on prescription by 5 and over the counter by 23 patients. Out of the test cohort of 14, all lesions had resolved in 10 patients who had adhered to therapy and were reviewed at the end of 8 and 10 weeks. While 5 reported burning on application of tacrolimus 1 developed folliculitis. Out of the control cohort of 14, though 5 had adhered to therapy all lesions had resolved only in 3 patients at the end of 8 and 10 weeks.</p><p class="abstract"><strong>Conclusions:</strong> Topical tacrolimus facilitates adherence to antifungal therapy in recalcitrant tinea incognito.</p>
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Ji, Yu, Yuqian Sun, Chenhua Yan, Xiaojun Huang, Daihong Liu, and Qifa Liu. "The Efficacy of CT-Diagnostic-Driven Antifungal Strategy with Voriconazole for Invasive Aspergillosis in Patients with Hematological Diseases: A Multicenter, Prospective Study." Blood 128, no. 22 (December 2, 2016): 2370. http://dx.doi.org/10.1182/blood.v128.22.2370.2370.
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Abstract Background The frequency of invasive fungal disease (IFD) has increased in recent two decades and has emerged as an important cause of life-threatening infections in immunocompromised patients, especially in those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). Empirical antifungal therapy has been the standard of care used to decrease the number of deaths due to IFD among neutropenic patients who have persistent or recurrent fever despite broad-spectrum antibacterial treatment. However, about two thirds of these patients may be potentially exposed to unnecessary empirical antifungal treatment with associated potential toxicity and considerable financial burden. It was demonstrated that high-resolution computerized tomography (HRCT) had early predictive value for fungal infection, and the major signs on chest CT scans generally precede the positive outcome of serum galactomannan test. It was also shown that the diagnosis-based treatment strategy only based on HRCT results could reduce more than a half use of antifungal agents in HSCT patients who had persistent febrile neutropenia. Thus, we would like to explore the feasibility of this new strategy for hematological patients with IA in China. Method This was a prospective and single-arm study. Up to now, 24 neutropenic patients after intensive chemotherapy or HSCT with high risk factors for IFD from three hospitals were enrolled. After recruitment, HRCT of thorax will be conducted within 24h. If HRCT shows any new changes suspicious of fungal infection, including halo sign, cavity, air-crescent sign, or other non-specific signs, voriconazole would be given intravenously for two weeks, followed by oral voriconazole. Six weeks after initiation of antifungal therapy, the outcome was evaluated by clinicians according to the patients' imagining and microbiological evidences and clinical conditions, and complete or partial responses were defined as successful outcome of antifungal therapy. Result The median age of this population was 38.5 years (range from 19 to 78). Four of 24 patients were the recipients of HSCT, and the others received intensive chemotherapy. There were four patients had history of IFD, and 7 take fluconazole orally for antifungal prophylaxis. At the beginning of antifungal therapy with voriconazole, 12 had non-specific infiltrates on pulmonary HRCT, 8 had dense lesions with halo sign, and 4 had cavity. At the end of six-week follow-up, 5 patients were diagnosed with possible IA, 6 with probable IA and 1 with proven IA. The total successful rate of antifungal therapy with CT-diagnostic-driven strategy was 50.0% (12/24). Notably, efficacies of the antifungal treatment in patients with specific IA signs on pulmonary HRCT were significant higher than that in patients with non-specific signs (75.0% vs. 25.0%, P=0.043). Conclusion The CT-diagnostic-driven antifungal strategy was effective and suitable for patients with hematological malignancies. Disclosures No relevant conflicts of interest to declare.