In vitro pharmacokinetics/pharmacodynamics modeling and efficacy against systemic candidiasis in Drosophila melanogaster of a bisaryloxypropanamine derivative

2020 ◽  
Vol 59 (1) ◽  
pp. 58-66
Author(s):  
Daiane Flores Dalla Lana ◽  
Taís Fernanda Andrzejewski Kaminski ◽  
Stefânia Neiva Lavorato ◽  
Simone Merkel ◽  
Régis Adriel Zanette ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Maximum Effect ◽  
Systemic Candidiasis ◽  
Candida Spp ◽  
Synthetic Compound ◽  
Starting Point ◽  
Time Kill

Abstract The number of deaths due to systemic fungal infections is increasing alarmingly, which is aggravated by the limitations of traditional treatments and multidrug resistance. Therefore, the research and development of new therapeutic options against pathogenic fungi is an urgent need. To evaluate the fungicidal activity of a synthetic compound, 1,3-bis-(3,4-dichlorophenoxy)propan-2-aminium chloride (2j), through time-kill studies and pharmacokinetics/pharmacodynamics (PK/PD) modeling. The protective effect of the compound was also evaluated using the Drosophila melanogaster minihost model of candidiasis. Mathematical modeling of time-kill data of compound 2j was performed to obtain PD characteristics. Additionally, Toll-deficient D. melanogaster flies were infected with a Candida albicans strain and treated with 2j. We observed that compound 2j demonstrated a time- and dose-dependent fungicidal effect against Candida spp. and dermatophytes, even at low concentrations, and rapidly achieved kill rates reaching the maximum effect in less than one hour. The efficacy of the compound against systemic candidiasis in D. melanogaster flies was comparable to that achieved by fluconazole. These results support the potential of compound 2j as a systemic antifungal agent candidate and serve as a starting point for further studies involving mammalian animal models.

scholarly journals 1376. Antifungal Activity of Cerium Nitrate Against Fungal Isolates Associated with Combat-Related Injuries Including Burns

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S422-S422
Author(s):  
Heather Pomerantz ◽  
Miriam Beckius ◽  
Dana Blyth ◽  
Kevin S Akers ◽  
David R Tribble ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Mucor Circinelloides ◽  
Cerium Nitrate ◽  
Time Dependent ◽  
Candida Spp ◽  
Burn Care ◽  
Fungal Isolates ◽  
Time Kill ◽  
Slow Growing

Abstract Background Fungal infections are a critical cause of morbidity and mortality in burn patients. In addition to debridement and systemic antifungal therapy, various topical adjuncts have been used, and topical burn care is a key component of infection prevention and treatment. Cerium nitrate (CN) has been used in combination with silver sulfadiazine (SS) in burn care. Previous studies showed that CN had bacteriostatic activity, and suggested anti-biofilm activity against Candida biofilms. In this study, we evaluated the in vitro activity of CN against fungal isolates associated with combat-related injuries. Methods The efficacy of CN was evaluated against 14 mold (three Aspergillus spp., two Fusarium spp., five different mucormycetes, two Bipolaris spp., one Alternaria spp., one Exophiala spp.) and 21 Candida spp. isolates collected as part of the Trauma Infectious Disease Outcomes Study. Fungicidal activity of various concentrations of CN (2.2%, 1%, 0.5% and 0.2%) was determined using an established time-kill assay. Standard conidia/cell suspensions were prepared according to Clinical and Laboratory Standards Institute guidelines and then exposed to the CN solutions for 24 hours. At different times (0, 5, 15, 30 minutes, 1, 1.5, 3, 6, 12, and 24 hours) aliquots were plated and incubated at 35ºC. Colony forming unit (CFU) counts were determined after 24 hours incubation or after an appropriate time for slow growing molds. Results All mold isolates had persistent growth at 24 hours with most having no significant change in colony counts over the 24-hour period. The only exception was Mucor circinelloides, which appeared to have a time-dependent reduction in CFUs at 24 hours for all CN concentrations. Exophiala did not grow as well in CN solutions compared with the control (mean 65 vs. 28.2 CFUs with a difference of mean 37.4 CFUs, P = 0.0001), but this was not time or concentration dependent. All yeast species showed a time-dependent killing after 6–12 hours. Conclusion CN demonstrated time-dependent killing of the yeasts. However, very little activity was observed against the tested molds. Since CN is often used in combination with SS there might be a synergistic effect against molds. Further research will evaluate higher concentrations of CN and its toxicity for cells and tissue. Disclosures All authors: No reported disclosures.

scholarly journals Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

2021 ◽  
Vol 7 (2) ◽  
pp. 113
Author(s):  
Anne-Laure Bidaud ◽  
Patrick Schwarz ◽  
Guillaume Herbreteau ◽  
Eric Dannaoui
Keyword(s):  
Animal Models ◽  
Fungal Infections ◽  
Acquired Resistance ◽  
Adequate Treatment ◽  
Combination Treatments ◽  
Target Organs ◽  
Fungal Load ◽  
Time Kill

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

scholarly journals Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor

2021 ◽  
Vol 7 (3) ◽  
pp. 163 ◽  
Author(s):  
Sabelle Jallow ◽  
Nelesh P. Govender
Keyword(s):  
Pathogenic Fungi ◽  
Candida Spp ◽  
Fungal Cell ◽  
Favourable Safety ◽  
Favourable Safety Profile ◽  
Synthase Inhibitor ◽  
Increased Activity ◽  
In Vitro Data

Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal or “fungerp” that inhibits biosynthesis of β-(1,3)-D-glucan in the fungal cell wall, a mechanism of action similar to that of echinocandins. Distinguishing characteristics of ibrexafungerp include oral bioavailability, a favourable safety profile, few drug–drug interactions, good tissue penetration, increased activity at low pH and activity against multi-drug resistant isolates including C. auris and C. glabrata. In vitro data has demonstrated broad and potent activity against Candida and Aspergillus species. Importantly, ibrexafungerp also has potent activity against azole-resistant isolates, including biofilm-forming Candida spp., and echinocandin-resistant isolates. It also has activity against the asci form of Pneumocystis spp., and other pathogenic fungi including some non-Candida yeasts and non-Aspergillus moulds. In vivo data have shown IBX to be effective for treatment of candidiasis and aspergillosis. Ibrexafungerp is effective for the treatment of acute vulvovaginal candidiasis in completed phase 3 clinical trials.

scholarly journals Evaluation of pathogenic fungi occurrence in traumatogenic structures of freshwater fish

2011 ◽  
Vol 44 (2) ◽  
pp. 182-185 ◽  
Author(s):  
Fabio Caetano Oliveira Leme ◽  
Marcos Mendes de Barros Negreiros ◽  
Fernando Akira Koga ◽  
Sandra de Moraes Gimenes Bosco ◽  
Eduardo Bagagli ◽  
...  
Keyword(s):  
Freshwater Fish ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Dematiaceous Fungi ◽  
Candida Spp ◽  
Pathogenic Potential ◽  
Infection Route ◽  
5.8S Rdna ◽  
Dorsal Fin ◽  
Pimelodus Maculatus

INTRODUCTION: Fungal infections in human skin, such as sporotrichosis, can occur after fish induced trauma. This work aimed to identify fungi in freshwater fish that are pathogenic to humans. METHODS: Extraction of dental arches from Serrassalmus maculatus (piranha) and Hoplias malabaricus (wolf fish), stings from Pimelodus maculatus (mandis catfish), dorsal fin rays from Plagioscion spp. (corvina) and Tilapia spp., for culture in Mycosel agar. Some cultures were submitted to DNA extraction for molecular identification by sequencing ITS-5.8S rDNA. RESULTS: Cultures identified most yeast as Candida spp., while sequencing also permitted the identification of Phoma spp. and Yarrowia lipolytica. CONCLUSIONS: While the search for S. schenckii was negative, the presence of fungus of the genera Phoma and Candida revealed the pathogenic potential of this infection route. The genus Phoma is involved in certain forms of phaeohyphomycosis, a subcutaneous mycosis caused by dematiaceous fungi, with reports of infections in human organs and systems. Traumatizing structures of some freshwater fish present pathogenic fungi and this may be an important infection route that must be considered in some regions of Brazil, since there are a large number of a fisherman in constant contact with traumatogenic fish.

scholarly journals 2106. Evaluation of Isavuconazole for the Prophylaxis and Treatment of Invasive Fungal Infections at a Large Academic Medical Center

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S712-S713
Author(s):  
Christine Vu ◽  
Meenakshi Rana ◽  
Patricia Saunders-Hao
Keyword(s):  
Fungal Infections ◽  
Medical Center ◽  
Academic Medical Center ◽  
Retrospective Chart Review ◽  
Invasive Fungal Infections ◽  
Prescribing Practices ◽  
Candida Spp ◽  
Antifungal Stewardship ◽  
Hospital Formulary

Abstract Background Isavuconazole is an azole antifungal with in vitro activity against various fungi, including Candida spp, Aspergillus, and Mucormycetes. Currently, isavuconazole is FDA approved for the treatment of invasive aspergillosis and mucormycosis; however, there remains limited data to support prophylaxis use. Compared with other first-line azoles, isavuconazole’s broad spectrum of activity, favorable safety profile, and oral bioavailability makes it an attractive antifungal option. In July 2017, isavuconazole was added to our hospital formulary as a restricted antimicrobial. Since then, we have seen increased use for both prophylaxis and treatment of invasive fungal infections. Methods A single-center, retrospective chart review was conducted on adult patients who received at least 1 dose of isavuconazole at The Mount Sinai Hospital between July 1, 2017 and December 31, 2018. The electronic medical record was utilized to collect information on therapeutic indication, dosing, formulation, duration, reasons for switching to isavuconazole, prior antifungals, and proven or probable breakthrough invasive fungal infections (bIFIs) based on EORTG/MTG definitions. Results 54 patients received 61 courses of isavuconazole. Reasons for switching to isavuconazole are described in Table 1. Eleven patients received inappropriate intravenous formulations and 14% of orders were prescribed isavuconazole without a loading dose (Table 2). We identified 4 proven/probable bIFIs, representing 7.4% of patients and 6.6% of courses (Table 3). All patients died within 60 days of bIFI onset. Conclusion Since its addition to hospital formulary, we have observed varying isavuconazole prescribing practices, highlighting the need for improved antifungal stewardship. Rates of bIFIs on isavuconazole were lower than previously reported studies. Additional studies are needed to provide guidance on isavuconazole use and determine its role as prophylaxis therapy. Disclosures All authors: No reported disclosures.

scholarly journals Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Visesato Mor ◽  
Antonella Rella ◽  
Amir M. Farnoud ◽  
Ashutosh Singh ◽  
Mansa Munshi ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Sequencing Analysis ◽  
Fungal Cell ◽  
New Class ◽  
Narrow Spectrum

ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.

scholarly journals SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Bernard Scorneaux ◽  
David Angulo ◽  
Katyna Borroto-Esoda ◽  
Mahmoud Ghannoum ◽  
Michael Peel ◽  
...  
Keyword(s):  
Fungicidal Activity ◽  
Candida Parapsilosis ◽  
Maximum Effect ◽  
Synthesis Inhibitor ◽  
Content Type ◽  
Orally Bioavailable ◽  
Glucan Synthesis ◽  
Time Kill ◽  
Time Point

ABSTRACT SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans 90028, Candida parapsilosis 90018, and Candida tropicalis 750), a quality-control (QC) strain (Candida krusei 6258), and four other strains (C. albicans MYA-2732, 64124, and 76485 and Candida glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4× MIC80. The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, and E max, respectively). The SCY-078 MIC range was between 0.0625 and 1 μg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log10) and achieved a 1.7-log10 reduction in CFU count/milliliter against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5-log10 reduction in the number of CFU/milliliter against C. albicans 90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC90 was reached at ∼5× MIC at each time point to 24 h. The EC50 and EC90 values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.

scholarly journals Antibiofilm Potential of Medicinal Plants against Candida spp. Oral Biofilms: A Review

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1142
Author(s):  
Rafaela Guimarães ◽  
Catarina Milho ◽  
Ângela Liberal ◽  
Jani Silva ◽  
Carmélia Fonseca ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Plants ◽  
Oral Cavity ◽  
Plant Extracts ◽  
Fungal Infections ◽  
High Capacity ◽  
Biologically Active ◽  
Antibiofilm Activity ◽  
Candida Spp

The use of natural products to promote health is as old as human civilization. In recent years, the perception of natural products derived from plants as abundant sources of biologically active compounds has driven their exploitation towards the search for new chemical products that can lead to further pharmaceutical formulations. Candida fungi, being opportunistic pathogens, increase their virulence by acquiring resistance to conventional antimicrobials, triggering diseases, especially in immunosuppressed hosts. They are also pointed to as the main pathogens responsible for most fungal infections of the oral cavity. This increased resistance to conventional synthetic antimicrobials has driven the search for new molecules present in plant extracts, which have been widely explored as alternative agents in the prevention and treatment of infections. This review aims to provide a critical view and scope of the in vitro antimicrobial and antibiofilm activity of several medicinal plants, revealing species with inhibition/reduction effects on the biofilm formed by Candida spp. in the oral cavity. The most promising plant extracts in fighting oral biofilm, given their high capacity to reduce it to low concentrations were the essential oils extracted from Allium sativum L., Cinnamomum zeylanicum Blume. and Cymbopogon citratus (DC) Stapf.

scholarly journals 2115. Activity of a Long-Acting Echinocandin Rezafungin and Comparator Antifungal Agents Tested against Contemporary Invasive Fungal Isolates: SENTRY 2018

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S716-S716 ◽  
Author(s):  
Michael A Pfaller ◽  
Cecilia G Carvalhaes ◽  
Shawn A Messer ◽  
Paul R Rhomberg ◽  
Mariana Castanheira
Keyword(s):  
Drug Exposure ◽  
Fungal Infections ◽  
Hot Spot ◽  
Good Activity ◽  
Candida Spp ◽  
Fluconazole Resistance ◽  
Fungal Isolates ◽  
Long Acting ◽  
In Vitro Data

Abstract Background Echinocandins are the first-line treatment of candidemia. We evaluated the activity of rezafungin (RZF), a novel long-acting echinocandin with front-loaded drug exposure and extensive distribution to sites of infection, and comparators using CLSI broth microdilution methods against 709 invasive fungal isolates collected worldwide during 2018. Methods Susceptibility (S) tests on 663 Candida spp. (6 species), 21 C. neoformans (CNEO), and 25 A. fumigatus (ASF) were conducted for RZF, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF), and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results RZF inhibited 99.7% of C. albicans (CA) isolates (MIC50/90, 0.015/0.06 mg/L), 100.0% of C. tropicalis (CT) (MIC50/90, 0.03/0.06 mg/L), 98.9% of C. glabrata (CG) (MIC50/90, 0.03/0.06 mg/L), 100.0% of C. krusei (CK) (MIC50/90, 0.015/0.12 mg/L), and 100.0% of C. dubliniensis (CD) (MIC50/90, 0.03/0.06 mg/L) at ≤0.12 mg/L. All (104/104 [100.0%]) C. parapsilosis (CP) isolates (MIC50/90,1/2 mg/L) were inhibited by RZF at ≤2 mg/L. Fluconazole resistance was detected among 9.0% of CG, 17.3% of CP, and 1.6% of CT. The activity of RZF against these 6 Candida spp. was similar to that of the other echinocandins, the vast majority of which were susceptible/wild type (WT) using CBP/ECV. A total of 5 isolates (3 CG, 1 CA, and 1 CT) displayed 1 or more non-WT or-resistant MIC values and were sequenced for fks HS mutations. Fluconazole and other azoles displayed good activity against CNEO whereas echinocandins including RZF displayed limited activity against CNEO isolates. Echinocandins displayed good activity against ASF, and RZF activity was similar to that of anidulafungin, caspofungin, and micafungin. All but 1 isolate (non-WT MIC for itraconazole, 2 mg/L) displayed WT MIC values for the mould-active azoles. Conclusion Rezafungin was as active as other echinocandins against common organisms recovered from invasive fungal infections. These in vitro data contribute to accumulating research demonstrating rezafungin potential for prevention and treatment of invasive fungal infection. Disclosures All authors: No reported disclosures.

QSAR Study of Some 1,3-Oxazolylphosphonium Derivatives as New Potent Anti-Candida Agents and Their Toxicity Evaluation

2019 ◽  
Vol 16 (2) ◽  
pp. 204-209
Author(s):  
Maria M. Trush ◽  
Vasyl Kovalishyn ◽  
Alla D. Ocheretniuk ◽  
Oleksandr L. Kobzar ◽  
Maryna V. Kachaeva ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Electric Organ ◽  
Biological Marker ◽  
Diffusion Method ◽  
Phosphonium Salts ◽  
Candida Spp ◽  
Qsar Study ◽  
Disk Diffusion Method ◽  
Qsar Models

Background: The incidence of invasive fungal infections caused by Candida spp. has increased continuously in recent decades, especially in populations of immunocompromised patients or individuals hospitalized with serious underlying diseases. Therefore, the goal of our study was the search for new potent Candida albicans inhibitors via the development of QSAR models that could speed up this search process. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and experimentally tested. Furthermore, the toxicity of the studied compounds was determined in vitro using acetylcholinesterase enzyme as a biological marker. Methods: The classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors on the Online Chemical Modeling Environment (OCHEM) platform. Аntifungal properties of the investigated compounds were performed using standard disk diffusion method. The enzyme inhibitory action of the compounds was determined by modified Ellman's method using acetylcholinesterase from the electric organ of Electrophorus electricus. Results: Three classification QSAR models were developed by the WEKA-RF, k-NN and ASNN methods using the ALogPS, E-State indices and Dragon v.7 descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA = 80-91%. All compounds demonstrated good antifungal properties against Candida spp. and slight inhibition of the acetylcholinesterase activity. Conclusion: The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against Candida spp. Furthermore, 1,3-oxazol-4- yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.

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