In Vitro Activity of Novel Antifungal Olorofim against Filamentous Fungi and Comparison to Eight Other Antifungal Agents

Olorofim is a novel antifungal drug that belongs to the orotomide drug class which inhibits fungal dihydroorotate dehydrogenase (DHODH), thus halting pyrimidine biosynthesis and ultimately DNA synthesis, cell growth and division. It is being developed at a time when many invasive fungal infections exhibit antifungal resistance or have limited treatment options. The goal of this study was to evaluate the in vitro effectiveness of olorofim against a large collection of recently isolated, clinically relevant American mold isolates. In vitro antifungal activity was determined for 246 azole-susceptible Aspergillus fumigatus isolates, five A. fumigatus with TR34/L98H-mediated resistance, 19 Rhizopus species isolates, 21 Fusarium species isolates, and one isolate each of six other species of molds. Olorofim minimum inhibitory concentrations (MICs) were compared to antifungal susceptibility testing profiles for amphotericin B, anidulafungin, caspofungin, isavuconazole, itraconazole, micafungin, posaconazole, and voriconazole. Olorofim MICs were significantly lower than those of the echinocandin and azole drug classes and amphotericin B. A. fumigatus wild type and resistant isolates shared the same MIC50 = 0.008 μg/mL. In non-Aspergillus susceptible isolates (MIC ≤ 2 μg/mL), the geometric mean (GM) MIC to olorofim was 0.54 μg/mL with a range of 0.015–2 μg/mL. Olorofim had no antifungal activity (MIC ≥ 2 μg/mL) against 10% of the collection (31 in 297), including some isolates from Rhizopus spp. and Fusarium spp. Olorofim showed promising activity against A. fumigatus and other molds regardless of acquired azole resistance.

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Susceptibility Patterns and Molecular Identification of Trichosporon Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4026-4034.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4026-4034 ◽

Cited By ~ 124

Author(s):

Juan L. Rodriguez-Tudela ◽

Teresa M. Diaz-Guerra ◽

Emilia Mellado ◽

Virginia Cano ◽

Cecilia Tapia ◽

...

Keyword(s):

Amphotericin B ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Intergenic Spacer ◽

Clinical Isolates ◽

Rrna Genes ◽

Correct Identification ◽

Its Sequencing ◽

Trichosporon Species

ABSTRACT The physiological patterns, the sequence polymorphisms of the internal transcriber spacer (ITS), and intergenic spacer regions (IGS) of the rRNA genes and the antifungal susceptibility profile were evaluated for their ability to identify Trichosporon spp. and their specificity for the identification of 49 clinical isolates of Trichosporon spp. Morphological and biochemical methodologies were unable to differentiate among the Trichosporon species. ITS sequencing was also unable to differentiate several species. However, IGS1 sequencing unambiguously identified all Trichosporon isolates. Following the results of DNA-based identification, Trichosporon asahii was the species most frequently isolated from deep sites (15 of 25 strains; 60%). In the main, other Trichosporon species were recovered from cutaneous samples. The majority of T. asahii, T. faecale, and T. coremiiforme clinical isolates exhibited resistance in vitro to amphotericin B, with geometric mean (GM) MICs >4 μg/ml. The other species of Trichosporon did not show high MICs of amphotericin B, and GM MICs were <1 μg/ml. Azole agents were active in vitro against the majority of clinical strains. The most potent compound in vitro was voriconazole, with a GM MIC ≤0.14 μg/ml. The sequencing of IGS correctly identified Trichosporon isolates; however, this technique is not available in many clinical laboratories, and strains should be dispatched to reference centers where these complex methods are available. Therefore, it seems to be more practical to perform antifungal susceptibility testing of all isolates belonging to Trichosporon spp., since correct identification could take several weeks, delaying the indication of an antifungal agent which exhibits activity against the infectious strain.

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Amphotericin B-conjugated polypeptide hydrogels as a novel innovative strategy for fungal infections

Royal Society Open Science ◽

10.1098/rsos.171814 ◽

2018 ◽

Vol 5 (3) ◽

pp. 171814 ◽

Cited By ~ 6

Author(s):

Chang Shu ◽

Tengfei Li ◽

Wen Yang ◽

Duo Li ◽

Shunli Ji ◽

...

Keyword(s):

Electron Microscopy ◽

Antifungal Activity ◽

Amphotericin B ◽

Fungal Infections ◽

Antifungal Drugs ◽

Water Soluble ◽

Naphthalene Acetic Acid ◽

Innovative Strategy ◽

Molecular Arrangement

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20–50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The in vitro drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against Candida albicans . The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.

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In VitroAntifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients

Journal of Clinical Microbiology ◽

10.1128/jcm.02524-16 ◽

2017 ◽

Vol 55 (6) ◽

pp. 1812-1820 ◽

Cited By ~ 23

Author(s):

Tsidiso G. Maphanga ◽

Erika Britz ◽

Thokozile G. Zulu ◽

Ruth S. Mpembe ◽

Serisha D. Naicker ◽

...

Keyword(s):

Amphotericin B ◽

Fungal Pathogen ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Outcome Data ◽

Internal Transcribed Spacer Region ◽

Content Type ◽

Susceptibility Data ◽

Custom Made

ABSTRACTDisseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused byEmergomycesafricanus, a newly described and renamed dimorphic fungal pathogen.In vitroantifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty uniqueE. africanusisolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limitedin vitroactivity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4;P= 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2;P= 0.03) (versus skin biopsy) was associated with death.In vitrosusceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent.

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Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

PLoS ONE ◽

10.1371/journal.pone.0258465 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0258465

Author(s):

Mohamed Hagras ◽

Nader S. Abutaleb ◽

Ahmed M. Sayed ◽

Ehab A. Salama ◽

Mohamed N. Seleem ◽

...

Keyword(s):

Antibacterial Activity ◽

Antifungal Activity ◽

Amphotericin B ◽

Antifungal Agent ◽

Fungal Infections ◽

Multidrug Resistant ◽

Candida Auris ◽

Conformationally Restricted ◽

Normal Human

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1’-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

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In Vitro Susceptibility of Talaromyces Marneffei In Malaysia: Comparison of Yeast and Mycelial Phases

10.21203/rs.3.rs-1158654/v1 ◽

2021 ◽

Author(s):

Xue Ting Tan ◽

Nurliyana binti Mohd Shuhairi ◽

Stephanie Jane Ginsapu ◽

Surianti Binti Shukor ◽

Fairuz Binti Amran

Keyword(s):

Amphotericin B ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Etiologic Agent ◽

Mycelial Form ◽

In Vitro Susceptibility ◽

Terbinafine Hydrochloride ◽

Acquired Immunodeficiency ◽

Immunodeficiency Syndrome

Abstract Talaromyces marneffei is an etiologic agent of talaromycosis. It can cause serious complications and death in immunocompromised patients, particularly in acquired immunodeficiency syndrome (AIDS) patients. This infectious disease is endemic in Southeast Asia including Malaysia. To date, published reports on the antifungal susceptibility profile of T. marneffei is very limited. The objective of this study is to determine the minimum inhibitory concentration (MIC) of T. marneffei in yeast and mycelial phases in Malaysia. In the year 2020, 27 clinical strains of T. marneffei were received from various hospitals in Malaysia. The identification was carried out using microscopic, macroscopic and molecular methods. Following that, the susceptibility of each isolate in both yeast and mycelial form to thirteen common antifungals was performed according to the broth microdilution in Clinical & Laboratory Standards Institute (CLSI) M38 method. The antifungals tested were anidulafungin, micafungin sodium, caspofungin diacetate, 5-fluorocytosine, amphotericin B and terbinafine hydrochloride, posaconazole, voriconazole, itraconazole, ketoconazole, ravuconazole, clotrimazole and isavuconazole. The geometric mean of all antifungals other than anidulafungin, micafungin sodium, caspofungin diacetate and 5-fluorocytosine against T. marneffei mould (mycelial) were >2 μg/ml. However, the geometric mean of all antifungals against T. marneffei yeast was <2 μg/ml. Our in vitro data suggests promising activities of amphotericin B, terbinafine hydrochloride, posaconazole, voriconazole, itraconazole, ketoconazole, ravuconazole, clotrimazole and isavuconazole against yeast and mould phases of T. marneffei.

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Linolenic acid-modified MPEG-PEI micelles for encapsulation of amphotericin B

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0580 ◽

2019 ◽

Vol 11 (20) ◽

pp. 2647-2662 ◽

Cited By ~ 2

Author(s):

Hongmei Xu ◽

Fangfang Teng ◽

Feilong Zhou ◽

Li Zhu ◽

Yi Wen ◽

...

Keyword(s):

Polyethylene Glycol ◽

Antifungal Activity ◽

Amphotericin B ◽

Linolenic Acid ◽

Water Solubility ◽

Fungal Infections ◽

Biofilm Inhibition ◽

Comparable Activity ◽

Reduced Toxicity

Aim: To encapsulate amphotericin B (AmB) with reduced toxicity and comparable activity. Results & methodology: The α-linolenic acid (ALA)-modified monomethoxy polyethylene glycol-g-PEI-g-ALA conjugate was employed to prepare AmB-loaded micelles (AmB-M). In vitro activity and release behavior of AmB-M were investigated. AmB-M enhanced AmB's water-solubility to 1.2 mg/ml, showing good storage stability. AmB-M could achieve a sustained and slow release of AmB, low hemolysis activity and negligible kidney toxicity when compared with commercial AmB injection. Antifungal activity and biofilm inhibition experiments confirmed that the antifungal activity of AmB-M against Candida albicans was similar to that of AmB injection. Conclusion: Monomethoxy polyethylene glycol-g-PEI-g-ALA micelles could be a preferable choice to treat systemic fungal infections as an efficient drug delivery system.

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Molecular typing and in vitro antifungal susceptibility of Cryptococcus spp from patients in Midwest Brazil

The Journal of Infection in Developing Countries ◽

10.3855/jidc.4446 ◽

2014 ◽

Vol 8 (08) ◽

pp. 1037-1043 ◽

Cited By ~ 13

Author(s):

Olivia Cometti Favalessa ◽

Daphine Ariadne Jesus De Paula ◽

Valeria Dutra ◽

Luciano Nakazato ◽

Tomoko Tadano ◽

...

Keyword(s):

Amphotericin B ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Cryptococcus Gattii ◽

Antifungal Drugs ◽

Northeastern Brazil ◽

In Vitro Susceptibility ◽

Mato Grosso ◽

Hiv Negative

Introduction: Cryptococcosis is a systemic fungal infection that affects humans and animals, mainly due to Cryptococcus neoformans and Cryptococcus gattii. Following the epidemic of acquired immunodeficiency syndrome (AIDS), fungal infections by C. neoformans have become more common among immunocompromised patients. Cryptococcus gattii has primarily been isolated as a primary pathogen in healthy hosts and occurs endemically in northern and northeastern Brazil. We to perform genotypic characterization and determine the in vitro susceptibility profile to antifungal drugs of the Cryptococcus species complex isolated from HIV-positive and HIV-negative patients attended at university hospitals in Cuiabá, MT, in the Midwestern region of Brazil. Methodology: Micromorphological features, chemotyping with canavanine-glycine-bromothymol blue (CGB) agar and genotyping by URA5-RFLP were used to identify the species. The antifungal drugs tested were amphotericin B, fluconazole, flucytosine, itraconazole and voriconazole. Minimum inhibitory concentrations (MICs) were determined according to the CLSI methodology M27-A3. Results: Analysis of samples yelded C. neoformans AFLP1/VNI (17/27, 63.0%) and C. gattii AFLP6/VGII (10/27, 37.0%). The MICs ranges for the antifungal drugs were: amphotericin B (0.5-1 mg/L), fluconazole (1-16 mg/L), flucytosine (1-16 mg/L), itraconazole (0.25-0.12 mg/L) and voriconazole (0.06-0.5 mg/L). Isolates of C. neoformans AFLP1/VNI were predominant in patients with HIV/AIDS, and C. gattii VGII in HIV-negative patients. The genotypes identified were susceptible to the antifungal drugs tested. Conclusion: It is worth emphasizing that AFLP6/VGII is a predominant genotype affecting HIV-negative individuals in Cuiabá. These findings serve as a guide concerning the molecular epidemiology of C. neoformans and C. gattii in the State of Mato Grosso.

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In Vitro Activities of Three Licensed Antifungal Agents against Spanish Clinical Isolates of Aspergillus spp

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.10.3085-3088.2003 ◽

2003 ◽

Vol 47 (10) ◽

pp. 3085-3088 ◽

Cited By ~ 62

Author(s):

Alicia Gomez-Lopez ◽

Guillermo Garcia-Effron ◽

Emilia Mellado ◽

Araceli Monzon ◽

Juan L. Rodriguez-Tudela ◽

...

Keyword(s):

Amphotericin B ◽

Aspergillus Terreus ◽

Antifungal Agents ◽

Fungal Infections ◽

Geometric Mean ◽

Common Species ◽

Medical Centers ◽

Susceptibility Patterns ◽

Skin Samples

ABSTRACT The aim of the present study was to identify retrospectively trends in the species distributions and the susceptibility patterns of Aspergillus species causing fungal infections in Spanish medical centers from 2000 to 2002. The susceptibilities of 338 isolates to amphotericin B, itraconazole, and voriconazole were tested. Aspergillus fumigatus was the most common species (54.7%), followed by Aspergillus terreus (14.8%) and Aspergillus flavus (13.9%). Non-A. fumigatus species were encountered in 45.3% of the samples studied. The majority of Aspergillus isolates were obtained from respiratory tract specimens, followed by ear and skin samples. The geometric mean (GM) MIC of amphotericin B was 0.56 μg/ml, and the amphotericin B MIC was >2 μg/ml for 16 isolates (4.7%). Nine of them were A. terreus. The GM MIC of itraconazole was 0.37, and the itraconazole MIC was >4 μg/ml for 12 (3.5%) isolates. The voriconazole MICs were also high for 8 of the 12 strains for which itraconazole MICs were high (voriconazole MIC range, 2 to 8 μg/ml).

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Effects of incubation temperature, inoculum size, and time of reading on broth microdilution susceptibility test results for amphotericin B fgainst Fusarium.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.4.808 ◽

1997 ◽

Vol 41 (4) ◽

pp. 808-811 ◽

Cited By ~ 18

Author(s):

I Pujol ◽

J Guarro ◽

J Sala ◽

M D Riba

Keyword(s):

Amphotericin B ◽

Incubation Time ◽

Incubation Temperature ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Inoculum Size ◽

Test Results ◽

Fusarium Spp ◽

In Vitro Antifungal Susceptibility

In vitro antifungal susceptibility testing for filamentous fungi remains unstandardized and is unreliable for determining adequate therapy. A study was performed to evaluate the effect of inoculum size (10(2), 10(3), 10(4), and 10(5) conidia/ml), incubation time (48 and 72 h), and temperature (25, 30, and 35 degrees C) on MICs of amphotericin B for Fusarium spp. (20 strains). The inoculum size showed the clearest effect: when the inoculum was varied from 10(2) to 10(5) conidia/ml, the geometric mean MICs showed increases of between 10- and 19-fold in all the combined conditions of temperature and incubation time assayed. Time of incubation had less effect (increases of between two- and threefold in approximately half of the geometric mean MICs), and temperature especially had little effect (the increases were no higher than twofold). The effects of interaction between inoculum size and temperature on MICs were not statistically significant, while the combined effects of inoculum size and time of reading and of time of reading and temperature produced systematic variation in MICs.

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In Vitro Antifungal Susceptibility ofCandidaSpecies Isolated from Iranian Patients with Denture Stomatitis

BioMed Research International ◽

10.1155/2018/3086586 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Saeid Mahdavi Omran ◽

Maryam Rezaei Dastjerdi ◽

Maryam Zuashkiani ◽

Vahid Moqarabzadeh ◽

Mojtaba Taghizadeh-Armaki

Keyword(s):

Amphotericin B ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Restriction Enzymes ◽

Denture Stomatitis ◽

Pcr Rflp ◽

Causative Agents ◽

In Vitro Antifungal Susceptibility ◽

Iranian Patients

Background.Candida-associated denture stomatitis (CADS) is a common fungal infection in people who wear dentures. The main objective of this study was to make molecular identification of causative agents of CADS and in vitro antifungal susceptibility testing (AFST) in the Iranian patients with denture stomatitis.Methods. A total of 134Candidaspp. were obtained from patients with denture stomatitis. TheCandidaspp. were identified using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) involving the universal internal transcribed spacer (ITS1 and ITS4) primers, which were subjected to digestion with MspI and BlnI restriction enzymes. The in vitro antifungal susceptibility ofCandidaspp. to fluconazole (FLC), terbinafine (TRB), itraconazole (ITC), voriconazole (VRC), posaconazole (POS), ketoconazole (KET), amphotericin B (AMB), and caspofungin (CAS) was evaluated using the Clinical and Laboratory Standards Institute M27-A3 and M27-S4 guidelines.Results. Overall,C. albicanswas the most commonly isolated species (n=84; 62.6%), followed byC. glabrata(n=23; 17.2%),C. tropicalis(n=16; 12%), andC. parapsilosis(n=11; 8.2%). Posaconazole had the lowest geometric mean minimum inhibitory concentration (MIC) (0.03 μg/ml), followed by AMB (0.05 μg/ml), ITC (0.08 μg/ml), VRC (0.11 μg/ml), CAS (0.12 μg/ml), KET (0.15 μg/ml), and FLC (0.26 μg/ml).Discussion. Our study showed thatC. albicanswas most prevalent in Iranian patients with CADS and was susceptible to both azoles and amphotericin B. In addition, POS could be an appropriate alternative to the current antifungal agents used for the treatment of CADS, as well as in the treatment of recurrent candidiasis.

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