Ambisome shows potent anti-Candida auris in vitro and in vivo activity

Candida auris is an emerging multidrug resistant Candida species that has been reported in many parts of the world for causing severe illness in hospitalized patients especially bloodstream infections. The challenge with this type of yeast is its resistance to commonly used antifungal drugs, thus identifying antifungals that are effective against this species is critical. In this study, we determined the in vitro activity of Ambisome against 35 clinical isolates of C. auris using minimum inhibitory concentration (MIC) assay as well as the efficacy of Ambisome compared to Amphotericin B and fluconazole using a C. auris murine disseminated model. Antifungal activity of C. auris against Ambisome and comparators was assessed using amicrodilution method performed according to the Clinical and Laboratory Standard Institute (CLSI) M27-A4 methodology. Mice were immunocompromised and challenged with 3 x 107 C. auris blastopores in 0.1 ml of normal saline (via the tail vein). Treatment efficacy was assessed by determining reductions in mortality as well as decrease in tissue fungal burden (CFUs). Ambisome showed lower MIC50 and MIC90 values (1 and 2 μg/mL, respectively) than the comparators tested. Significant efficacy was observed in the Ambisome 7.5 mg/kg -treated group (100% and 90% survival by day 7- and 14-days post inoculation, respectively). Additionally, Ambisome and fluconazole treated groups showed significant reduction in CFUs in the kidneys (P- values of 0.028 and 0.022, respectively) compared to the untreated group. Our data shows that Ambisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

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In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00306-21 ◽

2021 ◽

Author(s):

Janet Herrada ◽

Ahmed Gamal ◽

Lisa Long ◽

Sonia P. Sanchez ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Kidney Tissue ◽

Treated Group ◽

Untreated Group ◽

Candida Auris ◽

Fungal Burden ◽

In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

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Assessment of the In Vitro and In Vivo Antifungal Activity of NSC319726 against Candida auris

Microbiology Spectrum ◽

10.1128/spectrum.01395-21 ◽

2021 ◽

Author(s):

Jizhou Li ◽

Alix T. Coste ◽

Daniel Bachmann ◽

Dominique Sanglard ◽

Frederic Lamoth

Keyword(s):

Public Health ◽

Antifungal Activity ◽

Invasive Candidiasis ◽

Multidrug Resistant ◽

Candida Auris ◽

Content Type ◽

Health Threat ◽

Public Health Threat

Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals.

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Spilanthol as a promising antifungal alkylamide for the treatment of vulvovaginal candidiasis

Medical Mycology ◽

10.1093/mmy/myab054 ◽

2021 ◽

Author(s):

Rodrigo L Fabri ◽

Jhamine C O Freitas ◽

Ari S O Lemos ◽

Lara M Campos ◽

Irley O M Diniz ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Antifungal Activity ◽

Cell Membrane ◽

Multidrug Resistant ◽

Fungal Strain ◽

Vulvovaginal Candidiasis ◽

Biofilm Matrix

Abstract Spilanthol is a bioactive alkylamide from the native Amazon plant species, Acmella oleracea. However, antifungal activities of spilanthol and its application to the therapeutic treatment of candidiasis remains to be explored. This study sought to evaluate the in vitro and in vivo antifungal activity of spilanthol previously isolated from A. oleracea (spilanthol(AcO)) against Candida albicans ATCC® 10231™, a multidrug-resistant fungal strain. Microdilution methods were used to determine inhibitory and fungicidal concentrations of spilanthol(AcO). In planktonic cultures, the fungal growth kinetics, yeast cell metabolic activity, cell membrane permeability and cell wall integrity were investigated. The effect of spilanthol(AcO) on the proliferation and adhesion of fungal biofilms was evaluated by whole slide imaging and scanning electron microscopy. The biochemical composition of the biofilm matrix was also analyzed. In parallel, spilanthol(AcO) was tested in vivo in an experimental vulvovaginal candidiasis model. Our in vitro analyses in C. albicans planktonic cultures detected a significant inhibitory effect of spilanthol(AcO), which affects both yeast cell membrane and cell wall integrity, interfering with the fungus growth. C. albicans biofilm proliferation and adhesion, as well as, carbohydrates and DNA in biofilm matrix were reduced after spilanthol(AcO) treatment. Moreover, infected rats treated with spilanthol(AcO) showed consistent reduction of both fungal burden and inflammatory processes compared to the untreated animals. Altogether, our findings demonstrated that spilanthol(AcO) is an bioactive compound against planktonic and biofilm forms of a multidrug resistant C. albicans strain. Furthermore, spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans. Lay Abstract This study sought to evaluate the antifungal activity of spilanthol against Candida albicans ATCC® 10 231™, a multidrug-resistant fungal strain. Our findings demonstrated that spilanthol(AcO) can be potentially considered for therapeutical treatment of vulvovaginal candidiasis caused by C. albicans.

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Evaluation of the In Vitro and In Vivo Antifungal Activity of APX001A/APX001 Against Candida auris

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.1206 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S471-S472

Author(s):

Emily Larkin ◽

Lisa Long ◽

Christopher Hager ◽

Karen Joy Shaw ◽

Mahmoud Ghannoum

Keyword(s):

Antifungal Activity ◽

Candida Auris ◽

In Vivo Antifungal Activity

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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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A marine microbiome antifungal targets urgent-threat drug-resistant fungi

Science ◽

10.1126/science.abd6919 ◽

2020 ◽

Vol 370 (6519) ◽

pp. 974-978 ◽

Cited By ~ 1

Author(s):

Fan Zhang ◽

Miao Zhao ◽

Doug R. Braun ◽

Spencer S. Ericksen ◽

Jeff S. Piotrowski ◽

...

Keyword(s):

Mode Of Action ◽

Fungal Pathogens ◽

Antifungal Drugs ◽

Multiple Drug ◽

Drug Resistant ◽

Candida Auris ◽

Marine Animals ◽

Multiple Drug Resistant

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug–resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

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In Vitro Evaluation of Antifungal Drug Combinations against Multidrug-Resistant Candida auris Isolates from New York Outbreak

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02195-19 ◽

2020 ◽

Vol 64 (4) ◽

Cited By ~ 6

Author(s):

Brittany O’Brien ◽

Sudha Chaturvedi ◽

Vishnu Chaturvedi

Keyword(s):

New York ◽

Drug Combination ◽

Multidrug Resistant ◽

Drug Combinations ◽

Health Care Facilities ◽

Antifungal Drugs ◽

Candida Auris ◽

Pathogenic Yeast ◽

Content Type

ABSTRACT Since 2016, New York hospitals and health care facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over 1,000 C. auris isolates from affected facilities and found high resistance to fluconazole (MIC > 256 mg/liter) and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris. Broth microdilution antifungal combination plates were custom manufactured by TREK Diagnostic System. We used 100% inhibition endpoints for the drug combination as reported earlier for the intra- and interlaboratory agreements against Candida species. The results were derived from 12,960 readings, for 15 C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/liter potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB; MIC ≥ 2.0 mg/liter), AMB-5FC (0.25/1.0 mg/liter) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG], MIC ≥ 4.0 mg/liter; caspofungin [CAS], MIC ≥ 2.0 mg/liter; and micafungin [MFG], MIC ≥ 4.0 mg/liter) were 100% inhibited by AFG-5FC and CAS-5FC (0.0078/1 mg/liter) and MFG-5FC (0.12/1 mg/liter). None of the combinations were effective for C. auris 18-1 and 18-13 (fluconazole [FLC] > 256 mg/liter, 5FC > 32 mg/liter) except MFG-5FC (0.1/0.06 mg/liter). Thirteen isolates with a high voriconazole (VRC) MIC (>2 mg/liter) were 100% inhibited by the VRC-5FC (0.015/1 mg/liter). The simplified two-drug combination susceptibility test format would permit laboratories to provide clinicians and public health experts with additional data to manage multidrug-resistant C. auris.

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Efficacy of LAMB against Emerging Azole- and Multidrug-Resistant Candida parapsilosis Isolates in the Galleria mellonella Model

Journal of Fungi ◽

10.3390/jof6040377 ◽

2020 ◽

Vol 6 (4) ◽

pp. 377

Author(s):

Ulrike Binder ◽

Amir Arastehfar ◽

Lisa Schnegg ◽

Caroline Hörtnagl ◽

Suleyha Hilmioğlu-Polat ◽

...

Keyword(s):

Candida Parapsilosis ◽

Galleria Mellonella ◽

Drug Efficacy ◽

Bloodstream Infections ◽

Multidrug Resistant ◽

Therapeutic Failure ◽

Reliable Model ◽

Prompt Action

While being the third leading cause of candidemia worldwide, numerous studies have shown severe clonal outbreaks due to fluconazole-resistant (FLCR) Candida parapsilosis isolates associated with fluconazole therapeutic failure (FTF) with enhanced mortality. More recently, multidrug resistant (MDR) C. parapsilosis blood isolates have also been identified that are resistant to both azole and echinocandin drugs. Amphotericin B (AMB) resistance is rarely reported among C. parapsilosis isolates and proper management of bloodstream infections due to FLZR and MDR isolates requires prompt action at the time of outbreak. Therefore, using a well-established Galleria mellonella model, we assessed whether (a) laboratory-based findings on azole or echinocandin (micafungin) resistance in C. parapsilosis lead to therapeutic failure, (b) LAMB could serve as an efficient salvage treatment option, and (c) distinct mutations in ERG11 impact mortality. Our in vivo data confirm fluconazole inefficacy against FLCR C. parapsilosis isolates carrying Y132F, Y132F + K143R, Y132F + G307A, and G307A + G458S in Erg11p, while LAMB proved to be an efficacious accessible option against both FLCR and MDR C. parapsilosis isolates. Moreover, positive correlation of in vitro and in vivo data further highlights the utility of G. melonella as a reliable model to investigate azole and polyene drug efficacy.

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In Vitro Interactions of Echinocandins with Triazoles Against Multidrug-Resistant Candida auris

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.026 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S82-S82

Author(s):

Hamid Badalii

Keyword(s):

Amphotericin B ◽

Antifungal Susceptibility ◽

Multidrug Resistant ◽

In Vivo Studies ◽

Synergistic Activity ◽

Candida Auris ◽

Unsuccessful Treatment ◽

In Vitro Interactions

Abstract Background Blood stream infections due to Candida auris are related to a high mortality rate and treatment failure attributed to resistance to fluconazole, voriconazole, amphotericin B, and caspofungin. Thus, the precise identification of agents and in vitro antifungal susceptibility testing is highly recommended. Novel therapeutic strategies, such as combination therapy, are essential for increasing the efficacy and reducing the toxicity of antifungal agents. Therefore, we investigated the in vitro combination of micafungin plus voriconazole against multidrug-resistant C. auris isolated from cases of candidemia. Methods The in vitro interactions between echinocandins and azoles were determined against ten multidrug-resistant Candida auris strains by using a microdilution checkerboard technique. Results Results revealed that MICs range for voriconazole and micafungin were 0.5–8 and 0.25–8 mg/l, respectively. The checkerboard analysis revealed that the combination of micafungin with voriconazole exhibited synergistic activity against all 10 multidrug-resistant C. auris isolates (FICI range: 0.15–0.5). Overall, no antagonistic effects were observed in this experiments. Conclusion In vitro studies have previously suggested that among azoles isavuconazole and posaconazole are more active drugs against C. auris. In addition, the majority of isolates reported are resistant to fluconazole. Remarkably, unsuccessful treatment of C. auris infections with fluconazole, voriconazole, amphotericin B, caspofungin, and anidulafungin has been already on record. Here in we demonstrates that interaction between micafungin with voriconazole exhibited synergistic activity against multidrug-resistant C. auris isolates. It seems that lower concentrations of drugs cause fewer side-effects and improve the treatment outcomes. However, in vivo studies with suitable animal models of C. auris infection is highly recommended. Disclosures All authors: No reported disclosures.

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In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01124-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 1

Author(s):

YanChun Zhu ◽

Shannon Kilburn ◽

Mili Kapoor ◽

Sudha Chaturvedi ◽

Karen Joy Shaw ◽

...

Keyword(s):

New York ◽

Fungal Infections ◽

Geometric Mean ◽

Multidrug Resistant ◽

Antifungal Drugs ◽

New Drugs ◽

Wild Type ◽

Candida Auris ◽

Content Type

ABSTRACT An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

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