In vitro Evaluation of #Antifungal Drug #Combinations against #MDR #Candida auris isolates from #NY #Outbreak (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

In vitro Evaluation of Antifungal Drug Combinations against Multidrug-resistant Candida auris isolates from New York Outbreak

Brittany O’Brien, Sudha Chaturvedi, Vishnu Chaturvedi

DOI: 10.1128/AAC.02195-19

 

ABSTRACT

Since 2016, New York hospitals and healthcare facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over one thousand C. auris isolates from affected facilities and found high-resistance to fluconazole (MIC > 256 mg/L), and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris. Broth micro-dilution 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 inter-laboratory agreements against Candida species. The results were derived from 12,960 readings, for fifteen C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/L potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB, MIC ≥ 2.0 mg/L]), AMB/5FC (0.25/1.0 mg/L) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG, MIC ≥ 4.0 mg/L], caspofungin [CAS, MIC ≥ 2.0 mg/L], and micafungin [MFG, MIC ≥ 4.0 mg/L]), were 100% inhibited by AFG/5FC and CAS/5FC (0.0078/1 mg/L), and MFG/5FC (0.12/1 mg/L). None of the combinations were effective for C. auris 18-1 and 18-13 (FLC > 256 mg/L, 5FC > 32 mg/L) except MFG/5FC (0.1/0.006 mg/L). Thirteen isolates with high voriconazole MIC (VRC, > 2 mg/L) were 100% inhibited by the VRC/5FC (0.015/1 mg/L). 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.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: Drugs Resistance; Candida auris; USA.

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The Novel #Arylamidine T-2307 Demonstrates In vitro and In vivo Activity Against #Candida auris (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

The Novel Arylamidine T-2307 Demonstrates In vitro and In vivo Activity Against Candida auris

Nathan P. Wiederhold, Laura K. Najvar, Rosie Jaramillo, Marcos Olivo, Hoja Patterson, April Connell, Yoshiko Fukuda, Junichi Mitsuyama, Gabriel Catano, Thomas F. Patterson

DOI: 10.1128/AAC.02198-19

 

ABSTRACT

The in vitro and in vivo activity of the arylamidine T-2307 against C. auris was evaluated. T-2307 demonstrated in vitro activity (MIC range ≤ 0.008 – 0.015 μg/mL at 50% inhibition; 0.125 – >4 μg/mL at 100% inhibition). Treatment with T-2307 (3 mg/kg SC once daily) also significantly improved survival (70% at 21 days post-infection) and reduced kidney fungal burden (5.06 log10 CFU/g) compared to control (0% and 7.09 log10 CFU/g; p < 0.01).

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Candida auris; Arylamidine; Animal models.

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Impact of #Candida auris #infection in a #neutropenic murine model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Impact of Candida auris infection in a neutropenic murine model

Steven R. Torres, Amber Pichowicz, Fernando Torres-Velez, Renjie Song, Navjot Singh, Erica Lasek-Nesselquist, Magdia De Jesus

DOI: 10.1128/AAC.01625-19

 

ABSTRACT

Candida auris has become a global public health threat due to its multidrug resistance and persistence. Currently, there are limited murine models to study C. auris infection. These models use a combination of cyclophosphamide and cortisone acetate that suppress both innate and adaptive immunity. Here we compare C. auris infection in two neutrophil depleted (ND) murine models, where innate immunity is targeted using the monoclonal antibodies 1A8 and RB6-8C5.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Candida auris; Animal models.

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Simultaneous #Infection with #Enterobacteriaceae and #Pseudomonas aeruginosa harboring Multiple #Carbapenemases in a Returning #Traveler colonized with #Candida auris (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Simultaneous Infection with Enterobacteriaceae and Pseudomonas aeruginosa harboring Multiple Carbapenemases in a Returning Traveler colonized with Candida auris

Ayesha Khan, William C. Shropshire, Blake Hanson, An Q. Dinh, Audrey Wanger, Luis Ostrosky-Zeichner, Cesar A. Arias, William R. Miller

DOI: 10.1128/AAC.01466-19

 

ABSTRACT

We report our clinical experience treating a critically ill patient with polymicrobial infections due to multi-drug resistant Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa in a 56 year-old woman who received healthcare in India and was also colonized by Candida auris. A precision medicine approach using whole genome sequencing revealed a multiplicity of mobile elements associated with NDM-1, NDM-5, and OXA-181 and, supplemented by susceptibility testing, guided the selection of rational antimicrobial therapy.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; NDM1; E. Coli; Klebsiella pneumoniae; Pseudomonas aeruginosa; Candida auris.

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#Detection of #Candida auris #antifungal drug #resistance markers directly from #clinical skin #swabs (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Detection of Candida auris antifungal drug resistance markers directly from clinical skin swabs

Milena Kordalewska, Annie Lee, Yanan Zhao, David S. Perlin

DOI: 10.1128/AAC.01754-19

 

ABSTRACT

Accurate and rapid assessment of Candida auris antifungal drug resistance is crucial for effective infection prevention and control actions, and patient management. Here, performance of a molecular diagnostic platform, enabling rapid identification of FKS1 and ERG11 mutations conferring echinocandin and azole resistance, respectively, was evaluated on a panel of clinical skin swabs. Gene sequencing and antifungal susceptibility testing were used as “gold standard”. All swabs were correctly categorized as harboring wild-type or mutant C. auris.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Candida auris; Drugs resistance; Diagnostic tests; Echinocandins.

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#Isolation of #Candida auris from invasive and non-invasive samples of a #patient suffering from #vascular disease, #Italy, July 2019 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Isolation of Candida auris from invasive and non-invasive samples of a patient suffering from vascular disease, Italy, July 2019

Francesca Crea1,2, Giulia Codda2,3, Andrea Orsi4, Alberto Battaglini4, Daniele Roberto Giacobbe5, Emanuele Delfino5, Riccardo Ungaro5, Anna Marchese6

Affiliations: 1 Unità Operativa di Microbiologia, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy; 2 FC and GC contributed equally to this article; 3 Microbiology Unit, DISC University of Genoa, Genoa, Italy; 4 Unità Operativa di Igiene, University of Genoa (DISSAL) and Ospedale Policlinico San Martino-IRCCS, Genoa, Italy; 5 Unità Operativa Clinica Malattie Infettive, University of Genoa (DISSAL) and Ospedale Policlinico San Martino-IRCCS, Genoa, Italy; 6 Unità Operativa di Microbiologia, University of Genoa (DISC) and Ospedale Policlinico San Martino-IRCCS, Genoa, Italy

Correspondence:  Anna Marchese

Citation style for this article: Crea Francesca, Codda Giulia, Orsi Andrea, Battaglini Alberto, Giacobbe Daniele Roberto, Delfino Emanuele, Ungaro Riccardo, Marchese Anna. Isolation of Candida auris from invasive and non-invasive samples of a patient suffering from vascular disease, Italy, July 2019. Euro Surveill. 2019;24(37):pii=1900549. https://doi.org/10.2807/1560-7917.ES.2019.24.37.1900549

Received: 02 Sep 2019;   Accepted: 11 Sep 2019

 

Abstract

We recently isolated Candida auris from a blood culture and cutaneous swabs of a patient in her mid-70s. Our routine phenotypic methods failed to identify the microorganism, but it was identified by molecular tests and MALDI-TOF MS analysis. Our report, the first from Italy, further underlines the geographically wide distribution of C. auris and the need to confirm species identification of any suspicious colony as soon as possible to stop its spread.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Candida auris; Nosocomial outbreaks; Italy.

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What Is Known About #Candida auris (JAMA, summary)

[Source: Journal of the American Medical Association (JAMA), full page: (LINK). Summary, edited.]

JAMA Insights  / Clinical Update / September 6, 2019

What Is Known About Candida auris

Suzanne F. Bradley, MD1,2

Author Affiliations: 1 Infectious Diseases Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; 2 Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

JAMA. Published online September 6, 2019. doi:10.1001/jama.2019.13843

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Summary

Candida auris is a new species that was reported in Asia as a rare cause of ear infections in 2009; it had not been found among large repositories of yeast isolates collected prior to 2013.1,2 However, the widespread dissemination of C auris is not due to a single strain. For reasons that are not clear, multiple strains, called clades, have emerged independently in various parts of the world.1,2 Cases of C auris have been identified in 33 countries across 5 continents.1-3

(…)

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Article Information

Corresponding Author: Suzanne F. Bradley, MD, Infectious Diseases Section 111i, Veterans Affairs Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105 (sbradley@umich.edu).

Published Online: September 6, 2019. doi:10.1001/jama.2019.13843

Conflict of Interest Disclosures: Dr Bradley reported receiving grants from Pfizer and the Veterans Administration and is the editor in chief for the Infection Control & Hospital Epidemiology journal.

Keywords: Candida auris; Emerging diseases; Nosocomial outbreaks; Drugs resistance; Fluconazole.

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Efficacy of Delayed #Therapy with #Fosmanogepix (APX001) in a Murine Model of #Candida auris Invasive #Candidiasis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

Nathan P. Wiederhold, Laura K. Najvar, Karen J. Shaw, Rosie Jaramillo, Hoja Patterson, Marcos Olivo, Gabriel Catano, Thomas F. Patterson

DOI: 10.1128/AAC.01120-19

 

ABSTRACT

The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris. Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole resistant clinical isolate of C. auris. Twenty-four hours post-inoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg by intraperitoneal injection three times daily, or 260 mg/kg intraperitoneally twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (10 mg/kg intraperitoneally once daily) and continued for seven days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm, and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm, and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole resistant C. auris even when therapy is delayed.

Copyright © 2019 Wiederhold et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Candida auris; Invasive candidiasis; Drugs resistance; Fluconazole; Fosmanogepix; Capsofungin; Animal models.

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The NDV-3A #vaccine protects mice from #MDR #Candida auris #infection (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection

Shakti Singh, Priya Uppuluri, Zeinab Mamouei, Abdullah Alqarihi, Hana Elhassan, Samuel French, Shawn R. Lockhart, Tom Chiller, John E. Edwards Jr., Ashraf S. Ibrahim

Published: August 5, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1007460 / This is an uncorrected proof.

 

Abstract

Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host—a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.

 

Author summary

Candida auris has emerged as a major health concern to hospitalized patients and nursing home subjects. C. auris strains display multidrug resistance to current antifungal therapy and cause lethal infections. We have determined that C. auris harbors homologs of C. albicans Als cell surface proteins. The C. albicans NDV-3A vaccine, harboring the N-terminus of Als3p formulated with alum, generates cross-reactive antibodies against C. auris clinical isolates and protects neutropenic mice from hematogenously disseminated C. auris infection. Importantly, the NDV-3A vaccine displays an additive protective effect in neutropenic mice when combined with micafungin. Due to its proven safety and efficacy in humans against C. albicans infection, our studies support the expedited testing of the NDV-3A vaccine against C. auris in future clinical trials.

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Citation: Singh S, Uppuluri P, Mamouei Z, Alqarihi A, Elhassan H, French S, et al. (2019) The NDV-3A vaccine protects mice from multidrug resistant Candida aurisinfection. PLoS Pathog 15(8): e1007460. https://doi.org/10.1371/journal.ppat.1007460

Editor: Sarah L. Gaffen, University of Pittsburgh, UNITED STATES

Received: November 2, 2018; Accepted: June 26, 2019; Published: August 5, 2019

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This work was supported by NIH grant R01 AI063382 to JE and R01AI141202 to ASI. NovaDigm Therapeutics provided NDV-3A vaccine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JE, and AI are founders and shareholders of NovaDigm Therapeutics. All other co-authors have no formal association with NovaDigm. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or NIH.

Keywords: Candida auris; Drugs resistance; Vaccines; Animal models.

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#Epidemiologic #Shift in #Candidemia Driven by #Candida auris, South Africa, [#ZA] 2016–2017 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 9—September 2019 / Research

Epidemiologic Shift in Candidemia Driven by Candida auris, South Africa, 2016–2017

Erika van Schalkwyk2, Ruth S. Mpembe, Juno Thomas, Liliwe Shuping, Husna Ismail, Warren Lowman, Alan S. Karstaedt, Vindana Chibabhai, Jeannette Wadula, Theunis Avenant, Angeliki Messina, Chetna N. Govind, Krishnee Moodley, Halima Dawood, Praksha Ramjathan, Nelesh P. Govender2  , and for GERMS-SA

Author affiliations: National Institute for Communicable Diseases, Johannesburg, South Africa (E. van Schalkwyk, R.S. Mpembe, J. Thomas, L. Shuping, H. Ismail, N.P. Govender); Vermaak & Partners–Pathcare Pathologists, Johannesburg (W. Lowman); Wits Donald Gordon Medical Centre, Johannesburg (W. Lowman); University of the Witwatersrand, Johannesburg (W. Lowman, A.S. Karstaedt, V. Chibabhai, J. Wadula, A. Messina, N.P. Govender); University of Pretoria and Kalafong Provincial Tertiary Hospital, Pretoria, South Africa (T. Avenant); Netcare Hospitals Ltd, Johannesburg (A. Messina); Lancet Laboratories, Durban, South Africa (C.N. Govind, K. Moodley); University of KwaZulu-Natal, Durban (C.N. Govind, H. Dawood, P. Ramjathan); Grey’s Hospital, Pietermaritzburg, South Africa (H. Dawood); National Health Laboratory Service, Johannesburg (V. Chibabhai, J. Wadula, P. Ramjathan)

 

Abstract

Candida auris is an invasive healthcare-associated fungal pathogen. Cases of candidemia, defined as illness in patients with Candida cultured from blood, were detected through national laboratory-based surveillance in South Africa during 2016–2017. We identified viable isolates by using mass spectrometry and sequencing. Among 6,669 cases (5,876 with species identification) from 269 hospitals, 794 (14%) were caused by C. auris. The incidence risk for all candidemia at 133 hospitals was 83.8 (95% CI 81.2–86.4) cases/100,000 admissions. Prior systemic antifungal drug therapy was associated with a 40% increased adjusted odds of C. auris fungemia compared with bloodstream infection caused by other Candida species (adjusted odds ratio 1.4 [95% CI 0.8–2.3]). The crude in-hospital case-fatality ratio did not differ between Candida species and was 45% for C. auris candidemia, compared with 43% for non–C. auris candidemia. C. auris has caused a major epidemiologic shift in candidemia in South Africa.

Keywords: Candidemia; Candida auris; Nosocomial outbreaks; Drugs Resistance; South Africa.

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