Candida auris Further Differentiated: Possible Therapies?

Janis C. Kelly

March 31, 2017

The emerging Candida auris fungal pathogen is often multidrug resistant and hard to eradicate, but data from a systematic analysis suggest it may be susceptible to an experimental oral drug.

"This emerging fungal species has started to infect patients globally, causing invasive infections that are associated with a high death rate," senior author Mahmoud Ghannoum, PhD, from the Center for Medical Mycology, Case Western Reserve University and University Hospitals Cleveland Medical Center in Ohio, said in a university news release.

"It is multidrug-resistant, and some strains isolated from patients are resistant to all commercially available antifungal drugs. Multidrug-resistance used to be reported for bacteria only, and now we must add fungi to the list," he continued.

C auris infection has an associated-mortality rate approaching 60% and has a nasty propensity for evading diagnosis.

Emily Larkin, BS, and Christopher Hager, BS, both from the Center for Medical Mycology, Case Western Reserve University and University Hospitals Cleveland Medical Center, report their findings in an article published online February 21 and in the March issue of Antimicrobial Agents and Chemotherapy.

The company-funded study is the largest study to date of C auris characteristics, virulence factors, and antifungal sensitivity. The researchers also report in vitro data showing that the new, orally bioavailable antifungal drug SCY-078 (Scynexis, Inc) has potent activity against C auris, including growth inhibition, antibiofilm activity, and inhibition of cell division.

The researchers studied 16 different isolates from patients in India, Japan, South Korea, and Germany. The study's three main goals were to characterize the morphology and virulence factors of the isolates; assess the effectiveness of 11 drugs from different antifungal classes against each isolate; and evaluate the effect of the new, orally bioavailable antifungal drug SCY-078 on C auris growth, ultrastructure, and ability to form biofilms. SCY-078 is a 1,3-beta-D-glucan synthesis inhibitor active against multidrug-resistant Candida spp.

Larkin and colleagues tested the C auris isolates' drug susceptibility using broth microdilution to determine minimum inhibitory concentrations. The drugs tested were amphotericin B, anidulafungin, caspofungin, fluconazole, flucytosine, isavuconazole, itraconazole, micafungin, posaconazole, voriconazole, and the experimental drug SCY-078.

All but one of the C auris isolates had reduced susceptibility to fluconazole. Interestingly, the fluconazole-susceptible isolate was the only one taken from a nonblood source. More than one third of isolates were resistant to drugs from all three major classes of antifungals (azoles, polyenes, and echinocandins).

However, SCY-078 had potent antifungal activity against all isolates tested in vitro, showed antigrowth and antibiofilm activity, severely distorted yeast cell topography, and impeded yeast cell division.

"In summary, our study showed that C. auris expresses several virulence factors albeit to a lesser extent than C. albicans and in a strain-dependent manner. We demonstrated that SCY-078 is a potent drug and could be an important addition to the antifungal armamentarium to treat this multi-resistant species," the researchers conclude.

"There are clinical trial data accumulating for SCY078 for the treatment of candidiasis, which will be interesting to see. I am not sure that SCY-078 will offer any clinical benefit in treating C auris infections over the echinocandins, other than the advantage of oral administration," Cornelius J. Clancy, MD, associate professor of medicine, director of the Mycology Program, and chief of the Infectious Diseases Section, VA Pittsburgh Health Care System, Pennsylvania, told Medscape Medical News.

"The big question for the drug, in general, is whether completing a full course of treatment with an oral glucan synthase inhibitor is comparable or superior to courses of intravenous echinocandin treatment, or initial intravenous treatment with an echinocandin followed by stepping down to an oral agent like fluconazole," explained Dr Clancy, who was not involved in the current study.

Diagnosing C auris Remains a Challenge

"The clinical features of infections and the patients at risk are similar [for C auris and other Candida spp.] The major difference is the ability of C auris to persist in hospital environments and cause long-standing hospital outbreaks," said Dr Clancy, who recently coauthored An International Call to Arms about C auris.

"Hospitals in which C auris has emerged have had difficulty eradicating it from the environment, despite enhanced infection control efforts," he continued. "The almost universal resistance to fluconazole and high rates (35% - 40%) of resistance to amphotericin B are also notable. Fluconazole resistance, in particular, is important clinically, since this agent is commonly used to treat patients, particularly after the first couple of days of treatment."

Experts say two of the main challenges in C auris detection are the lack of specific clinical symptoms and signs and the fact that most widely available commercial phenotypic laboratory systems cannot identify the species.

"The key for clinicians is to communicate with the clinical microbiology laboratory at their centers, and understand whether the laboratory has the capacity to identify C auris," Dr Clancy said. "This will depend on the identification methods used in the lab. If a center is performing MALDI-TOF or DNA-based identification, then it should be able to detect C auris. If the microbiology lab is using less sophisticated testing methods, then C auris may be misidentified as unusual yeasts such as Candida haemulonii, [Candida] sake, [Candida] famata, Saccharomyces cerevisiae, or Rhodotorula glutinis," he explained.

"If clinicians are at centers that don't have the technology to identify C auris, and a case due to these unusual yeasts is encountered, then the isolate should be sent to a reference lab to make sure that it is not C auris."

The Centers for Disease Control and Prevention is actively tracking C auris infections and has asked laboratory workers who identify the species in a patient sample to contact state or local public health authorities, or send an email to candidaauris@cdc.gov.

"From a public health perspective, the major question right now is how extensive the emergence of C auris will be," Dr Clancy told Medscape Medical News. "Will it emerge all over the world? Will it emerge in most hospitals in a given geographic region, or be more isolated? Once it gets into a hospital, will it always prove difficult to eradicate? What infection control strategies are effective in controlling and eradicating it from the hospital? From an ecologic perspective, what environmental niches does it occupy? Why has it emerged now?"

The study was supported by Scynexis Inc and by the National Institutes of Health. One coauthor is an employee of Astellas Pharma Global Development, Inc. Three coauthors are employees of Scynexis Inc. Dr Clancy has disclosed no relevant financial relationships.

Antimicrob Agents Chemother. Published online February 21, 2017. Abstract

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