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In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak
YanChun Zhu1, Shannon Kilburn1, Mili Kapoor2
1Mycology Laboratory, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
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.
Insights
Manogepix (MGX) effectively combats drug-resistant Candida auris, including panresistant strains, demonstrating potent antifungal activity. This novel agent shows promise for treating challenging C. auris infections, supporting further clinical development of its prodrug, fosmanogepix.
Area of Science:
- Mycology
- Infectious Diseases
- Antimicrobial Resistance
Background:
- The New York metropolitan area faces a significant outbreak of *Candida auris*, a multidrug-resistant fungal pathogen.
- Existing antifungal treatments show variable efficacy against *C. auris*, with some isolates exhibiting panresistance, necessitating novel therapeutic agents.
- Manogepix (MGX), a Gwt1 enzyme inhibitor, represents a first-in-class antifungal candidate, with its prodrug fosmanogepix undergoing clinical trials.
Purpose of the Study:
- To evaluate the in vitro susceptibility of *Candida auris* isolates from a New York outbreak to Manogepix (MGX) and comparator antifungal drugs.
- To assess the activity of MGX against panresistant *C. auris* strains.
- To determine the potential of fosmanogepix for treating *C. auris* infections.
Main Methods:
- Susceptibility testing of 200 New York *C. auris* isolates against MGX and 10 other antifungal drugs using Clinical and Laboratory Standards Institute (CLSI) methodology.
- Determination of Minimum Inhibitory Concentrations (MICs), MIC50, MIC90, and geometric means for all tested agents.
- Comparison of MGX activity against wild-type and panresistant *C. auris* strains.
Main Results:
- MGX exhibited potent activity against all *C. auris* isolates, with lower MIC values (MIC50/MIC90 = 0.03 mg/liter) compared to comparator drugs.
- All isolates tested were susceptible to MGX, falling within the wild-type (WT) population, with an epidemiological cutoff value (ECV) of 0.06 mg/liter.
- MGX demonstrated significantly higher potency than echinocandins, azoles, and amphotericin B, and retained activity against six panresistant *C. auris* isolates (MIC range: 0.008-0.015 mg/liter).
Conclusions:
- Manogepix (MGX) displays robust in vitro activity against a wide range of *Candida auris* isolates, including highly resistant strains.
- The potent and consistent activity of MGX supports its further clinical evaluation as a promising therapeutic option for invasive *C. auris* infections.
- Fosmanogepix represents a viable treatment strategy to address the growing challenge of antifungal resistance posed by *Candida auris*.
