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Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
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Antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections

Bing Zhai1,2,3, Chen Liao4, Siddharth Jaggavarapu5,6,7,8

  • 1Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. bing.zhai@siat.ac.cn.

Nature Medicine
|August 2, 2024
PubMed

Insights

Breakthrough fungal infections in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are often caused by Candida parapsilosis heteroresistance to micafungin. Standard tests miss this resistance, impacting treatment effectiveness.

Area of Science:

  • Mycology
  • Infectious Diseases
  • Hematology

Background:

  • Breakthrough fungal infections, particularly invasive candidiasis, pose significant risks in patients receiving antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT).
  • Candida parapsilosis, a WHO high-priority pathogen, is a frequent cause of invasive candidiasis, and its resistance patterns are critical for patient outcomes.
  • Unexplained antifungal prophylaxis failures in high-risk allo-HCT recipients necessitate investigation into underlying resistance mechanisms.

Purpose of the Study:

  • To investigate the role of micafungin heteroresistance in breakthrough Candida parapsilosis bloodstream infections in patients undergoing allo-HCT.
  • To assess the prevalence of micafungin heteroresistance in C. parapsilosis isolates globally.
  • To develop a novel diagnostic approach for detecting micafungin heteroresistance.

Main Methods:

  • Analysis of 219 clinical C. parapsilosis isolates from diverse geographical regions.
  • Evaluation of standard antimicrobial susceptibility testing methods for their ability to detect micafungin heteroresistance.
  • Development and validation of a machine learning framework utilizing genomic features for heteroresistance prediction.

Main Results:

  • Micafungin heteroresistance, characterized by a low-frequency resistant subpopulation, was identified as a key factor in breakthrough C. parapsilosis infections in allo-HCT patients.
  • Widespread prevalence of micafungin heteroresistance was observed across global isolates of C. parapsilosis.
  • Standard susceptibility assays failed to detect micafungin heteroresistance, highlighting a critical diagnostic gap.

Conclusions:

  • Heteroresistance in Candida parapsilosis explains previously unexplained micafungin prophylaxis failures in allo-HCT recipients.
  • A machine learning framework offers a promising tool for rapid and accurate detection of micafungin heteroresistance.
  • This diagnostic approach has the potential to guide clinical decision-making and improve patient care in high-risk populations.

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