Tag Archives: Candida Auris

Microbiology

Antiviral drugs may be a new treatment strategy in the fight against Candida auris

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Reviewed by Megan Craig, M.Sc.May 25 2023

Antiviral drugs can make antifungals work again.

That, at its simplest, is the approach Mohamed Seleem’s lab at the Center for One Health Research has found may be a key treatment strategy in the battle against Candida auris, a frighteningly deadly fungal pathogen discovered in 2009 that is considered an urgent threat by the Centers for Disease Control and Prevention (CDC).

Candida auris, first discovered in Japan as an ear infection, has a staggering 60 percent mortality rate among those it infects, primarily people with compromised health in hospitals and nursing homes.

Recently, Seleem and Ph.D. students Yehia Elgammal and Ehab A. Salama published a paper in the American Society for Microbiology’s Antimicrobial Agents and Chemotherapy journal detailing the potential use of atazanavir, an HIV protease inhibitor drug, as a new avenue to improving the effectiveness of existing antifungals for those with a Candida auris infection.

A perfect storm of antimicrobial resistance, global warming and the COVID-19 pandemic has resulted in the rapid spread of Candida auris around the world, said Seleem, director of the center, a collaboration between the Virginia-Maryland College of Veterinary Medicine and the Edward Via College of Osteopathic Medicine.

We don’t have lots of drugs to use to treat fungal pathogens. We have only three classes of antifungal drugs. With a fungal pathogen, it’s often resistant to one class, but then we have two other options. What’s scary about Candida auris is it shows resistance to all three classes of the antifungal.

The CDC has a list of urgent threats, but on that list there is just one fungal pathogen, which is Candida auris. Because it’s urgent, we need to deal with it.”

Mohamed Seleem, the Tyler J. and Frances F. Young Chair in Bacteriology at Virginia Tech

Widespread use of fungicides in agriculture, in addition to the three classes of antifungal drugs used widely in medicine, has contributed to fungal pathogens developing more resistance, particularly Candida auris.

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Also, its rise has been linked to rising global temperatures and to easier spread through hospitals filled with COVID-19 patients in recent years during the global pandemic.

Atazanavir, an HIV protease inhibitor drug, has been found by Seleem’s lab to block the ability of Candida auris to excrete antifungals through its efflux pumps.

Think of a boat taking on water and hoses siphoning that water out of the boat to keep it afloat. Atazanavir stops up the hoses.

That allows the azole class of antifungal drugs to not be expelled as easily and perform better against Candida auris, the Seleem lab’s research has found.

The research on atazanavir builds on work three years ago by Seleem’s lab, then at Purdue University, finding potentially similar benefit in lopinavir, another HIV protease inhibitor.

HIV protease drugs are already in wide use among HIV patients, who can also be extra susceptible to Candida auris. Some HIV patients have likely been taking HIV protease drugs and azole-class antifungals in tandem for separate purposes, providing a potential source of already existing data that can be reviewed on whether those patients had Candida auris and what effects the emerging pathogen had on them.

Repurposing drugs already on the market for new uses can allow those treatments to reach widespread clinical use much more rapidly than would happen with the discovery of an entirely new drug, as existing drugs have already been tested and approved by the Food and Drug Administration and have years of further observation of effects in prescriptive use.

In 2022, the Center for One Health Research received a $1.9 million grant from the National Institutes of Health for the Seleem lab’s research on repurposing already approved drugs for treating gonorrhea.

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Virginia Tech

Microbiology

How do Candida auris and other fungi develop drug resistance? A microbiologist explains

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One of the scariest things you can be told when at a doctor’s office is “You have an antimicrobial-resistant infection.” That means the bacteria or fungus making you sick can’t be easily killed with common antibiotics or antifungals, making treatment more challenging. You might have to take a combination of drugs for weeks to overcome the infection, which could result in more severe side effects.

Unfortunately, this diagnosis is becoming more common around the world.

The yeast Candida auris has recently emerged as a potentially dangerous fungal infection for hospital patients and nursing home residents. First discovered in the late 2000s, Candida auris has very quickly become a major health challenge due to its ease of spread and ability to resist common antifungal drugs.

How did this fungus become so strong, and what can researchers and physicians do to combat it?

I am a microbiologist researching new ways to kill fungi. Candida auris and other fungi use three common cellular tricks to overcome treatments. Luckily, exciting new research hints at ways we can still fight this fungus.

Fungal cells contain a structure called a cell wall that helps maintain their shape and protects them from the environment. Fungal cell walls are constructed in part from several different types of polysaccharides, which are long strings of sugar molecules linked together.

Two polysaccharides found in almost all fungal cell walls are chitin and beta-glucan. The fungal cell wall is an attractive target for drugs because human cells do not have a cell wall, so drugs that block chitin and beta-glucan production will have fewer side effects.

Some of the most common drugs used to treat fungal infections are called echinocandins. These drugs stop fungal cells from making beta-glucan, which significantly weakens their cell wall. This means the fungal cell can’t maintain its shape well. While the fungus is struggling to grow or is breaking apart, your immune system has a much better chance of fighting off the infection.

Unfortunately, some strains of Candida auris are resistant to echinocandin treatment. But how does the fungus actually do it? For decades, scientists have been studying how fungi overcome drugs designed to weaken or kill them. In the case of echinocandins, Candida auris commonly uses three tricks to beat these treatments: hide, build and change.

The first trick is to hide in a complex mixture of sugars, proteins, DNA and cells called a biofilm. Made with irregular 3D structures, biofilms have lots of places for cells to hide. Drugs aren’t good at penetrating biofilms, so they can’t access and kill cells deep inside. Biofilms are especially problematic when they grow on medical equipment like ventilators or catheters. Once free of a biofilm, cells that have gained the ability to resist the drugs a patient was taking become more dangerous.

The second trick fungi use to evade treatment is to build cell walls differently. Fungal cells treated with echinocandins can’t make beta-glucan. So instead, they start to make more chitin, another important polysaccharide in the fungal cell wall. Echinocandins are unable to stop chitin production, so the fungus is still able to build a strong cell wall and avoid being killed. While there are some drugs that can stop chitin production, none are currently approved for use in people.

The third trick fungi rely on is to change the shape of the beta-glucan production enzyme so echinocandins cannot block it. These mutations allow beta-glucan production to continue even in the presence of the drug. It is not surprising that Candida uses this trick to resist antifungal drugs since it is very effective at keeping the cells alive.

What can be done to treat echinocandin-resistant fungal infections? Thankfully, scientists and physicians are researching new ways to kill Candida auris and similar fungi.

The first approach is to find new drugs. For example, there are two drugs in development, rezafungin and ibrexafungerp, that appear to be able to stop beta-glucan production even in fungi resistant to echinocandins.

A complementary approach my research group is exploring is whether a class of enzymes called glycoside hydrolases might also be able to combat drug-resistant fungi. Some of these enzymes actively destroy the fungal cell wall, breaking apart both beta-glucan and chitin at the same time, which could potentially help prevent fungi from surviving on medical equipment or on hospital surfaces.

My lab’s work on discovering enzymes that strongly degrade fungal cell walls is part of a new strategy to combat antifungal resistance that uses a combination of approaches to kill fungi. But the end goal of this research is the same: having a physician tell you, “You’ve got a fungal infection, but we have a good treatment for it now.”


Jeffrey Gardner

The Conversation

Microbiology

Possible pathways of C. auris emergence and the hypothetical role of interspecies transmission

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Tarun Sai LomteBy Tarun Sai LomteMar 27 2023Reviewed by Lily Ramsey, LLM

In a recent study published in the journal Clinical Microbiology and Infection, researchers in Spain, summarized the current understanding of the emergence and ecologic niches of Candida auris.

Study: Climate change, animals, and Candida auris: insights into the ecological niche of a new species from a one health approach. Image Credit: Kateryna Kon/Shutterstock.com
Study: Climate change, animals, and Candida auris: insights into the ecological niche of a new species from a one health approach. Image Credit: Kateryna Kon/Shutterstock.com

Background

C. auris was first identified in a Japanese inpatient in 2009. The United States (US) Centers for Disease Control and Prevention (CDC) categorized the pathogen as an urgent threat. Moreover, C. auris has been designated as a fungal pathogenic species of critical concern by the World Health Organization (WHO) in their fungal priority list in October 2022.

Five clonally distinct clades of this fungus emerged independently and concurrently on three continents. Whole-genome sequencing of 47 isolates identified many single nucleotide polymorphisms (SNPs) with minimal intra-regional genetic diversity, suggesting a near-contemporary emergence in distinct geographic locations.

In the present study, the authors discussed the likely pathways of the emergence of C. auris and the role of inter-species transmission. In doing so, the study postulates that climate change has played a major role in high thermotolerant C. auris emergence. Thus, hypothesizing that climate change induced an environmental ancestor to become pathogenic through thermal adaptation.

Hypothetical emergence due to global warming

Global warming is proposed as the likely explanation for the independent and contemporary emergence of distinct C. auris clades. Few fungal species are pathogenic in endothermal animals and humans; very few fungi thrive at mammals’ high basal temperatures, creating a thermal barrier preventing infections.

Several reports suggest that increasing environmental temperatures due to climate change may result in the selection of thermotolerant fungal lineages that can circumvent the thermal barrier and infect/colonize endothermic animals.

One study showed that C. auris could grow at elevated temperatures than its close phylogenetic relatives. In addition, the remarkable halotolerance exhibited by this fungus suggested that it could have previously existed as an environmental species in wetlands/marshes.

These ancestors might have become pathogens in humans after gaining thermotolerance due to climate change adaptation. Nevertheless, this hypothesis cannot explain the geographic dispersion of the independently evolved clades of C. auris.

Ecological niche(s) of C. auris

The first environmental isolates of C. auris were reported in 2021 from a salt marsh in the Andaman Islands and recently in Colombian estuaries. Notably, one of the isolates was less multidrug-resistant and less heat-tolerant.

It was also significantly different from clinical isolates suggesting a higher similarity to its wild ancestors from marine ecosystems.

C. auris also exhibits high-stress resistance, allowing for continued survival in stressful environments. This plasticity might contribute to its emergence and growing prevalence. Further, this fungus was detected in stored but not freshly pickled apples in India, suggesting a new human transmission pathway and a possible selection route for drug-resistant isolates in agriculture, storage, and supply chains.

Isolation from animal cultures or the environment has not been documented yet. Nonetheless, a study employing in silico DNA metabarcoding screened the internal transcribed spacer region in public datasets.

DNA metabarcoding identified partial matches in non-human sources, such as activated sludge, air dust, the ear canal of a dog with otitis, peanut fields, and the skin of newts. This provided evidence of the ubiquitous presence of the fungus in anthropogenic and natural environments.

One Health approach to understand and manage C. auris

One Health is an integrative, collaborative, multi/trans-disciplinary approach for sustainable balance and optimization of the health of humans, animals, and ecosystems.

Zoophilic fungi and, hypothetically, C. auris might have a dual life cycle wherein host, and environmental reservoirs may serve as durable sources of propagules. This might contribute to the global rise of emergent fungal diseases across continents.

Concluding remarks

The striking plasticity and the ability of C. auris to adapt to harsh environments could allow the fungus to thrive in sludge, wastewater, and fresh/marine waters.

Global warming, the impact of changes in the environment and human population, and indiscriminate antifungal use in agriculture might have led to C. auris evolving into a much more resistant/invasive pathogen that can infect/colonize endothermic animals.

Aquatic marine hosts could have spread primitive strains to humans. Therefore, adopting the One Health approach can help understand the relationship between animal/human health and ecological changes as factors in the emergence and transmission of fungal pathogens.

Journal reference:
Microbiology

High-resolution mass spectrometric rapid identification of Candida auris

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Dr. Priyom Bose, Ph.D.By Dr. Priyom Bose, Ph.D.Mar 23 2023Reviewed by Danielle Ellis, B.Sc.

A recent study published in the Journal of Fungi used a novel OrbitrapTM high-resolution mass spectrometric technology coupled with liquid chromatography to identify geographically different clades of Candida auris (C. auris) isolates. This proof-of-concept methodology could accurately detect C. auris in the microbiology laboratory.

Study: Fast and Accurate Identification of Candida auris by High Resolution Mass Spectrometry. Image Credit: Jens Goepfert / ShutterstockStudy: Fast and Accurate Identification of Candida auris by High Resolution Mass Spectrometry. Image Credit: Jens Goepfert / Shutterstock

Background

Over a decade ago, C. auris was first found in East Asia, causing bloodstream infections. Although this fungal infection was initially found in India, South America, South Africa, and the Middle East, it soon prevailed globally. 

C. auris soon became a common nosocomial fungal pathogen, particularly among intensive care unit (ICU) patients. As a result, the Centers for Disease Control and Prevention (CDC) has classified C. auris as an urgent threat pathogen.

An important factor that allows C. auris outbreaks worldwide is the improper identification of yeast pathogens in hospital laboratories. Hence, there is an urgent need for accurate and rapid identification of C. auris in hospital laboratories, which can reduce their transmission in healthcare facilities.

Genomic analysis of worldwide C. auris isolates has indicated that around five clades have emerged in the last 20 years, independently and simultaneously. These five distinct geographically restricted clades are clade I: South Asia, clade II: East Asia, clade III: Africa, clade IV: South America, and clade V: Iran. Each clade differs from the other by around ten thousand single-nucleotide polymorphisms. 

Each clade has differential resistance to antifungal agents; for example, clade I is more resistant to fluconazole, while clade II exhibits susceptibility. Currently, C. auris isolates belonging to these clades have been introduced to many countries worldwide. Scientists have highlighted the importance of quickly identifying and monitoring these clades to restrict further spread. 

C. auris possesses several structurally unique sphingolipids and mannoproteins, enabling it to adhere to medical devices and hospital environments persistently. These proteins also aid in biofilm formation and prevent elimination by common disinfectants.

Several studies have indicated that molecular techniques fail to identify C. auris, whereas matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) technology can accurately identify this fungus at the species level.

The Study and its Findings

102 clinical C. auris strains were selected, representing all five clades. These clades were determined based on a short tandem repeat (STR) typing assay, which was subsequently compared to whole-genome sequencing results.

The current study applied OrbitrapTM high-resolution mass spectrometric technology to identify C. auris based on protein analysis methods. This technique was combined with liquid chromatography (LC) for initial separation. In this method, electrospray ionization (ESI) transfers proteins into the gas phase for ionization and is subsequently introduced to the mass spectrometer (LC-MS).

Mass analysis is conducted by either fragment ions or intact mass (MS) through tandem mass spectrometry (MS/MS). Some of the key features of the OrbitrapTM mass analyzer are a high resolution of up to 200,000, a high mass-to-charge ratio of 6,000, high mass accuracy between 2 and 5 ppm, and a dynamic range greater than 104.

C. auris clade differentiation using monoisotopic mass measurements depicted as heat map. Color scale ranges from blue (max signal) to dark red (no signal), representing abundance of measured monoisotopic masses in each strain. Clade specific differential protein masses are visible from the rectangular vertical boxes indicating the geographic affiliation and clade assignment and its vertically associated dendrogram indicating observed protein masses (columns vs. rows). X-axis indicating clade assignment and y-axis indicating observed MS1 protein masses.

In addition, this method is highly sensitive and can measure the exact mass of a compound. It can also identify minor structural changes due to a translated single nucleotide polymorphism into an amino acid change.

Importantly, this newly developed technology could identify all C. auris isolates with high confidence. Furthermore, it could differentiate C. auris across clades. Even though a limited number of isolates were present from each clade, this spectrometric technology identified C. auris clades with 99.6% identification accuracy.

Based on a principal component analysis (PCA) and a subsequent affinity clustering study, the South Asian, East Asian, and Iranian C. auris clades were more proteomically closely related. Long branches in the affinity clustering analysis suggested that the C. auris strains were present as outliers that required more attention, regardless of the detection technique.

Proteomic typing results indicated the capacity to track strains of the same origin isolated from diverse geographical locations. In the future, more precise matching and alignment of typing schemes (based on next-generation sequencing) is required to build on these results. This would significantly reduce false identifications and classifications of unknown strains associated with new clades or lineage.

Conclusions

Although the workflow linked to mass spectrometry and next-generation sequencing are not directly comparable, their results are similar, i.e., identifying unknown clinical microbes. The standard next-generation sequencing method is a highly time-consuming process that requires many delicate time-intensive quality-control steps, particularly during multiplexed sample runs.

In contrast, the newly developed methodology can provide results within 60 minutes. Therefore, applying the high-resolution OrbitrapTM mass spectrometer to accurately and rapidly identify C. auris clades is an attractive alternative to conventional platforms.

Journal reference:
  • Jamalian, A. et al. (2023) “Fast and Accurate Identification of Candida auris by High Resolution Mass Spectrometry”, Journal of Fungi, 9(2), p. 267. doi: 10.3390/jof9020267, https://www.mdpi.com/2309-608X/9/2/267
Microbiology

Candida auris infection without epidemiologic links to a prior outbreak

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Dr. Priyom Bose, Ph.D.By Dr. Priyom Bose, Ph.D.Mar 23 2023Reviewed by Danielle Ellis, B.Sc.

The Centers for Disease Control and Prevention (CDC) has classified Candida auris (C. auris) as an urgent public threat due to its role in elevating mortality, its ability to persist in hospital environments, and the high possibility of developing pan-drug resistance.

Notably, a recent study published in the journal Open Forum Infectious Diseases has pointed out that surfaces near patients with C. auris quickly become re-contaminated after cleaning.

Existing research has not adequately elucidated the environmental reservoirs of C. auris. Further, few studies have reported epidemiologic links associated with C. auris infection. 

Study: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship?. Image Credit: Kateryna Kon / ShutterstockStudy: The Emergence and Persistence of Candida auris in Western New York with no Epidemiologic Links: A Failure of Stewardship? Image Credit: Kateryna Kon / Shutterstock

Background

C. auris is a species of fungus that grows as yeast. It is one of the few species of the genus Candida which cause candidiasis in humans. In the past, C. auris infection was primarily found in cancer patients or those subjected to feeding tubes.

In the United States (US), the emergence of C. auris was traced to New York, and surveillance for this fungal infection was focused mainly on New York City to detect outbreaks. Recently, scientists investigated the association between genomic epidemiology and C. auris infection in Western New York.

A Case Study

The study describes the emergence of C. auris in a patient hospitalized at a small community hospital in Genesee County, New York (NY). In January 2022, C. auris was isolated from the urine culture of a 68-year-old male on the 51st day of hospitalization.

This patient had no known epidemiological connections outside his immediate community. Before his hospitalization, he was not exposed to other patients or family members associated with C. auris infection.

This patient had no history of organ transplantation, decubitus ulcers, hemodialysis, feeding tubes, or nursing home stays. He had an active lifestyle with a history of mild vascular dementia. He was hospitalized due to pneumonia and was prescribed azithromycin treatment.

Post hospitalization, he tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and was treated with dexamethasone (6 mg) daily for 10 days and remdesivir (200 mg) once, followed by 100 mg daily for five days.

Since the patient’s chest radiograph showed left lobar consolidation, he was further treated with empiric ceftriaxone and azithromycin. As the respiratory symptoms deteriorated, he received non-invasive positive pressure ventilation, with subsequent endotracheal intubation for eight days. He was successfully extubated. He developed a fever and received antimicrobial therapy for 73 days. The patient had a urinary catheter and a peripherally inserted central line in his arm for 35 days. 

Microbiology culture test and serum procalcitonin levels remained negative and within normal levels. On the 22nd day of hospitalization, Candida albicans were isolated from respiratory samples. On the 51st day, the urine culture revealed the presence of azole-resistant C. auris.

The isolated C. auris (MRSN101498) was forwarded to the Multidrug-resistant organism Repository and Surveillance Network (MRSN), where genomic sequencing was performed. After the patient was discharged, the hospital room was cleaned using hydrogen peroxide and peracetic acid, followed by ultraviolet-C light. Other patients who shared rooms with the patient with C. auris were tested for infection.

Study Outcomes

C. auris was not detected in the Western NY community hospital in the past year. Physicians stated that the patient received excessive antibiotic treatment for a prolonged period. Genomic studies revealed that the MRSN101498 genome sequence was closely related to the 2013 Indian strain with minor genomic differences. Interestingly, the K143R mutation in ERG11 was found in MRSN101498, which is associated with triazole resistance in Candida albicans.

Whole genome single nucleotide polymorphism (SNP) analysis also highlighted that MRSN101498 was strongly genetically related to four other isolates, with marginal differences.

These isolates were linked to an outbreak in March 2017 in a hospital 47 miles northeast of Rochester, NY. Based on the current findings, it is highly likely that isolates from Western NY share a recent common ancestor.

Study Importance

This case study is important for several reasons, including the absence of epidemiologic links to C.auris infection. Since reports from rural sectors are rare, this study addresses a vital surveillance ‘blind spot.’ 

However, the current study failed to identify the potential reservoirs of MRSN101498 in Western NY. Sporicidal disinfectants were inefficient for both Clostridioides difficile and C. auris. However, terminal cleaning protocols that included UV irradiation and sporicidal cleaning agents were able to eradicate C. auris effectively.

The current study highlights the role of excessive antibiotic exposure in the emergence of C. auris. It also indicates the challenges in eliminating fungi from hospital settings. The authors recommend proper antibiotic treatment and cleaning procedures for drug-resistant pathogens.

Journal reference: