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Published Date: 2019-04-07 14:39:14
Subject: PRO/AH/EDR> Candida auris: MDR, emergence due to agricultural use of azoles, susp.
Archive Number: 20190407.6409119
CANDIDA AURIS: MULTIDRUG RESISTANT, EMERGENCE DUE TO AGRICULTURAL USE OF AZOLES, SUSPECTED
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International Society for Infectious Diseases
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Date: Sat 6 Apr 2019
Source: New York Times [abridged, edited]
https://www.nytimes.com/2019/04/06/health/drug-resistant-candida-auris.html


A deadly, drug-resistant fungus is infecting patients in hospitals and nursing homes around the world. The germ, a fungus called _Candida auris_, preys on people with weakened immune systems, and it is quietly spreading across the globe. Over the last 5 years, it has hit a neonatal unit in Venezuela, swept through a hospital in Spain, forced a prestigious British medical center to shut down its intensive care unit, and taken root in India, Pakistan and South Africa. Recently _C. auris_ reached New York, New Jersey and Illinois, leading the federal Centers for Disease Control and Prevention to add it to a list of germs deemed "urgent threats."

_C. auris_ is so tenacious, in part, because it is impervious to major antifungal medications, making it a new example of one of the world's most intractable health threats: the rise of drug-resistant infections. For decades, public health experts have warned that the overuse of antibiotics was reducing the effectiveness of drugs that have lengthened life spans by curing bacterial infections once commonly fatal. But lately, there has been an explosion of resistant fungi as well, adding a new and frightening dimension to a phenomenon that is undermining a pillar of modern medicine. "It's an enormous problem," said Matthew Fisher, a professor of fungal epidemiology at Imperial College London, who was a co-author of a recent scientific review on the rise of resistant fungi. "We depend on being able to treat those patients with antifungals."

Simply put, fungi, just like bacteria, are evolving defenses to survive modern medicines. Yet even as world health leaders have pleaded for more restraint in prescribing antimicrobial drugs to combat bacteria and fungi -- convening the United Nations General Assembly in 2016 to manage an emerging crisis -- gluttonous overuse of them in hospitals, clinics and farming has continued.

Resistant germs are often called "superbugs," but this is simplistic because they don't typically kill everyone. Instead, they are most lethal to people with immature or compromised immune systems, including newborns and the elderly, smokers, diabetics and people with autoimmune disorders who take steroids that suppress the body's defenses.

Scientists say that unless more effective new medicines are developed and unnecessary use of antimicrobial drugs is sharply curbed, risk will spread to healthier populations. A study that the British government funded projects that if policies are not put in place to slow the rise of drug resistance, 10 million people could die worldwide of all such infections in 2050, eclipsing the 8 million expected to die that year from cancer.

In the United States, 2 million people contract resistant infections annually, and 23 000 die from them, according to the official CDC estimate. That number was based on 2010 figures; more recent estimates from researchers at Washington University School of Medicine put the death toll at 162 000. Worldwide fatalities from resistant infections are estimated at 700 000.

Antibiotics and antifungals are both essential to combat infections in people, but antibiotics are also used widely to prevent disease in farm animals, and antifungals are also applied to prevent agricultural plants from rotting. Some scientists cite evidence that rampant use of fungicides on crops is contributing to the surge in drug-resistant fungi infecting humans.

Yet as the problem grows, it is little understood by the public, in part because the very existence of resistant infections is often cloaked in secrecy.

With bacteria and fungi alike, hospitals and local governments are reluctant to disclose outbreaks for fear of being seen as infection hubs. Even the CDC, under its agreement with states, is not allowed to make public the location or name of hospitals involved in outbreaks. State governments have in many cases declined to publicly share information beyond acknowledging that they have had cases.

All the while, the germs are easily spread, carried on hands and equipment inside hospitals; ferried on meat and manure-fertilized vegetables from farms; transported across borders by travelers and on exports and imports; and transferred by patients from nursing home to hospital and back.

Other prominent strains of the fungus _Candida_ -- one of the most common causes of bloodstream infections in hospitals -- have not developed significant resistance to drugs, but more than 90 percent of _C. auris_ infections are resistant to at least one drug, and 30 percent are resistant to 2 or more drugs, the CDC said. Dr. Lynn Sosa, Connecticut's deputy state epidemiologist, said she now saw _C. auris_ as "the top" threat among resistant infections. "It's pretty much unbeatable and difficult to identity," she said.

Nearly half of patients who contract _C. auris_ die within 90 days, according to the CDC. Yet the world's experts have not nailed down where it came from in the 1st place. "It is a creature from the black lagoon," said Dr. Tom Chiller, who heads the fungal branch at the CDC, which is spearheading a global detective effort to find treatments and stop the spread. "It bubbled up, and now it is everywhere."

On 24 Jun 2016, the CDC blasted a nationwide warning to hospitals and medical groups and set up an email address, <candidaauris@cdc.gov>, to field queries. Dr. Snigdha Vallabhaneni, a key member of the fungal team, expected to get a trickle, "maybe a message every month." Instead, within weeks, her inbox exploded. In the United States, 587 cases of people having contracted _C. auris_ have been reported, concentrated with 309 in New York, 104 in New Jersey and 144 in Illinois, according to the CDC. Most cases in the United States have been in nursing homes in New York City, Chicago and New Jersey.

As the CDC works to limit the spread of drug-resistant _C. auris_, its investigators have been trying to answer the vexing question: Where in the world did it come from?

The 1st time doctors encountered _C. auris_ was in the ear of a woman in Japan in 2009 (auris is Latin for ear). It seemed innocuous at the time, a cousin of common, easily treated fungal infections. Three years later, it appeared in an unusual test result in the lab of Dr. Jacques Meis, a microbiologist in Nijmegen, the Netherlands, who was analyzing a bloodstream infection in 18 patients from 2 hospitals in India. Soon, new clusters of _C. auris_ seemed to emerge with each passing month in different parts of the world. The CDC investigators theorized that _C. auris_ started in Asia and spread across the globe. But when the agency compared the entire genome of _auris_ samples from India and Pakistan, Venezuela, South Africa and Japan, it found that its origin was not a single place, and there was not a single _auris_ strain. The genome sequencing showed that there were 4 distinctive versions of the fungus, with differences so profound that they suggested that these strains had diverged thousands of years ago and emerged as resistant pathogens from harmless environmental strains in 4 different places at the same time.

"Somehow, it made a jump almost seemingly simultaneously, and seemed to spread, and it is drug resistant, which is really mind-boggling," Dr. Vallabhaneni said.

There are different theories as to what happened with _C. auris_. Dr. Meis, the Dutch researcher, said he believed that drug-resistant fungi were developing thanks to heavy use of fungicides on crops. Dr. Meis became intrigued by resistant fungi when he heard about the case of a 63-year-old patient in the Netherlands who died in 2005 from a fungus called _Aspergillus_. It proved resistant to a front-line antifungal treatment called itraconazole. That drug is a virtual copy of the azole pesticides that are used to dust crops the world over and account for more than 1/3rd of all fungicide sales.

A 2013 paper in Plos Pathogens said that it appeared to be no coincidence that drug-resistant _Aspergillus_ was showing up in the environment where the azole fungicides were used [1]. The fungus appeared in 12 percent of Dutch soil samples, for example, but also in "flower beds, compost, leaves, plant seeds, soil samples of tea gardens, paddy fields, hospital surroundings, and aerial samples of hospitals." Dr. Meis visited the CDC last summer [2018] to share research and theorize that the same thing is happening with _C. auris_, which is also found in the soil: Azoles have created an environment so hostile that the fungi are evolving, with resistant strains surviving.

This is similar to concerns that resistant bacteria are growing because of excessive use of antibiotics in livestock for health and growth promotion. As with antibiotics in farm animals, azoles are used widely on crops. "On everything, potatoes, beans, wheat, anything you can think of, tomatoes, onions," said Dr. Rhodes, the infectious disease specialist who worked on the London outbreak. "We are driving this with the use of antifungicides on crops."

Dr. Chiller theorizes that _C. auris_ may have benefited from the heavy use of fungicides. His idea is that _C. auris_ actually has existed for thousands of years, hidden in the world's crevices, a not particularly aggressive bug. But as azoles began destroying more prevalent fungi, an opportunity arrived for _C. auris_ to enter the breach, a germ that had the ability to readily resist fungicides now suitable for a world in which fungi less able to resist are under attack.

The mystery of _C. auris_'s emergence remains unsolved, and its origin seems, for the moment, to be less important than stopping its spread.

For now, the uncertainty around _C. auris_ has led to a climate of fear, and sometimes denial.

[Byline: Matt Richtel, Andrew Jacobs]

[The unabridged article is available at the source URL. - ModML]

[1. Chowdhary A, Kathuria S, Xu J, Meis JF (2013) Emergence of Azole-Resistant _Aspergillus fumigatus_ Strains due to Agricultural Azole Use Creates an Increasing Threat to Human Health. PLoS Pathog 9(10): e1003633. Available at: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003633.]

--
Communicated by:
Tom Baugh
Biologist/Ecologist
Hidden Springs

[The news article above concerns the relatively recent global emergence of a multidrug resistant yeast, _Candida auris_, as a human pathogen. The editors of the New York Times judged its importance by placing it on the top of the front page of its Sunday edition today (Sun 7 Apr 2019).

Much of the information in the article was presented in prior ProMED-mail posts that 1st appear in 2016, when the CDC issued an alert that healthcare facilities around the world found _C. auris_ was causing invasive healthcare-associated infections with high mortality, with a potential to cause nosocomial outbreaks. Patients were found to have similar risk factors for infections that other _Candida_ spp. have, including diabetes mellitus, recent surgery, recent antibiotics, and presence of central venous catheters. At the time, _C. auris_ was found in 9 countries (South Korea, India, South Africa, Kuwait, Colombia, Venezuela, Pakistan, U.S. and the United Kingdom) on 4 continents since 2009; only one isolate of _C. auris_ had been detected in the United States in 2013. Isolates persist on body surfaces and in the environment for prolonged periods. Strains of _C. auris_ had elevated minimum inhibitory concentrations (MICs) to the 3 major classes of antifungals, including azoles, echinocandins, and polyenes, severely limiting treatment options; echinocandins remain the drugs most likely to be active against this emerging infection.

Also _C. auris_ may have been and is still being missed by many labs when relying on traditional, commercially available, biochemical methods, which can mistakenly identify _C. auris_ as other species or report it as simply "other _Candida_ spp." Some matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) devices and molecular methods based on gene sequencing can identify _C. auris_; but these tests may only be available at reference laboratories. Many hospital labs also do not perform antifungal sensitivities on the _Candida_ isolates.

Molecular typing showed that _C. auris_ isolates are highly related within a region but are highly distinct between continents, with 4 distinctive versions of the fungus. In the U.S., isolates were highly related to one another within each state and grouped with isolates from overseas locations: New York isolates grouped in the same clade as isolates from South Asia; New Jersey isolates also grouped with isolates from South Asia, but were distinct from those in New York; and Illinois isolates grouped with isolates from South America. These data suggested multiple introductions of _C. auris_ into the United States followed by local transmission within healthcare settings.

Causes for the emergence of multidrug-resistant _C. auris_ are unknown, but an intriguing idea in this news report is the influence that widespread application of azoles on crops may have had on the evolution of this azole-resistant _Candida_ species. The following is extracted from the journal article referenced in the news report above:

"The hypothesis that clinical azole resistance in _A. fumigatus_ is related to the use of fungicides in agriculture was first proposed by investigators from the Netherlands [19]. The resistant genotype TR34/L98H was found in 90% of ARAF [azole-resistant _Aspergillus fumigates_] isolates obtained from azole-naive patients [11] and they hypothesized that if strains of _A. fumigatus_ received sufficient azole challenge in the environment through nonmedical application of azole compounds, azole-resistant strains would be selected and spread [27]. Demethylase inhibitors (DMIs) including azole fungicides are commonly used for crop protection and for the preservation of a variety of materials such as wood [27]. For example, azole fungicides are broadly used to control mildews and rusts of grains, fruits, vegetables, and ornamentals; powdery mildew in cereals, berry fruits, vines, and tomatoes; and several other plant pathogenic fungi. Over 1/3rd of total fungicide sales are azoles (mostly triazoles) and over 99% of the DMIs are used in agriculture. In addition, there are over 25 types of azole DMIs for agricultural uses, far more than the three licensed medical triazoles for the treatment of aspergillosis. Furthermore, the azoles could persist and remain active in many ecological niches such as agricultural soil and aquatic environments for several months.

The widespread application of triazole fungicides and their persistence in the environment are significant selective forces for the emergence and spread of ARAF. These environmental triazoles can reduce the population of azole-susceptible strains and selecting for azole-resistant genotypes [27]. Intensive use of DMI fungicides for post-harvest spoilage crop protection against phytopathogenic molds is known to cause the development of resistance in many fungi of agricultural importance. For example, resistance or tolerance to triazole fungicides has been reported for important crop pathogens such as _Mycosphaerella graminicola_ (wheat), _Rhynchosporium secalis_ (barley), and _Botrytis cinerea_ (strawberry) [28]. Since _A. fumigatus_ shares its natural environments with many fungal plant pathogens, strains of _A. fumigatus_ are also exposed to the same strong and persistent pressure from fungicides. Indeed, the presence of a tandem repeat at the 5′-end upstream of the 14-a-demethylase gene is an important mechanism found in many plant pathogenic molds resistant to sterol DMI fungicides [19]."

The widespread agricultural application of antifungal azoles likely contaminates the environment broadly, and its effects on the soil microbiome could be similar to the effects raised in 2 recent ProMED-mail posts that concern the recent EPA approval of spraying streptomycin on all citrus crops in the U.S. 3x per year. Please see ProMED-mail posts Antibiotic resistance - USA: spraying streptomycin on citrus trees, EPA 20190320.6377319 and Antibiotic resistance - USA: spraying streptomycin on citrus trees, EPA 20190319.6372775. - Mod.ML]

See Also

Antibiotic resistance - USA: spraying streptomycin on citrus trees, EPA 20190320.6377319
Antibiotic resistance - USA: spraying streptomycin on citrus trees, EPA 20190319.6372775
2018 
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Candida auris - Europe: 2013-2017 20180425.5767936
Candida auris - UK: (England) ICU, shared axillary thermometers 20180423.5763268
2017 
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Candida auris - Canada: (BC) ex India, coinfect. carbapenemase-pos. bacteria,VRE 20170923.5335411
Candida auris - UK: nosocomial, epidemiology 20170815.5252095
Candida auris - USA (04): nosocomial, epidemiology, drug resistance 20170520.5050111
Candida auris - USA (03): (NY) fatality 20170430.5004770
Candida auris - USA (02): (IL, NY) 20170429.5003259
Candida auris - Panama: (Panama City) nosocomial 20170412.4966492
Candida auris - USA 20170312.4895788
2016 
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Candida auris - Americas (02): USA, 1st isolates 20161105.4608846
Candida auris - Americas: emerg, drug-resist, nosocom pathogen, PAHO/WHO, alert 20161005.4537152
Candida auris: emerging, drug-resistant, nosocomial pathogen, alert 20160702.4322149
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