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The agricultural applications help generate drug resistance across multiple human bacterial infections, killing 23,000-100,000 Americans a year and, with an increasing amount of antibiotics applied abroad, 700,000 people worldwide.
A quick review of agroecological examples suggests that a combination of disease modeling and cultural practices such as crop rotation and cover cropping and intercropping can greatly reduce the presence of fungal diseases and thus dependence on fungicides.
Eighty percent of U.S. antibiotics are used to promote livestock and
poultry growth and protect the animals from the bacterial consequences of
the manure-laden environments in which they are grown. That’s 34 million
pounds a year of antibiotics as of 2015.
The agricultural applications help generate drug resistance across multiple
human bacterial infections, killing 23,000-100,000 Americans a year and,
with an increasing amount of antibiotics applied abroad, 700,000 people
worldwide.
Now a fungal species, Candida auris, has developed multidrug resistance and
is rapidly spreading across human populations across the globe (see figure).
The CDC reports 90% of C. auris infections are clocking in resistant to one
antifungal drug and 30% to two or more.
C. auris, a yeast, is killing immunocompromised patients in hospitals,
clinics, and nursing homes at a prodigious clip, up to 40-60% of those who
suffer bloodstream infections in a month’s time.
In the rooms of the infected and the dead, the fungus appears intransigent
to nearly all attempts at eradication. The fungus can survive even a
floor-to-ceiling spray of aerosolized hydrogen peroxide.
How have drug-resistant fungi come to haunt the modern hospital and
jeopardize the sterile spaces asepsis addressed 150 years ago?
It is becoming increasingly apparent that C. auris’s resistance, and that of
many other fungi species, is traceable to industrial agriculture’s mass
application of fungicides. These chemicals approximate the molecular
structures of antifungal drugs.
Across crops — wheat, banana, barley, apple, among many others — the
fungicides select for resistant strains that find their way into hospitals
where they are also resistant to the drugs administered to patients.
The Path of Yeast Resistance
Matthew Fisher and colleagues recently classified six main classes of
fungicides, all rarely used in the U.S. Midwest before 2007.
The azoles and morpholines target the ergosterol
biosynthetic pathway, which generates the plasma membrane of fungi cells.
The benzimidazoles interfere with fungi cytoskeleton, preventing
the assembly of cell microtubules. The strobilurins and
succinate dehydrogenase inhibitors take more physiological routes,
inhibiting the electron transfer chain of mitochondrial respiration. The
anilinopyrimidines appear to target mitochondrial signalling pathways.
Candida auris has evolved resistance to a suite of azole
antifungals, including fluconazole, with variable susceptibilities to other
azoles, amphotericin B, and echinocandins. Azoles, used in both crop
protection and medical settings, are broad-spectrum fungicides, annihilating
a wide range of fungi rather than targeting a specific type.
How Did Fungus and Fungicide Find Each Other in the Field?
C. auris, likely long circulating on its own for thousands of years
as CDC’s Tom Chiller hypothesizes, was first isolated in humans from the ear
canal of 70-year old Japanese woman at a Tokyo hospital in 2009 (although a
1996 isolate was subsequently identified). Later isolation found the yeast
capable of bloodstream infection.
In an effort to identify the source of the infection, an international team
sequenced resistant isolates collected from hospitals across Pakistan,
India, South Africa, and Venezuela, 2012–2015.
Against expectations, the team found divergent amino acid replacements
associated with azole resistance among the ERG11 single nucleotide
polymorphisms — one among several such SNPs — across four geographic
regions. They weren’t the same strain, indicating that each resistant
phenotype had emerged independently.
In other words, strains isolated by distance from each other evolved unique
solutions to the fungicides to which they were exposed.
That might indicate molecular adaptations to different exposures. But it
also might indicate that in response to such wide exposure to fungicides in
the field, each strain evolved its own unique solution to the problem.
Even though fungi do not horizontally transfer their genes at rates that
virus and bacteria do, migration of patients and fungi alike, the latter by
way of agricultural trade, can help increase diversity in the fungicidal
resistance circulating in any one locale.
A second team identified multiple genotypes of different international
origins in the relatively bounded confines of the United Kingdom. A third
team, as the nearby map shows, identified a similar mix in U.S. cases.
But it isn’t clear other than travel-related cases whether all the cases
originated from strains from abroad. Without a baseline of fungal load
among, say, domestic agricultural workers, an endogenous source remains a
possibility.
To add to the complexity, there also appear multiple mechanisms by which
resistance emerges.
Dominique Sanglard summarizes three: decreases in drug concentration in
fungal cells, alterations of the drug target, and compensatory mechanisms
that depress drug toxicity. Atop these, the three can be arrived at by a
variety of genetic events. Alongside SNPs are insertions into the fungus
genome, deletions, and structural changes, including gene or chromosome copy
events.
One study found 51 genes related to how sensitive circulating strains of a
Fusarium blight were to propiconazole, only a single class of
triazole fungicide.
The road to such resistance can be complex, winding beyond merely evolving
out from underneath an antifungal directly.
In 2015, researchers found that the C. auris genome hosts several
genes for the ATP-binding cassette transporter family, a major facilitator
superfamily (MFS). MFS transports a large variety of substrates across cell
membranes and been shown to effectively dispose of broad classes of drugs.
It permits C. auris to survive an onslaught of antifungal drugs.
The team found that that the C. auris genome also encodes a slew of gene
families that facilitate the fungi’s virulence. C. auris adaptively forms
biofilms that support antifungal resistance by way of a high density of
cells, the presence of sterols on biofilm cells, and efficient nutrient use
and growth.
Other Fungi, Other Dangers
Candida auris is hardly the only deadly fungus converging upon
multidrug resistance. The nearby map shows multiple species overlapping in
plant and human resistance.
One fungus, Aspergillus fumigatus, may offer a conditional preview
of C. auris’s trajectories present and future.
Azole antifungals itraconazole, voriconazole, and posaconazole have long
been used to treat pulmonary asperillogosis, the infection caused by A.
fumigatus. The fungi causes approximately 200,000 deaths per year, in
the past decade rapidly developing resistance to antifungal drugs.
Studies comparing long-term azole users and patients just beginning to
take the drug have shown that drug-resistant A. fumigatus was
prevalent in both groups, suggesting that resistance evolved in agricultural
rather than medical settings.
Researchers have found biogeographical evidence that suggests
multi-triazole-resistant A. fumigatus strains in clinical and
environmental settings share significant overlap. In the figure nearby, drug
resistant A. fumigatus found in the field (green) and in clinical
trials (red) map together, demonstrating their coupling in Europe and Asia.
Other work recently found azole-resistant A. fumigatus related
to the use of triazole fungicides in agricultural fields outside of Bogotá,
Colombia. Soils were sampled from an array of crop fields and A.
fumigatus was grown on agar treated with itraconazole or voriconazole
fungicides. In more than 25% of cases, A. fumigatus persisted
despite the fungicide treatment.
That is, due to agricultural practices, Aspergillus is entering hospitals
already adapted to the slew of antifungal cocktails designed to check its
spread. Dumping azoles to control for fungi on grapes, corn, stone fruit,
and a myriad of other crops generated the conditions to accelerate drug
resistance in human patients.
While extensive phylogenetic and biogeographical research remains to be
conducted, a quick perusal of existing distribution maps suggests
similarities between Aspergillus fumigatus and its younger (and
suddenly more infamous) cohort Candida auris. The strains share
similar geographical distributions, occupying many of the same zones
described above for C. auris.
Industrial Agriculture’s Role
With zones of overlapping human and crop resistant cases of Aspergillus
fumigatus and the rising specter of a new azole resistant fungus
ravaging clinical settings and evolving at lightning speed, one would hope
that azole fungicide use would be closely monitored if not just phased out.
The dangers of continuing upon this path of agricultural development are
acute.
Medical and agricultural azole fungicides share similar modes of action, so
when resistance pops up in one arena it is easily transferable to another.
In both agricultural and medical fungicides, the phenyl group of the
chemical forms van der Waals contact with the active site of gene cyp51A.
Organic chemistry specifics aside, the close similarities that the Chowdhary
group depict in the nearby figure suggest that a mutation in Aspergillus
fumigatus to prevent binding to the cyp51A gene in an agricultural setting —
specifically a modification of the 14-α sterol demethylase enzyme — would
likely confer resistance to medical applications of stereochemically similar
drugs.
Agricultural azole fungicides comprise a third of the total
fungicide market. Twenty-five different forms of agricultural azole
demethylation inhibitors are in use, compared to just three forms of
licensed medical azoles.
So we shouldn’t be surprised that in applying these fungicides at landscape
scales in the millions of pounds annually, the medical use of triazole
antifungals, using the same mode of action, would rapidly turn ineffective.
Instead of intervening in the interests of global public health to limit
these long-problematic applications, government policy in recent years has
promoted the lucrative global expansion of fungicide use, fostering the
conditions for virulent drug-resistant fungi.
In 2009, fungicides were applied on 30% of corn, soybean, and wheat acreage
in the U.S., totaling 80 million acres. Preventative use of fungicides to
control soybean rust quadrupled between 2002 and 2006, despite a dubious
economic rationale. Global sales continue to skyrocket, nearly tripling
since 2005, from $8 billion to $21 billion in 2017.
Fungicides expanded not only in sales but also in geographic distribution.
From the maps nearby, we see tetraconazole, an agricultural triazole, moved
from isolated usage in the western Plains in the late 1990s to massive
application throughout California’s Central Valley, the upper Midwest, and
the Southeast. Boscalid, a fungicide used in fruit and vegetable crops, has
increased from ~ 0.15 to 0.6 million pounds from 2004 to 2016, a 400%
increase, and is now widely applied across the country.
From within each new locale, the fungicides percolate into the local
environment.
In 2012, USGS scientists studied 33 different fungicides used in potato
production and found at least one fungicide in 75% of tested surface waters
and 58% of ground water samples. With half-lives stretching to several
months, azole fungicides are able to easily reach and persist in aquatic
environments by runoff and spray drift, becoming highly mobile.
As climate change fundamentally reshapes the U.S., bringing higher overall
temperatures and extreme oscillations between drought and heavy rainfall,
fungi are predicted to expand outside of their current ranges while also
responding specifically to new climate regimes. Aspergillus flavus,
the producer of a cancer-causing aflatoxin that reduces corn yields and
poisons humans, thrives in drought conditions and large crop-water deficits.
With the market treated as a force of nature stronger than climate or public
health, under current agricultural production, broad-spectrum fungicide use
is likely only to increase.
Farming as Its Own Fungus Control
In response to drug-resistant bacteria and fungi, research institutions are
calling for the collection of better data on agricultural antibiotic use and
on the potential economic costs of transitioning away from from high rates
of application.
A 2016 UK report, citing the overapplication of agricultural fungicides,
recommended increased surveillance of antibiotic usage overall and a
regulatory apparatus organized by the WHO, FAO, and OIE that among its
duties would list critical antibiotics that should be barred from
agriculture use.
But aside from collecting more information and calling for what appears
minimal regulation, what is to be done?
Given recent travails in antibiotic and herbicide resistance, it seems
likely that chemical companies and their farming clients will pursue
developing new fungicides based on targeted molecular research, multiple
drug cocktails, and gene-edited resistance.
Governmental agencies are likely to impose increased if dubious biosecurity
measures, which also frequently foment xenophobic anxieties and are used to
blame workers for contamination, rather than addressing the systemic
failures of industrial agriculture.
The conjoined motives of powerful medical and agricultural companies are
almost certain to promote ‘solutions’ that exacerbate an arms race between
toxic drug applications and fungal resistance, spew growing permutations of
lethal chemicals into the environment, and further consolidate and privatize
the agro-pharmaceutical sector.
There is, however, a different, evidence-based paradigm for responding to
fungicidal collapse.
A quick review of agroecological examples suggests that a combination of
disease modeling and cultural practices such as crop rotation and cover
cropping can greatly reduce the presence of fungal diseases and thus
dependence on fungicides.
In California’s Central Valley, strawberry producers accustomed to
fumigating soils with fungicides to control incidence of Verticillium
wilt, a pathogenic soil fungi, have found that planting broccoli crops in
between rotations of strawberry crops greatly reduced levels of
Verticillium.
Dating back several decades, similar results have been found in the
diversification of potato crop rotations.
Researchers in India — a country where drug-resistant A. fumigatus
and C. aurishave both been found — have studied novel approaches to
controlling late blight in potato.
Potato crops often receive large doses of azole fungicides to control for
fungal pathogens such as late blight. Rather than fungicide treatments,
scientists applied silica to foliar tissue, finding that silica was absorbed
and strengthened the potato’s cell walls against fungal invasion. Disease
infestation rates ranged from 2.8 – 7.9% in the silica-based integrated
management systems and 49.4 – 66.7% in the conventional fungicide dependent
systems.
In general, organic farming supports mutualistic fungi to a much greater
degree than conventional farming, crowding out pathogenic strains. Crop
rotations, the incorporation of legumes, and the cultivation of soil
aggregates support ecological niches for soil microbiota.
Reducing chemical fertilizers and limiting tillage, two agroecological
practices with major benefits for reduced pollution and enhanced carbon
storage, also select for beneficial strains of arbuscular mycorrhizal fungi
that form mutualistic relationships with plant roots and can confer
resistance to soil pathogens.
Integrating agricultural production into a broader matrix of non-crop
vegetation is also important for controlling fungal pathogens. Wild
landscapes reduce the potential for pathogen populations to adapt to crops
and modeling suggests that contiguous swaths of wild patches reduce the
aggressiveness of pathogens upon agricultural crops.
Ivette Perfecto and John Vandermeer’s labs have done yeoman work, written up
in depth here and summarized here, tracing the means by which thatches of
ecological relationships — predation, mutualism, competition, etc. — up and
down the food web in which a crop finds itself can box out pest damage,
including, their teams find, from rust fungi.
The nitty-gritty as it applies to fungi can be found in Vandermeer student
Douglas Jackson’s dissertation on agroecological fungal control in coffee.
Zachary Hajian-Forooshani (pictured), another University of Michigan
student, followed up research from the 1970s and found Mycodiplosis
fly larvae feed on the coffee rust the Perfecto-Vandermeer team study in
Mexico and Puerto Rico.
More Than Mining Soil
All this work squares well with agroecological theory that under current
political policies and demographic trends, farm fields integrated into a
matrix of nature conservation are more likely than ‘land-sparing’ approaches
to conserve natural resources while simultaneously supporting rural
livelihoods and low-external input food production.
What emerges is a picture of ecological complexity in which fungicidal
warfare is exactly the wrong tool.
Instead, throwing bad money after bad, fungicides today are applied in a
system in which diseases thrive out of simplified landscapes, vast and
uninterrupted genetically identical monocultures, rapidly accelerating
global warming, and an ever quickening pace of global trade.
In a cruel irony, fungicide application places evolutionary pressure on
pathogens to develop resistance at the same time that industrial
management provides the near-perfect conditions for fostering and spreading
these virulent mutations.
It all makes sense only when we recognize that the agribusiness sector views
nature as its stiffest competition.
Wiping out local ecologies and the near-free work these offer in helping
farmers enrich their soils, clean their water, pollinate their plants, feed
their livestock, and control pests — pathogenic fungi among them — means the
largest companies can now sell commodified equivalents to a captured market.
The damage done is more than agricultural or economic. It’s a business plan
pursued even at the risk of eroding our capacity to socially reproduce
ourselves as a civilization.
Farmers and food activists have complained industrial agriculture represents
little more than nutrient and carbon mining. Companies are compelling
farmers to grow so much so fast that production squeezes carbon out of the
soil in the form of food commodities. As a result, land and water are
polluted into such oblivion that food safety cannot be accounted for.
By that pollution, occupational exposures, outbreaks of increasing virulence
and extent, metabolic diseases such as diabetes, antibiotic resistance, and
now the growing threat of fungicide resistance, carbon mining now extends to
gouging out global public health.
Once the order of the day, alternate agricultures long pursued and updated
by smallholders worldwide, and backed by a growing scientific literature,
offer a way out of that trap.
Return to Food Hazards in Animal Flesh and By-products
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