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The Emerging Battle Against Fungal Infections - What Healthcare Organizations Can Do To Help

Hospitals have been waging a war against antibiotic-resistant pathogens since the late 1980s. Yet still today, antibiotic-resistant infections are a costly, life-threatening burden to patients and the health care system.

Drug resistance among common bacterial pathogens, such as Streptococcus pneumoniae and Mycobacterium tuberculosis, is epidemic, and Methicillin-Resistant Staphylococcus aureus kills more Americans each year than HIV/AIDS, Parkinson's disease, emphysema, and homicide combined. (Pharmacy & Therapeutics, April 2015)

A lesser-known challenge is the rise in systemic fungal infections, which are a common cause of hospital-acquired infections and constitute a disproportionate percentage of mortalities in infectious disease. Contributing to this problem is the fact that common fungal infections – as well as new and emerging stains of fungi - are becoming increasingly resistant to existing antifungal therapies. The lack of efficient diagnostic tools enabling rapid and accurate diagnosis is part of this problem – physicians prescribe antifungal medications "to be safe" in the absence of confirmed infection. But a bigger contributor is pricing pressures and reimbursement issues that lead to overuse and misuse of older, relatively inexpensive and often ineffective antifungal agents. As a result, existing antifungal treatments, particularly azoles, have lost efficacy against selected pathogens.

Generally speaking, fungal infections are an under-recognized problem and vastly under-served area of medical research, particularly in comparison to the attention and resources devoted to bacterial infections. To the general public, "fungal infection" brings to mind benign, bothersome, conditions such as athlete's foot or toenail fungus. The reality is that fungal infections can be fatal and dangerous, especially systemic, invasive infections that proliferate in the bloodstream and other organs such as the liver, kidney and lung.

In just one poignant example of the personal and institutional impact of these infections, in 2015, a U.S. Hospital with a world class transplant center was forced to temporarily shut down its cardiothoracic intensive care unit and suspend all transplant operations due to a mold infection issue that resulted in several patient deaths. The hospital had to call in the Centers for Disease Control and Prevention, the Joint Commission and other health agencies to help remedy the situation.

Quantifying the fungal infections issue

Severe hospital-related fungal infections are difficult to prevent and treat. Patients with compromised immune systems, such as those undergoing organ or bone marrow transplants, chemotherapy, people with AIDS, and those with long ICU or hospital stays, are at a high risk of contracting serious fungal infections. Other risk groups include patients with central venous catheters and patients undergoing surgery of any kind, but especially abdominal surgery.

Approximately 97,000 Americans die from hospital-related fungal infections each year alone. Ninety percent of these often deadly infections are caused by just two common fungi, Candida and Aspergillus.

Candidemia is one of the most common causes of hospital-acquired bloodstream infections. Patients are typically treated with azoles, which have seen increased resistance of late; polyenes, which can have negative side effects; and echinocandins, which, while effective, must be administered daily by IV infusion, limiting their use mainly to inpatients and potentially leading to longer lengths of stay. For multi-drug resistant Candida infections that are resistant to both fluconazole and an echinocandin, the few remaining treatment options are expensive and can be toxic for patients who are already very sick. (Centers for Disease Control and Prevention) The impact of candidemia from a health and economic perspective is disturbing.

Here's what the numbers tell us:

• The CDC estimates that approximately 46,000 cases of healthcare-associated invasive candidemia occur each year in the United States.• The infection is associated with a high mortality rate. According to a study published in Clinical Infectious Disease (2009), candidemia has a mortality rate of 35 percent within 12 weeks of diagnosis. By contrast, the CDC reports that the mortality rate due to MRSA infections is 12.8 percent.• Candidemia is also costly and increases length of stay. Each case of candidemia is estimated to result in an additional three to 13 days of hospitalization and $6,000 to $29,000 in healthcare costs. (CDC)• A recent U.S. Study found that the percentage of non-albicans Candida species increased from 46 percent in 2006 to 60 percent in 2011.

An alarming example of the last statistic is a new Candida strain known as Candida auris. The emergence of C. Auris was first chronicled by the CDC in June 2016, as a "multidrug-resistant yeast causing invasive healthcare-associated infections with high mortality." A CDC alert warned U.S. Healthcare facilities to be on the lookout for the infection. Just a few months later, in November, the CDC reported 13 cases of C. Auris in the United States that resulted in four fatalities. This new, virulent strain is particularly concerning in light of the fact that the last new class of antifungals was introduced to the market in 2001 and no new antifungal agents have been approved for Candida bloodstream infection since 2007.

As the second most common cause of fungal-related mortality, Aspergillus poses serious risks to immuno-suppressed patients when it infects the lungs and subsequently spreads through the bloodstream to other organs such as the brain and skin. Ultimately, patients die from widespread organ infection. Over 200,000 patients develop invasive aspergillosis annually, according to the Fungal Research Trust. This number includes 10 to 20 percent of leukemia patients, along with significant percentages of patients undergoing allogeneic stem cell transplants and recipients of solid organ transplants.

Voriconazole is the standard of care for treating invasive aspergillosis, even though resistance rates can be as high as 20 percent, according to 2009 data from The MycologyReference Centre in Manchester, UK. Mortality rates remain at approximately 50 percent and most hospitals don't have internal capabilities for rapidly diagnosing this infection.

Efforts to battle systemic fungal infections

In September 2016, the United Nations General Assembly held a high-level meeting at the organization's headquarters in New York to focus on the global problem of antimicrobial resistance. This was only the fourth time the UN has met to discuss a health-related issue. The fact that the meeting focused on antimicrobial resistance – versus the more high-profile and specific issue of antibiotic resistance – signaled an important step for fungal infection awareness, as well as recognition of the growing threat that these infections represent.

During that same week, the Mycoses Study Group Education and Research Consortium, a think tank of global experts in the field of mycology, convened to address the state of the union on invasive fungal infections. The MSGERC is represented by more than 160 physicians and scientists from leading national and international universities. The parent organization, MSG, has conducted dozens of clinical trials over the years, helping patients suffering from invasive candidiasis, cryptococcosis from AIDS, and other fungal infections.

Participants at this year's MSGERC meeting focused on a three-pronged approach to fight systemic fungal infections:

• Need for better diagnostic tools to help quickly and accurately identify infecting pathogens and assess antimicrobial susceptibility. It can take several days, and even up to weeks to diagnose infections, delaying treatment and leading to higher mortality rates.• Need for improved awareness about the rise in antifungal drug resistance and concerns specific to immunocompromised patients.• Need for new antifungals, such as treatments in development for use alone or in combination with others, to address growing antifungal drug resistance.

What healthcare organizations can do to help

At the MSGERC meeting, there was general consensus that hospitals have a crucial role in helping to stem the morbidity and mortality associated with invasive fungal infections.

Antimicrobial stewardship programs can promote the appropriate use of antimicrobials, leading to better patient outcomes and a reduction in the spread of infections caused by multidrug-resistant organisms. These programs can help educate medical professionals about best practices for continuity of care, following the patient from the inpatient to the outpatient setting.

Prevention and infection control strategies are equally important. These would include participating in and leading efforts within the hospital setting to improve antifungal prescribing practices, ensuring that the right antifungal is given to the right patient at the right time.

Healthcare executives, clinicians and other stakeholders can also help in a broader way, by supporting staff participation in clinical research programs that will improve diagnosis, intervention and treatment. Physician involvement in research studies is critical to support much-needed drug development for novel antifungals which address resistant pathogens.

Fungal infections should be a more visible part of the larger national campaign to reduce hospital-acquired and drug-resistant infections. Inpatient infections continue to cause high percentages of avoidable deaths and contribute to waste and high healthcare costs. The fact that many of these infections are preventable, and could soon be treated more effectively with new drugs in development now, makes the battle to combat fungal infections a worthy cause. Nearly 100,000 patients are dying from these infections every year. Healthcare executives and physician leaders can help their organizations tremendously, by participating in internal and external initiatives to bring new life-saving processes and treatments into their facilities.

Jeffrey Stein, PhD, is President and Chief Executive Officer of Cidara Therapeutics and Chairman of the Antimicrobials Working Group (AWG)

Dr. Stein has been President, CEO and Director of Cidara since January 2014. He is also Chairman of the Antimicrobials Working Group, an industry leading 501(c)(6) organization. Previously he was CEO of Trius Therapeutics, Inc. From 2007 until its acquisition by Cubist Pharmaceuticals, Inc. In September 2013. Previously, Dr. Stein was a Venture Partner and Kauffman Fellow with Sofinnova Ventures and opened the firm's San Diego office in 2005. Prior to joining Sofinnova Ventures, Dr. Stein was co-founder and Chief Scientific Officer of Quorex Pharmaceuticals, which was acquired by Pfizer Pharmaceuticals in 2005. He has also served as a Principal Scientist with Diversa Corporation and the Agouron Institute. Dr. Stein conducted his postdoctoral research as an Alexander Hollaender Distinguished Postdoctoral Fellow at the California Institute of Technology and his graduate work as a NASA Graduate Student Researcher Fellow at the University of California, San Diego.

https://www.Cidara.Com/about/management-team/

Peter G. Pappas, MD, FACP is Director of Mycoses Study Group Education and Research Consortium (MSGERC) and is Professor of Medicine in the Division of Infectious Diseases at the University of Alabama

Peter Pappas is the William E. Dismukes Professor of Medicine in the Division of Infectious Diseases, and was the first Tinsley Harrison Clinical Scholar, Department of Medicine at the University of Alabama in Birmingham. Dr. Pappas attended medical school at the University of Alabama at Birmingham, graduating in 1978. He completed his residency in internal medicine, chief medical residency and infectious diseases fellowship at the University of Washington in Seattle. Following completion of his fellowship, he was on the clinical faculty at the University of North Carolina School of Medicine in Chapel Hill, NC, through its affiliated hospital in Wilmington, North Carolina. In 1988, he joined the faculty at the University of Alabama in Birmingham School of Medicine, with a focus on HIV and transplant-associated opportunistic infections, especially the invasive mycoses. He is the Principal Investigator for the Mycoses Study Group Education and Research Consortium, an academic consortium that continues to perform multicenter trials, create treatment guidelines for invasive mycoses, and coordinate CME training in the epidemiology, diagnosis and treatment of invasive mycoses. As Director of the MSG, Dr. Pappas has been instrumental in moving the organization towards its current NPO status.

https://msgerc.Wildapricot.Org/Peter-Pappas

The views, opinions and positions expressed within these guest posts are those of the author alone and do not represent those of Becker's Hospital Review/Becker's Healthcare. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them.

Unruly Gut Fungi Can Make Your Covid Worse

When the team infected mice with Candida albicans strains taken from the severely affected Covid patients, they discovered that the mice generated increased fungal antibodies and neutrophils. And when they then treated these infected mice with the common antifungal drug fluconazole, numbers of these fungal-induced neutrophils decreased—as did the quantity of fungal antibodies. This indicated that overgrowth of those fungi helped cause the number of neutrophils to rise, with the coronavirus itself kickstarting the process.

Neutrophils are an important part of the immune system, says Iliev, but excessive activity can lead to prolonged inflammation that is characteristic of Covid. "Neutrophils will keep coming because they think there is inflammation and infection," he adds. "They basically start exploding to make these structures called neutrophil extracellular traps—which, instead of helping you, actually makes the disease worse."

And the impact of this fungal overgrowth didn't end once the patients' Covid had subsided. By looking again at blood samples from the severe Covid patients, and comparing these to samples from healthy controls, the scientists found that the stem cells that created these neutrophils had become specifically adapted to target fungi. These stem cells were active long after the initial infection, even after levels of fungal antibodies and neutrophils had died down—essentially priming the body to respond dramatically to a future fungal threat. At this stage, it's not clear if this would be helpful or problematic for patients—it's plausible that the patients' bodies might be primed to overreact to other fungal infections in future.

There was one final question puzzling Iliev and his colleagues. How, then, did the fungi nestled in the gut cause such drastic changes in the immune system located elsewhere—all the way down to the stem cells? To answer that question, the scientists looked for signaling molecules, known as cytokines. One of these, called IL6, they noticed was elevated in the infected mice, alongside the elevated neutrophils and fungal antibodies. When the team blocked IL6, both the neutrophils and fungal antibodies decreased in quantity. "Maybe the mediator here is a cytokine that the fungi induce," Iliev says, suggesting that these are potentially the sign of some communication across the body that sets all of these processes in motion.

This complex crosstalk between the gut microbiome and the immune system is an example of how most things in the body are intertwined, says Alessio Fasano, a gastroenterologist at Massachusetts General Hospital, who was unaffiliated with the study. "The gut is not like Las Vegas," he says. "What happens in the gut does not stay in the gut."

Fasano can envision this kind of work pointing to a future of more personalized medicine. Measuring for increased levels of fungal antibodies in Covid patients, he says, could potentially uncover a subset of people who might benefit from taking antifungal drugs like fluconazole.

All the scientists note, though, that it is unfair to assign the blame of upending the immune system to one single strain of fungi. Because the microbiome is always in flux, reestablishing balance after infection is key—throwing lots of antibiotics or antifungals at the problem can result in a never-ending game of biological whack-a-mole where one imbalance leads to another.

Now, Iliev and Kusakabe are interested in exploring how fungal overgrowth may appear in long Covid—and how immunity is affected. "What's the impact of this reprogramming of the immune system by the fungus and the virus?" Iliev asks. "What happens long-term if you have suffered from that?"

An Often Overlooked Body Part Could Give You Clues About Your Health

Editor's note: The views expressed in this commentary are solely those of the writer. CNN is showcasing the work of The Conversation, a collaboration between journalists and academics to provide news analysis and commentary. The content is produced solely by The Conversation.

The Conversation —

From skin to hair, scabs and even tears, the external appearance of the body can offer clues about the state of your health.

But there's another part of the anatomy that's often overlooked: the feet.

Feet are wired up to nerve fiber tracts from the brain so you can stand, balance and wiggle your toes. They're also plumbed by blood vessels, which lead all the way from the heart.

The appearance and function of our feet then can indicate viral infections, diseases of the cardiovascular system and even neurological disorders. Here are a couple of examples.

READ MORE: Is the 'barefoot-boy summer' trend bad for your feet?

Hand, foot and mouth disease

Infectious diseases tend to affect different parts of the body.

Measles usually starts off on the face, or in the mouth, as little spots that look like grains of sugar. Pityriasis versicolor, a type of fungal infection, tends to begin and stay on the torso. The reasons why they tend to affect these areas is not well understood.

Hand, foot and mouth disease, or HFM, begins in exactly these areas. It's caused by a virus known as coxsackie and tends to produce raised pink-red spots that can blister and weep. The name is a bit of a misnomer — the rash can also affect the legs and buttocks, too. Noticing a new rash on the feet should prompt a doctor to consider HFM.

HFM is a common childhood illness that's very contagious. Thankfully, it's also usually short-lived, clearing without treatment after a few days.

It shouldn't be confused with foot and mouth — or better, hoof and mouth, however. Foot and mouth is a different virus from HFM that (mainly) affects cloven-hoofed animals, such as cows and sheep. It's the disease that resulted in a UK epidemic in 2001.

READ MORE: How much time should you spend sitting versus standing? New research reveals the optimal mix

Heart, vessels and feet

Our circulatory system supplies blood to every part of the body — from the crown of the head to the tips of the toes. By the time blood vessels reach these extremities, like twigs from a tree, they have branched and got much smaller in size.

At some point, we've all experienced the discomfort of icy cold feet, especially when going barefoot around the house or during chillier days. It's normal for feet to feel cool to the touch, but they should not change color from their usual skin color to blue — nor should they ever get painfully cold.

Severe symptoms of discoloration and pain can point toward a phenomenon called blue toe syndrome. It can be triggered by tiny little masses called microemboli, made up of blobs of cholesterol. These emboli pass easily through large vessels but will struggle as they become smaller.

On reaching the smaller vessels of the feet, they finally become stuck, cutting off the blood supply. The tissues then become starved of oxygen, causing the feet to change color and become painful.

In serious cases, blue toe syndrome can lead to tissue death, breakdown and the formation of gangrene, which may require amputation of toes — or even the whole foot.

This rare condition is sometimes called "trash foot," because of the way in which the feet become so discolored.

What's the underlying cause of these tiny cholesterol fragments? Most likely aneurysms and atherosclerosis — vessels that have ballooned or hardened upstream of the feet. When trash foot does occur, it is often following surgical treatment for these conditions, such as aortic aneurysm repair. The procedures disrupt the vessel, which can cause emboli to break off.

As well as trash foot, there are other signs in the feet that can point toward cardiovascular disease. Raised red swellings appearing on the feet (as well as the hands) can indicate an infection of the heart called bacterial endocarditis. These can be painless — in which case we call them Janeway lesions — or sore, which are called Osler's nodes.

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