Rise in antifungal resistance may portend global health crisis

In late June, the CDC issued a clinical alert to health care facilities in the United States regarding Candida auris, an emerging multidrug-resistant yeast reported to have caused invasive health care-associated infections with high mortality across nine countries on four continents.

First discovered in the external ear discharge of a hospital patient in Japan in 2009, C. auris infections have since been described in published reports in South Korea, India, South Africa and Kuwait, with known infections in Pakistan, Colombia, Venezuela and the United Kingdom.

Image courtesy of Stony Brook University

While the pathogen has not yet been reported in the U.S., CDC officials have voiced concern over international reports that noted C. auris resistance to all three major classes of antifungals, as well the inability of standard laboratory methods to differentiate between various invasive Candida infections, which could lead to inappropriate treatment.

Although antifungal resistance and possible misidentification of an invasive infection present sufficient cause for alarm, public health authorities are more concerned that C. auris has already caused outbreaks within the hospital setting. International reports have mentioned that C. auris, unlike other invasive Candida infections, has demonstrated an unusual tendency for transmission between hospital patients.

Mere days after the CDC issued its warning, Public Health England alerted health care providers that sporadic cases of C. auris had been identified throughout England going back to 2013, including an outbreak among more than 40 immunocompromised patients in an adult critical care unit.

The CDC has estimated that 60% of patients infected with C. auris have died; however, officials and investigators have based this on a limited number of patients, many of whom had other comorbidities. To this end, the CDC has urged U.S. health care facilities to place suspected C. auris patients in isolated hospital rooms and to immediately report any incidents involving the pathogen.

While the majority of antifungal resistance has been noted among Candida species, C. auris is not the sole representative of an emerging threat of invasive fungal infections with multidrug resistance. As with Candida, Aspergillus infections — specifically, Aspergillus fumigatus — have been associated with high mortality and demonstrated an estimated 3% to 6% resistance to azoles globally.

To explore the complexities of this issue, Infectious Diseases in Children spoke with molecular microbiologists and infectious disease experts regarding the rise of invasive fungal diseases as a major medical problem for immunosuppressed patients, including NICU and pediatric transplant patients. The experts also addressed why fungal infections should be at the forefront of national discussion for medical research and development.

A threat millennia in the making

In contrast to viral, bacterial or parasitic diseases, most humans do not fear invasive fungal diseases, largely because they occur very rarely in healthy individuals. However, the high resistance shared by humans and other mammals is unique in the animal kingdom as fungi represent major pathogens of plants, insects, reptiles and amphibians.

According to Arturo Casadevall, MD, PhD, the Alfred and Jill Sommer Professor and Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health, the fungal resilience exhibited by mammals and birds is a joint result of high metabolic temperatures — temperatures that exclude most fungal pathogens — and an advanced immune system.

“There is a possibility that the rise of mammals that occurred after the Cretaceous-Tertiary boundary, 65 million years ago, was the result of a ‘fungal filter’ that allowed our particular group of organisms to become the dominant animals on the planet,” Casadevall told Infectious Diseases in Children.

Although all vertebrates have adaptive immunity, only mammals and birds are endothermic, maintaining a metabolic temperature that may place them beyond the tolerance threshold of most fungal pathogens, creating a thermal exclusionary zone that inhibits fungal proliferation.

Casadevall said the value of this thermal barrier was made clear in recent years by the spread of white-nose syndrome among North American bats. Named for the white fungus on the muzzle, ears, and wings of bats, Pseudogymnoascus destructans invades its host during hibernation when bats’ body temperatures drop to conserve energy during the winter. Since it was first identified in the winter of 2007-2008, millions of bats in 25 states and five Canadian provinces have died from this fungal pathogen.

“A few years ago, I was involved in a study in which we examined the thermal tolerance of 4,802 fungal species, specifically analyzing the temperatures at which they could grow,” Casadevall said. “We found that an overwhelming number could not grow at the human body temperature of 37°C. In fact, for every 1° gained in body temperature in the range of 30 to 42°C, we found that approximately 6% of the fungal species were excluded as potential pathogens.”

However, there remains some concern that global warming could select for more thermally tolerant fungi, with the possibility that some fungi could eventually acquire the capacity to survive at mammalian temperatures and create a new generation of fungal pathogens.

“No one is afraid of dying of fungal disease as we are intrinsically resistant to them,” Casadevall said. “However, as the planet gets warmer as a result of climate change, higher ambient temperatures and environmental fluctuations will create an opportunity for fungi to adapt, and we may end up with new invasive fungal diseases.”

Fungal infections: A 20th century invention

Although fungal diseases are quite common in humans, causing considerable morbidity, such as onychomycosis, dandruff and athlete’s foot, they are generally not life-threatening.

According to Casadevall, invasive fungal diseases only became a major medical problem in the second half of the 20th century when immunosuppressive medical therapies and the HIV/AIDS epidemic resulted in widespread severely compromised immunity. As only the most recent in a long line of known fungal pathogens, C. auris could simply be a well-established fungus seizing an opportunity to flourish.

In a recent study published in PLoS Neglected Tropical Diseases, Bridget M. Barker, PhD, assistant professor of pathogen genomics at the Translational Genomics Research Institute, and colleagues examined 234 worldwide samples of Histoplasma capsulatum — a fungus endemic to the United States, as well as parts of Central and South America, Africa, Asia and Australia — to analyze variations between different species.

The researchers determined that Histoplasma was, in fact, distributed among six distinct species of fungus, and that its global spread paralleled the spread and diversification of bat species as the fungus was carried to new areas, and flourished in soil rich with bird or bat feces.

“We need to better understand this disease so we can be better prepared for infectious outbreaks, and to see its relationship to similar fungal infections, such as valley fever,” Barker said in a press release. “There currently is no cure and no vaccine for this disease.”

Responsible for up to 30% of all HIV/AIDS-related deaths in Latin America, histoplasmosis poses a significant threat in resource-limited countries with inadequate access to antiretroviral drugs. Similarly, the CDC estimates that in sub-Saharan countries, where HIV prevalence is high and health care access limited, fungal infections such as cryptococcal meningitis and Pneumocystis jirovecii pneumonia account for more than half a million deaths annually.

“Fortunately, most fungi are opportunistic pathogens, so despite widespread exposure, development of serious disease typically ensues only if there are deficiencies in host immune functions,” Chad Rappleye, PhD, of The Ohio State University Wexner Medical Center, told Infectious Diseases in Children. “However, other individuals with a decreased number or function of white blood cells can also develop disease, such as patients undergoing immunosuppression due to chemotherapy or transplant receipt.”

In a recent study published in Transplant Infectious Disease, Andes and colleagues analyzed cases of invasive candidiasis from nearly 17,000 solid organ transplant recipients. The researchers found that among 639 cases of invasive candidiasis, the most common species were Candida albicans (46.3%), C. glabrata (24.4%) and C. parapsilosis (8.1%). They also observed that 39% of patients who received antifungal prophylaxis exhibited breakthrough invasive candidiasis.

“While emerging fungal pathogens are not typically dangerous to a normal person with a healthy immune system, they become extraordinarily dangerous for immunologically suppressed patients, as well as neonates and burn patients,” Elaine G. Cox, MD, pediatric disease specialist and medical director of infection prevention for Riley Hospital for Children at Indiana University Health, said during an interview. “In the event of an Aspergillus infection, or even C. auris, these are the populations at highest risk, compounded by the fact that we do not have the drugs to treat them until their immune system returns, turning these infections fatal.”

Emerging multidrug resistance

In December 2015, a British project, titled Review on Antimicrobial Resistance, published the first warning about antimicrobial resistance among fungal pathogens. The project was ordered by former British Prime Minister David Cameron to examine the increase of global antibiotic resistance. The investigators found that overused agricultural fungicides built up resistance in the environment through soil samples.

The Review and experts said that finding alternatives for pesticides in crops is paramount. However, according to Maurizio Del Poeta, MD, associate professor in the department of molecular genetics and microbiology at Stony Brook University, the development of new antifungal therapies should be at the forefront of discussion in clinical settings to avoid further increased mortality and spread of infection.

“It is absolutely essential that in the long term we are not only addressing these emerging fungal infections, but also the current infections: the candidiasis by Candida albicans, aspergillosis by Aspergillus genicanthus and cryptococcosis by Cryptococcus neoformans var gattii,” Del Poeta said in an interview. “These three common infections kill more than 1.3 million people per year.”

Although cases of C. auris are not present in U.S. hospitals and strains are not intercontinental, the fungal infection has the potential to mutate into a different strain of C. auris. Experts believe the disease is transmitted via skin interaction and possibly contaminated surfaces in hospitals. Newborns, organ or marrow transplant recipients, cancer patients and people on rheumatologic drugs have suppressed immune systems that allow for the fungi to invade the bloodstream as candidemia.

“Candidemia, that is to say Candida organisms inside the blood, is lethal unless treated appropriately and in a timely manner with antifungal drugs,” Dimitrios Farmakiotis, MD, the transplant-oncology infectious diseases attending physician at Rhode Island Hospital, told Infectious Diseases in Children. “C. auris presents an additional threat as there is some evidence that it might be clonally transmitted, that is, it is possible that the same organism can go from patient to patient by means of contact, such as hospital surfaces and health care employee hands.”

Along with its resistance to major antifungal medications, C. auris can be misidentified in biochemical-based tests as other Candida species and treated inappropriately, according to the CDC. This poses a problem in correctly treating fungal infections in a time-sensitive manner, which threatens patient safety and lives.

“Normal laboratory indication would not be able to differentiate between different Candida species and also between Candida and Saccharomyces, which is another yeast normally present in our mucosa or in our teeth,” Del Poeta said.

Experts call for methods of developing additional testing, but researching fungal diseases that are multidrug resistant could be difficult because new species may be developing. Further, environmental sources and abilities to cling to skin or gut tissue are unknown. One theory the CDC and experts cited for drug resistance was the global overuse of antibiotics. Unnecessary antimicrobial use paves the way for fungi to become resistant to antifungals because bacteria that controlled the fungus are killed, Cox said in an interview.

“[The antimicrobial] cycle just sets us up to continuing to breed all the types of resistance, including fungal infections,” she said. “I think we could decrease our antibiotic use, that would be one thing; secondly, antifungals have always been more difficult for us to use unlike antibiotics, since in bacteria we have really defined breaking points of what is susceptible, what is not, and the turnaround time on that information is very quick in labs, which is not the case with most fungi.”

A change in armaments

Aside from difficulty differentiating and treating infections from Candida and other drug-resistant fungal organisms promptly, treatment of invasive fungal infections is especially costly. Candida is the most common perpetrator in health care-associated bloodstream infections in the U.S., and according to a study by Juliette Morgan, MD, and colleagues, candidemia represents an estimated additional cost of $6,000 to $29,000 with 3 to 13 days added to length of hospital stay.

Antifungals that are presently used, including amphotericin B, caspofungin and voriconazole, are sufficient to eliminate some strains of Candida but not others, and combination therapy is generally advised against for multidrug-resistant Candida.

“Antifungal drugs are often used blindly to protect patients at risk for candidemia and elusive mold infections, further contributing to: high costs; newly recognized toxicities, such as skin cancer and; of course, antifungal resistance.” Farmakiotis said. “There is an urgent need and promising ongoing research to develop reliable diagnostic methods to diagnose fungal infections early, such as blood and even breath tests. New modalities are expected to help diagnose invasive fungal infections accurately and in a timely manner or rule them out with near certainty, thus limiting the inappropriate use of antifungals.”

In a recent study published in Nature Medicine, Jian Zhang, MD, associate professor of microbial infection and immunity at The Ohio State University, and colleagues demonstrated that inactivating the CBLB gene in mice produced an increased pro-inflammatory response from the immune system to C. albicans, and protected mice from disseminated candidiasis.

“It is very clear that through this process, we can boost our immune response against fungal pathogens and reduce the invasive fungal infection,” Zhang told Infectious Diseases in Children. However, there is still an additional need for newly developed antifungal therapies, he added.

Identifying a pathogen quickly, followed by immediately isolating the pathogen and preventing spread of the infection, is critical to containing a multidrug resistant fungus and possibly developing new antifungals, according to Del Poeta.

“I think that during the next 5 years we will see a dramatic increase of new antifungal agents compared to what we have right now – and the fungal community is very united in this,” he told Infectious Diseases in Children. “The FDA have granted Fast Track, Qualified Infectious Disease Product and orphan drug designations for many antifungals, in comparison to other antibiotics, suggesting that the government recognizes the dire need for new drugs to combat invasive fungal infections.”

Peter G. Pappas, MD, FACP, William E. Dismukes professor of medicine in the division of infectious disease at University of Alabama at Birmingham, claims that the prevalence of invasive fungal diseases is just not as alarming as bacterial infections, and that is the main obstacle in developing new antifungals: simply not enough is known about them.

“It takes something drastic like C. auris to get you to start doing the right things sometimes,” Pappas said in an interview. “The truth is that we are dealing with several multidrug resistant fungi, both yeasts and molds, that really require our attention and we need to respond in a similar way, especially as it relates to unnecessary use of antifungal agents.”

Considerations for the future

In late September, the U.N. General Assembly conducted a high-level meeting to coordinate a global effort against antimicrobial resistance in human and animal health. As only the fourth time in the history of the U.N. that a health topic had been discussed at the General Assembly, the danger of antimicrobial overuse and the interventions designed to curb its impact were finally receiving international attention.

Addressing the assembled heads of state, Ban Ki-moon, secretary-general of the U.N., expressed concern at the severe threat posed by various antimicrobial-resistant diseases, including multidrug-resistant typhoid, growing resistance to HIV/AIDS medications, widespread drug-resistant tuberculosis, and reported resistance to antimalarial medicines. Even on the world stage, emerging multidrug-resistant fungal infections appear to stand just beyond the spotlight.

On the front lines of the battle against antimicrobial resistance, many infectious disease physicians have adopted a ‘watch and wait’ policy. Until more information about C. auris can be gathered, the CDC has recommended timely reporting, prompt laboratory involvement of suspicious infections, a careful adherence to hand hygiene and using contact precautions within health care settings, and most importantly, caution when considering antifungal use.

“The first step in preventing the spread of C. auris, and other invasive fungal infections, should be consistent antifungal stewardship – monitoring and promoting the effective use and dosages of antifungals,” Pappas told Infectious Diseases in Children. “I think that the CDC warning on C. auris gives us an opportunity to focus on this even more. The second step is preventing the spread of fungal infection within the hospital setting, as most of these infections are going to occur within the hospital rather than outside.

“I would imagine, given the CDC warning, that very soon there will be rapid methods by which we can assess whether patients have a C. auris infection, and if so, I would suspect that hospitals will begin treating these patients by placing them in contact isolation, perhaps restricting visitors. However, until we start learning more about this particular pathogen, we can only monitor transmission from one person to the next.”

Since its emergence in 2009, C. auris has proceeded to raise more questions than answers, including why this multidrug-resistant fungus has recently emerged in multiple locations across the globe yet has been shown, through molecular analysis, to include highly distinct strains across different continents. Without knowing why this fungus has emerged, the precise mode of transmission within health care facilities, and without viable defenses against a possible outbreak, ID physicians find themselves wading cautiously into the unknown.

“We do not know much about the mechanisms of multidrug resistance development among Candida species, its molecular basis, or the potential contribution of factors other than exposure to antifungals,” Farmakiotis said in an interview. “We do not even know if the use of more than one antifungal drug against multidrug-resistant Candida and other pathogens is beneficial or harmful.”

“The ancient Greeks said ‘μέτρον άριστον’ – which means ‘balance is excellence’ – this concept, I believe, can be applied to infectious disease specialists in patient care as they weigh the risk of patients rapidly deteriorating from an active infection against the risk of increasing resistance for antimicrobials and antifungals as the result of their unnecessary use.” – by Kate Sherrer

• References:
• Andes DR, et al. Transpl Infect Dis. 2016; doi: 10.1111/tid.12613.
• Casadevall A, et al. J Infect Dis. 2009; doi: 10.1086/644642.
• Morgan J, et al. Infect Control Hosp Epidemiol. 2005; doi: 10.1086/502581
• Teixeira M, et al. PLoS Negl Trop Dis. 2016; doi: 10.1371/journal.pntd.0004732.
• Xiao Y, et al. Nat Med. 2016; doi:10.1038/nm.4141.

• For more information:
• Arturo Casadevall, MD, PhD, can be reached at John Hopkin Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD 21205; email: acasade1@jhu.edu.
• Elaine G. Cox, MD, can be reached at Riley Children’s Health, 705 Riley Hospital Dr #5837, Indianapolis, IN 46202.
• Maurizio Del Poeta, MD, can be reached at 150 Life Science Building, Stony Brook, NY 11794.
• Dimitrios Farmakiotis, MD, can be reached at dimitrios.farmakiotis@lifespan.org.
• Peter G. Pappas, MD, FACP, can be reached at University of Alabama at Birmingham, 1900 University Blvd, 229 THT, Birmingham, AL 35294-0006.
• Jian Zhang, MD, can be reached at jian.zhang@osumc.edu.

Disclosures: Casadevall, Cox, Del Poeta, Farmakiotis, Pappas, Rappleye and Zhang report no relevant financial disclosures.