Superfungi: emerging challenge in global health

Antifungal resistance represents a silent but devastating threat that could compromise the treatment of several fungal diseases and increase morbidity and mortality worldwide.

Fungi play essential roles in natural ecosystems; however, a new and worrying phenomenon has drawn the attention of the scientific community and public health around the world: the ‘superfungi’. These multidrug resistant organisms represent an emerging challenge that jeopardizes the effectiveness of antifungal treatments and human health. Among the most worrisome superfungi is Candida auris , a species that has been spreading rapidly. Other fungi, such as Aspergillus fumigatus and Cryptococcus neoformans , have also shown increasing resistance to available antifungal treatments.

The microbiologist and head of the Mycology Laboratory at the Evandro Chagas National Institute of Infectology of the Oswaldo Cruz Foundation (INI/Fiocruz), Dr. Rodrigo de Almeida Paes, explains that Candida auris is an emerging pathogen that demonstrates resistance to antifungals commonly used in clinical practice, resulting in significant morbidity and mortality. “This pathogen has been widely known as a ‘superfungus’ due to its high transmission capacity, resistance to multiple antifungals, long survival in hospital environments and serious clinical outcomes”, he adds, noting that this species is not the only one with these characteristics, and there are other fungi, both yeast-like and filamentous, with the potential to cause clinical conditions similar to those caused byC. auris .

One of the main concerns is the increasing incidence of resistant fungal infections in hospitals and intensive care units (ICU). Immunosuppressed or immunocompromised patients, such as those who have undergone organ transplants, cancer treatments or with weakened immune systems, the elderly and newborns are particularly vulnerable to invasive fungal infections caused by these microorganisms. Furthermore, these fungi can survive on surfaces and objects for long periods of time, which makes controlling the spread even more challenging. Superfungi can cause everything from skin and nail infections to more serious infections such as candidemia, a widespread fungal infection that can be fatal. There are some studies on the reasons for the multidrug resistance of C. aurisand other fungi, but there is still much to be discovered.

“Research conducted in 2021 in Belgium and the United States revealed, through genomic sequencing of C. auris , that this species quickly acquires genetic alterations that guarantee its resistance to antifungals. This process involves the gradual accumulation of new mutations and variations in the number of copies of known and unknown genes related to resistance to antifungal drugs”, details Dr. Paes adding that resistance to echinocandins is associated with the deletion of amino acids in a protein that influences the fungal cell wall synthesis. Resistance to azoles is related to the overexpression of efflux pumps, which transport the antifungal agent out of the fungal cell.

Still according to the microbiologist, this overexpression occurs due to duplications in certain chromosomal regions that house the genes of these pumps. “In addition, several mutations were observed that drastically modify enzymes involved in the synthesis of ergosterol, which is associated with resistance to both amphotericin B and fluconazole”, he points out. Another feature that increases resistance to antifungal drugs in C. auris and in several other fungi is their ability to form biofilms on different surfaces.

As with antibiotic-resistant bacteria, inappropriate use of antifungals can select for resistant fungal strains, rendering conventional treatments ineffective. The threat posed by superfungi highlights the urgent need for comprehensive action. It is essential to invest in research and development of new antifungal drugs, as well as to promote better management of existing antifungals, avoid indiscriminate use and encourage appropriate prescribing practices. In addition, public awareness of the risks and prevention of fungal infections should be increased. Proper hand hygiene, sterilization of medical instruments, cleanliness of hospital environments, and adoption of infection control practices are critical to minimizing the spread of superfungi.

Brazil registers cases of the superfungus

In December 2020, Brazil recorded the first case of Candida auris infection, in Salvador (BA). “ Candida auris has already been isolated from several countries, with different climatic and social conditions, so the Northeast region should not be the only one to report cases of this fungus in Brazil. Recently, a case of C. auris infection was diagnosed in the Southeast region, in the state of São Paulo. What may be happening in other places are identification failures, since this species is difficult to diagnose. It is entirely possible that this species will still be diagnosed in other parts of Brazil”, highlights the microbiologist. According to a work by Fiocruz, the biggest outbreak of C. aurisoccurred in Recife, between November 2021 and February 2022, totaling 48 cases, the highest number since the presence of this fungus was confirmed for the first time in the country, in 2020.

In the United States, C. auris was first identified in a New York hospital in 2016. Since then, the number of cases has grown dramatically, prompting the Centers for Disease Control and Prevention (CDC) to issue an alert about how C. aurisspread at an “alarming rate” during the pandemic. Throughout 2021, 1,474 clinical cases were confirmed, an increase of about 200% compared to almost 500 cases in 2019. The fungus was first reported in Japan in 2009, in a case of otomycosis. Since then, it has been identified on all continents with the exception of Antarctica. The exact origin of the microorganism, however, is still little known. The most grounded theory attributes the emergence and spread across the planet to climate change and global warming.

The challenge posed by superfungi is a global issue that requires collaboration between governments, research institutions, healthcare professionals and the pharmaceutical industry. Antifungal resistance represents a silent but devastating threat that can compromise the treatment of several fungal diseases and increase morbidity and mortality worldwide. Combating superfungi requires joint efforts to ensure effective therapies and solid prevention strategies. Only with a comprehensive approach and widespread awareness of the problem can this growing threat to global health be tackled.

There are no specific symptoms in cases of infection by C. auris or other emerging multiresistant fungi. However, according to Dr. Paes, there are risk factors that are associated with a greater chance of developing infection by this species. Such factors include advanced age, diabetes mellitus, recent surgery, presence of permanent medical device (eg, central venous catheter), immunosuppression, use of hemodialysis, neutropenia, chronic kidney disease, or use of broad-spectrum antibiotics and/or antifungals.

Outbreak of Candida vulturna caused by multidrug-resistant strains in China

Although considered a rare species, Candida vulturna, an opportunistic fungus phylogenetically related to C. haemulonii and C. auris , also deserves attention because it is considered a multiresistant yeast, mainly to amphotericin B. This species was initially isolated from flowers and was later described as a cause of invasive candidiasis in humans.

One study analyzed 19 patients, 17 men and 2 women, who were infected with C. vulturna between January 1, 2019 and October 26, 2022. Sixteen strains of C. vulturna were isolated from blood cultures and 7 strains from central lines peripherally inserted devices (PICCs) of the 19 patients. Initially, the strains were identified as C. haemulonii complex species by growth on CHROMagar Candida and confirmed by molecular analysis. Hygiene measures taken at that time may have mitigated the spread of _C. vulturna_ in the hospital. Based on phylogenetic analyzes of the isolates, all strains were closely related and grouped into 1 clade.

Read the case report “ Candida vulturna Outbreak Caused by Cluster of Multidrug-Resistant Strains, China ” here 

Recommended actions to prevent occurrence of cases

– Adequate identification, at species level, of all yeasts isolated from patients at high risk of infection;

– Isolate patients infected or colonized by C. auris ;

– Ensure the use of personal protective equipment and hand hygiene during patient care;

– Inform the medical and nursing staff of the affected organizational unit about C. auris and the associated risks;

– Change disinfection procedures. To ensure safe inactivation of C. auris , peracetic acid-based disinfectant should be used rather than quaternary ammonium compounds with or without alcohol;

– Initiate antifungal therapy only if C. auris is related to a clinically relevant infection;

– Track contacts close to the index case for C. auris colonization ;

– Conduct long-term surveillance for the presence of C. auris in organizational units with documented transmission.

Guidelines for identification, prevention and control of C. auris infections

According to the TECHNICAL NOTE GVIMS/GGTES/ANVISA No. 02/2022 – Guidelines for the identification, prevention and control of Candida auris infections in health services, updated on 09/15/2022, it is recommended to follow the following procedures for diagnosis and identification of multiresistant fungi: (i) perform microbiological tests to obtain pure colonies, preferably in chromogenic medium, and incubate for more than 2 days at a temperature of 35-37ºC; (ii) observe the color of the colonies on the chromogenic agar. C. auris colonies may be nonspecific cream, pink, or lilac; (iii) perform microscopy with India ink (Chinese ink) to rule out the presence of encapsulated yeasts, characteristic of the genus Cryptococcus; (iv) perform screening tests for presumptive identification of C. auris; (v) after presumptive identification, carry out proteomic identification by MALDI-TOF or genetic sequencing of the D1-D2 region or ITS. If the laboratory does not have the appropriate equipment for proteomic and genomic analyses, it is essential to forward the isolates to reference laboratories, in order to confirm the case and trigger a specific national task force to support surveillance and outbreak control actions. as soon as possible.