Healthcare-Associated Fungal Infections (Candida and Invasive Molds)

Kaitlin Forsberg

Karlyn D. Beer

Brendan Jackson

Tom Chiller

Healthcare-associated fungal infections and associated outbreaks have become important causes of morbidity and mortality among hospitalized patients, and the incidence of infections caused by some Candida species and molds such as Aspergillus and mucormycetes has increased, likely as a result of a growing immunocompromised population.¹^,²^,³^,⁴ Because these infections have high mortality rates and are also associated with substantial inhospital morbidity, swift detection and treatment or management are critical for patients’ well-being and survival. Fungal disease should be suspected in patients with infections that do not respond to antibacterial therapy. Diagnosis as well as source identification and mitigation can be challenging because fungi are environmental organisms commonly found indoors, outdoors, and as members of the human skin and gut microbial communities. As a result, both Candida⁵^,⁶^,⁷^,⁸ and various molds⁹^,¹⁰^,¹¹^,¹²^,¹³ have caused numerous well-documented HAI outbreaks, highlighting important systems-level opportunities for ongoing infection prevention. Importantly, small clusters of infections can serve as sentinels that lead facilities to identify longstanding deficiencies in building design and construction and to discover preventable outbreak-associated infections previously considered sporadic. Similarly, Candida auris has become an important window into the longstanding need to improve infection prevention practices in high-acuity long-term care facilities and their influence on healthcare.⁵^,¹⁴ This chapter reviews current knowledge on diagnosis, detection, transmission, and prevention and control of HAIs caused by Candida species and molds such as Aspergillus and mucormycetes. Special attention is given to identifying and investigating fungal disease outbreaks in healthcare settings for both Candida and mold infections. Because Coccidioides and other dimorphic fungi have rarely been associated with HAI transmission,¹⁵^,¹⁶ these fungi will not be covered in this chapter. A review of the fundamentals of fungal disease pathogenesis, clinical care, treatment, and epidemiologic risk factors is beyond the scope of this chapter, but has been described extensively elsewhere.³^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴

CANDIDA SPECIES INFECTIONS

Introduction

Candida are the leading cause of healthcare-associated fungal infections.²⁵ Although the Candida genus of yeast includes hundreds of species, only some have been found to be pathogenic in humans. In the United States, sentinel surveillance for candidemia, four species (C albicans [39%], C glabrata [28%], C parapsilosis [15%], and C tropicalis [9%]) accounted for >90% of cases.¹⁸ Other notable species associated with invasive candidiasis include C krusei, C lusitaniae, C dubliniensis, C guilliermondii, and C auris (Table 21-1). C albicans is the most common pathogenic Candida species, but non-albicans species are on the rise and represent the majority of candidiasis in some institutions, changing the species epidemiology.²⁶^,²⁷ This is important because C albicans is largely susceptible to antifungal drugs, but drug resistance is a concern for other species, like C glabrata and C auris. C auris, though rare except in a few areas, is a species of great concern due to its high levels of drug resistance and ability to spread in healthcare facilities.²⁸^,²⁹

Candida cause a variety of different infections, and severity differs among body sites. Common noninvasive infections include oral thrush, vulvovaginal yeast infections, and diaper rash. Invasive candidiasis may involve the blood, eyes, brain, bones, heart, and other body sites and can lead to severe outcomes, like sepsis. Bloodstream infections (candidemia) are associated with high mortality rates (about 30%-60%) and have become one of the leading causes of healthcare-associated bloodstream infections in the United States.²^,²⁷^,³⁰^,³¹^,³²

Risk factors for candidemia and other invasive candidiasis include immunosuppression, recent surgery (especially gastrointestinal) or intensive care, antibacterial use, indwelling catheters and other medical devices, diabetes, intravenous drug use, and low birth weight.¹⁸^,³²^,³³ Improved survival among cancer and transplant patients, along with newer immunosuppressive medications, has increased the population at risk for invasive candidiasis. Risk factors for C auris infections have differed slightly from other Candida
species and have included mechanical ventilation, tracheostomy, broad-spectrum antibacterials, and care in a highacuity post-acute care facility.

This section focuses on the detection, transmission, and prevention of invasive candidiasis among in-patient populations.

TABLE 21-1 List of Common and Notable Pathogenic Candida and Molds

*Candida or mold*	*Genus*	*Species*
*Candida*
	Candida	albicans^a
	Candida	auris
	Candida	dubliniensis
	Candida	glabrata^a
	Candida	guilliermondii^a
	Candida	krusei^a
	Candida	lusitaniae
	Candida	parapsilosis^a
	Candida	tropicalis^a
Molds
	Absidia^b	any
	Alternaria	any
	Aspergillus	flavus
	Aspergillus	fumigatus
	Aspergillus	niger
	Aspergillus	terreus
	*Apophysomyces*	elegans
	Bipolaris	cynodontis
	Bipolaris	micropus
	Bipolaris	setariae
	Cladophialophora	bantiana
	*Cunninghamella*	*bertholletiae*
	Curvularia	americana
	Curvularia	australiensis
	Curvularia	brachyspora
	Curvularia	chlamydospora
	Curvularia	clavata
	Curvularia	hawaiiensis
	Curvularia	hominis
	Curvularia	inaequalis
	Curvularia	lunata
	Curvularia	muehlenbeckiae
	Curvularia	pallescens
	Curvularia	pseudolunata
	Curvularia	senegalensis
	Curvularia	spicifera
	Curvularia	verruculosa
	Exophiala	dermatitidis
	Exophiala	oligosperma
	Exophiala	xenobiotica
	Exserohilum	rostratum
	Fusarium	moniliforme
	Fusarium	oxysporum
	Fusarium	solani
	*Lichtheimia*	*corymbifera*
	*Mucor*	*circinelloides*
	*Mucor*	*racemosus*
	Pseudallescheria	boydii
	*Rhizomucor*	*pusillus*
	*Rhizopus*	*microsporus*
	*Rhizopus*	*oryzae*
Saksenaea	vasiformis
	Scedosporium	apiospermum
	Scedosporium	prolificans
	*Syncephalastrum*	*racemosum*
^aCLSI interpretative susceptibility breakpoints available.³⁴ ^bBoldface mold names indicate members of the mucormycetes, which can cause mucormycosis.

Detection

Identification Because invasive candidiasis lacks pathognomonic symptoms, laboratory confirmation is required for detection and diagnosis. Often, the first sign that a patient may have candidiasis is nonresponse to antibacterial treatment. Rapid detection is important to avoid treatment delays as well as to expedite infection prevention measures when transmission is suspected or possible.

Candida can be detected though culture and cultureindependent methods. Commonly used culture-based methods for identifying Candida include automated biochemical methods, matrix-assisted laser desorption ionization/time-of-flight (MALDI-TOF) mass spectrometry, germ tube test, and peptide nucleic acid fluorescence in situ hybridization (PNA-FISH). Unfortunately, the sensitivity of Candida blood culture is low (˜50%).³⁵ Culture-independent diagnostics include polymerase chain reaction (PCR) and T2 Candida. MALDI-TOF and DNA sequencing are considered the most accurate methods but are not available in all laboratories. VITEK 2 is an automated biochemical method with high accuracy and a large species database and is commonly used. Conversely, germ tube tests and some other automatic biochemical methods are relatively common, but limit laboratories to identifying only the most common species.³⁶

The ability to identify the species of Candida once it is detected is important because it can inform treatment and infection prevention decisions. Laboratories differ in their protocols for Candida species identification. Some laboratories may only identify the species from sterile body sites because Candida from noninvasive sites are often considered colonization rather than infection and are typically not clinically relevant. Therefore, identification of Candida in certain body sites does not necessarily mean treatment should be provided. For instance, in most circumstances, Candida in the urine or lungs would not prompt treatment as these usually indicate colonization.²⁴

However, the recent advent of C auris has led to an increased appreciation of Candida species identification in body sites not necessarily reflective of infection. While person-to-person transmission is not a major concern for most Candida, C auris spreads rapidly in healthcare settings and therefore identifying C auris from any body site should prompt Transmission-based Precautions and infection prevention measures. Improved accessibility of accurate species identification from multiple body sites could help identify emerging species of concern and ensure appropriate infection prevention measures are implemented and effective treatment provided.

Drug Resistance The U.S. Centers for Disease Control and Prevention’s (CDC’s) 2019 Antibiotic Resistant Threat Report listed drug-resistant Candida as a serious threat and C auris as an urgent threat.³⁰ Drug resistance is concerning for multiple Candida species, though resistance levels vary within and among species. C albicans is rarely drug-resistant. In contrast, about 8% of C glabrata
isolates are resistant to azoles and about 3% are resistant to echinocandins in the United States.¹⁸ C auris is highly drug-resistant. About 90% of C auris isolates are resistant to azoles, about 35% are resistant to amphotericin B, and about 5% are resistant to echinocandins.³⁷ Some C auris isolates have been resistant to all three major antifungal drug classes.³⁷

Because of this resistance, antifungal susceptibility testing may be important for treatment decisions, especially for patients with invasive disease, as well as for epidemiologic tracking. The Infectious Diseases Society of America (IDSA) recommends azole susceptibility testing for all invasive candidiasis and echinocandin susceptibility testing if the patient received echinocandin treatment or if the infection was with C glabrata or C parapsilsosis.²⁴ Antifungal susceptibility testing is commonly conducted by broth microdilution, gradient strips, disk diffusion, and automated methods. Broth microdilution is considered the gold standard by the Clinical and Laboratory Standards Institute (CLSI).²⁶ Unfortunately, antifungal susceptibility testing is often even less accessible for facilities than species identification. Susceptibility testing is additionally limited in that standardized interpretative breakpoints are only available for the six most common species and for the azole and echinocandin drug classes (Table 21-1). Public health departments are increasingly capable of assisting with or providing guidance on Candida species identification and susceptibility testing (eg, through the Antibiotic Resistance Laboratory Network, www.cdc.gov/drugresistance/laboratories.html).

Acquisition and Transmission

Many pathogenic Candida species are commensal organisms, colonizing the body, especially in the gastrointestinal, respiratory, and urinary tracts; vagina; and skin. Most Candida infections are caused by the patient’s normal fungal flora. Barriers, like the skin and gastrointestinal mucosa, protect against invasive infections. Infections may occur through autoinoculation due to disruption of such barriers (eg, wounds, placement or management of indwelling devices, or surgery). For example, abdominal surgery may trigger candidemia by enabling normal gut microbiota to translocate to the bloodstream. Candidiasis may also result from dysbiosis, or a disruption of a person’s normal microbial community, causing overgrowth of Candida (as seen with vulvovaginal candidiasis). Such overgrowth may put patients at higher risk of invasive infection, especially in the gastrointestinal tract.

Because Candida infections are typically caused by normal flora, person-to-person transmission is often not considered a concern for Candida. However, transmission, and even outbreaks, has been documented. C auris has led to a change in the paradigm and is highly transmissible in healthcare settings and has caused outbreaks across the world.²⁹^,³⁸ C parapsilosis has caused outbreaks, often in neonatal intensive care units.⁶^,⁸ Outbreaks of other species are rare. Molecular typing has increasingly been used to confirm transmission.³⁹^,⁴⁰ For instance, whole-genome sequencing has aided epidemiologic investigations of C auris outbreaks, by linking acquisition to the receipt of healthcare abroad and identifying local spread.⁴

Transmission of some Candida species may occur through person-to-person contact (eg, hand hygiene breaches), contaminated shared medical equipment, or general environmental contamination.⁴⁰^,⁴¹^,⁴²^,⁴³ Historically, environmental surfaces and fomites were not generally considered a source for Candida infection. This thinking has changed with the emergence of C auris, which has been shown to contaminate the environment when a patient with C auris is present. C auris has been isolated from many healthcare surfaces including bedrails, windowsills, and blood pressure monitoring cuffs and can persist on surfaces for weeks.⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸ In the United Kingdom, one C auris outbreak was linked to reusable temperature probes.⁷

Prevention

Prevention of Transmission Prevention of invasive Candida infection largely occurs within healthcare facilities, since infections tend to be healthcare-associated rather than community-associated. The basic tenets of infection prevention can help prevent infections and transmission. For nearly all Candida species, Standard Precautions are considered sufficient as most infections are believed to arise from the patient’s normal flora. When transmission occurs, spread may be interrupted through increased adherence to Standard Precautions. C auris is the only Candida species that prompts Transmission-based Precautions (eg, Contact Precautions) given its high propensity for spread between patients.

For hand hygiene, alcohol-based hand sanitizer is effective against Candida, including C auris, and is preferred unless hands are visibly soiled, in which case soap and water are preferred.⁴⁹^,⁵⁰ Thorough disinfection of the environment, including shared and mobile equipment, can prevent environmental transmission. For C auris, disinfectants used should be effective against C auris. The first Environmental Protection Agency (EPA) C auris claims for disinfectants were approved in 2019, and the list of EPA-registered hospital-grade disinfectants against C auris is rapidly growing. However, when a product with a C auris claim is not available, facilities may consider using products with an EPA claim for Clostridioides difficile. C auris is not susceptible to quaternary ammonium compounds (QACs), which are commonly used in healthcare facilities,⁵⁰ and it should not be assumed that products with EPA claims against C albicans or fungi are effective against C auris.

For C auris, Transmission-based Precautions additionally dictate considerations for room placement and use of personal protective equipment, depending on the healthcare setting. In acute care settings, Contact Precautions is appropriate, with patients placed in single rooms and gown and gloves required for all patient interactions. In nursing homes, Enhanced Barrier Precautions may be appropriate in situations where Contact Precautions are not required (eg, if the patient does not have active diarrhea or uncontained wounds). Under Enhanced Barrier Precautions, patients may be placed in rooms with other patients and leave their rooms, and gowns and gloves are required for high-touch activities, like bathing, toileting, or dressing wounds (www.cdc.gov/hai/containment/PPE-Nursing-Homes.html). Early detection of C auris cases is important so that infection control interventions can begin rapidly. As with all multidrug-resistant organisms (MDROs), communication of C auris status upon patient transfer helps promote the uninterrupted continuation of infection prevention measures.

Tools used for other contact-driven transmissible HAIs can be applied to assess needs or progress in preventing Candida transmission. These include, but are not limited to, infection control assessment and response (ICAR) program tools (www.cdc.gov/hai/prevent/infection-control-assessment-tools.html) and audit tools for environmental cleaning, device disinfection, and hand hygiene.

Prevention of Invasive Infection When patients are known to be colonized with Candida (either from transmission or as a part of the normal body flora), invasive candidiasis can be prevented through prophylactic antifungal treatment of certain high-risk patients and standard surgical and catheter care infection prevention techniques.²⁴^,⁵¹ Standard infection prevention guidelines apply to candidiasis prevention.⁵¹^,⁵² These include hand hygiene, use of sterile equipment, use of surgical site or catheter site antiseptics, and prompt removal of catheters and indwelling devices when no longer needed.²⁴

Antibiotic stewardship, including for both antibacterials and antifungals, should be implemented to reduce the risk of candidiasis and antifungal drug resistance. Antibacterial drugs can disrupt the body’s microbiome, allowing for Candida overgrowth. Patients who must receive antibacterials should be monitored for drug responsiveness (possibly indicating a fungal and not a bacterial infection) and for the development of candidiasis resulting from antibacterial use. Antifungal resistance may develop in response to treatment, and resistant strains of Candida may flourish in the wake of susceptible strains when antifungals are used, making antifungal stewardship an important tool for combating antifungal resistance.⁵³^,⁵⁴

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