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Chapter 222 | Candidiasis

Part 5 | Infectious Diseases · Part 5 – Infectious Diseases: Fungal

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. C. auris is an emerging multidrug-resistant pathogen designated an urgent threat by CDC (2019) and critical priority by WHO (2022).
  2. Echinocandins are the first choice of treatment for disseminated candidiasis.
  3. C. auris exhibits unique tolerance to high temperature (up to 42°C) and saline concentrations (10%).
  4. Candidemia treatment duration is 2 weeks beyond the last positive blood culture and resolution of signs and symptoms.
  5. CMC is associated with monogenic disorders of IL-17 receptor signaling (e.g., STAT1, IL-17RA/RC mutations).
  6. C. auris strains can be resistant to all three major antifungal classes (azoles, echinocandins, polyenes).
  7. Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection.
  8. The presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.
  9. For C. auris, echinocandin treatment continues until sensitivities are determined.
  10. C. auris was first identified in 2009 from the ear drainage of a patient with an ear infection in Japan.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Macronodular skin lesions associated with hematogenously disseminated candidiasis
2 🖼 Figure Hematogenous Candida endophthalmitis
3 🖼 Figure Hematogenous Candida endophthalmitis
4 🖼 Figure Hematogenous Candida endophthalmitis
5 🖼 Figure Hematogenous Candida endophthalmitis

1. DEFINITION & OVERVIEW

  • The genus Candida encompasses >150 species, only a few of which cause disease in humans.
  • With rare exceptions (although the exceptions are increasing in number), the human pathogens are C. albicans, C. guilliermondii (recently revised to Meyerozyma guilliermondii), C. krusei (recently revised to Pichia kudriavzevii), C. parapsilosis, C. tropicalis, C. lusitaniae (recently revised to Clavispora lusitaniae), C. dubliniensis, C. glabrata (recently revised to Nakaseomyces glabratus), and the emerging, multidrug-resistant C. auris.
  • C. auris has been responsible for several outbreaks in health care facilities in recent years.
  • Ubiquitous in nature, they inhabit the gastrointestinal tract (including the mouth and oropharynx), the female genital tract, and the skin in the majority of healthy persons.
  • Although cases of candidiasis have been described since antiquity in debilitated patients, the advent of Candida species as common human pathogens dates to the introduction of modern therapeutic approaches that suppress normal host defense mechanisms.
  • Of those advances, the most important are the use of antibacterial agents that alter the normal human microbiota and allow nonbacterial species to become more prevalent in the commensal flora, the use of indwelling intravenous catheters, and the use of cytotoxic, immunosuppressive treatments for malignant and autoimmune disorders.
  • With the introduction of antifungal agents, the causes of Candida infections shifted from an almost complete dominance of C. albicans to the common involvement of C. glabrata and the other species listed above.
  • The non-albicans species now account for approximately half of all cases of candidemia and hematogenously disseminated candidiasis.
  • Recognition of this change is clinically important since the various species differ in susceptibility and are increasingly resistant to the newer antifungal agents.
  • Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm in diameter and reproduces by budding.
  • Organisms of this genus occur in three forms in tissue: blastospores, pseudohyphae, and hyphae.
  • Candida grows readily on simple media; lysis centrifugation enhances its recovery from blood.
  • Species are identified by biochemical testing (currently with automated devices) or on special agar (e.g., CHROMagar).
  • C. auris was designated an urgent threat in the 2019 Centers for Disease Control and Prevention (CDC) Antimicrobial Resistance Threat Report, and it was included within the critical priority group in the 2022 World Health Organization (WHO) fungal priority pathogens list.
  • This concern stems from its occurrence in health care facilities, its ability to adhere to and persist long term on inanimate objects (in hospitals) and the human skin despite decolonization efforts, its association with substantial mortality, its propensity for misidentification as other Candida species, the incomplete understanding of its environmental reservoirs, and its multidrug resistance to the current antifungal therapeutic armamentarium, with some C. auris strains being resistant to all antifungal drug classes currently available for treatment.

1.1 Species Classification

  • C. albicans
  • C. guilliermondii (recently revised to Meyerozyma guilliermondii)
  • C. krusei (recently revised to Pichia kudriavzevii)
  • C. parapsilosis
  • C. tropicalis
  • C. lusitaniae (recently revised to Clavispora lusitaniae)
  • C. dubliniensis
  • C. glabrata (recently revised to Nakaseomyces glabratus)
  • C. auris

2. EPIDEMIOLOGY

  • Candida are present in humans as commensals, in animals, in foods, and on inanimate objects.
  • In developed countries, where contemporary medical therapeutics are commonly used, Candida species are now among the most common nosocomial pathogens.
  • In the United States, these species are among the four most common pathogens isolated from the blood of hospitalized patients.
  • In fact, in a recent point-prevalence study in the United States, Candida species were the most common organisms infecting the bloodstream of hospitalized patients.
  • In regions where advanced medical care is not readily available, mucocutaneous Candida infections, such as thrush, are more common than deep-organ infections, which rarely occur.
  • However, the incidence of deep-organ candidiasis has been increasing steadily as advances in health care—such as therapy with broad-spectrum antibiotics, more aggressive treatment of cancer, and the use of immunosuppression for sustaining organ transplants—have been implemented.
  • In aggregate, the global incidence of infections due to Candida species has risen over the past few decades.
  • C. auris is an emerging species of Candida that has spread rapidly in recent years to >50 countries and is a major public health concern.
  • It was designated an urgent threat in the 2019 Centers for Disease Control and Prevention (CDC) Antimicrobial Resistance Threat Report, and it was included within the critical priority group in the 2022 World Health Organization (WHO) fungal priority pathogens list.
  • This concern stems from its occurrence in health care facilities, its ability to adhere to and persist long term on inanimate objects (in hospitals) and the human skin despite decolonization efforts, its association with substantial mortality, its propensity for misidentification as other Candida species, the incomplete understanding of its environmental reservoirs, and its multidrug resistance to the current antifungal therapeutic armamentarium, with some C. auris strains being resistant to all antifungal drug classes currently available for treatment.
  • C. auris (auris meaning ear in Latin) was first identified in 2009 from the ear drainage of a patient with an ear infection in Japan.
  • However, subsequent retrospective analysis of Candida strain collections identified the earliest known C. auris strain to date back to 1996 in South Korea.
  • Notably, whole genome sequencing analysis of C. auris strains from South Asia, East Asia, South America, South Africa, and Iran found that although strains within each geographic region are closely related to each other, they are distinct compared to strains from other geographic regions.
  • These findings indicate that C. auris emerged independently in multiple geographic locations around the same time; the epidemiologic reasons for this emergence remain poorly understood but may relate to the increasing use of antifungal drugs and climate change.
  • The presence of a central venous catheter and/or other invasive Candida medical devices and recent residence in nursing homes are major risk factors for C. auris colonization and infection.
  • Screening of selected patients who are in a hospital or nursing home where C. auris has been cultured and are at risk for dissemination from a colonization site may help in implementing effective infection control measures.
  • Hand hygiene with an alcohol-based hand sanitizer is recommended when hands are not visibly soiled, in which case washing with soap and water is preferred.
  • Identifying the source of contamination, if possible, and using an Environmental Protection Agency (EPA)-registered hospital-grade disinfectant effective against Clostridioides difficile spores are desirable.
  • If a patient develops an invasive or bloodstream infection, it is recommended that the health care facility informs the CDC, or a similar agency in other countries, and adheres to recommendations for infection control, including isolation of patients (contact or enhanced barrier precautions), use of proper personal protective coverings, enforcement of hospital environment hygiene, and communicating with other health care facilities if the patient is being transferred.

2.1 Risk Factors for Disseminated Candidiasis

  • Antibacterial agents
  • Indwelling intravenous catheters
  • Hyperalimentation fluids
  • Indwelling urinary catheters
  • Parenteral glucocorticoids
  • Respirators
  • Severe burns
  • Myeloperoxidase deficiency
  • CARD9 deficiency (central nervous system)
  • Neutropenia
  • Low birth weight (neonates)
  • Diabetes
  • Abdominal and thoracic surgery
  • Cytotoxic chemotherapy
  • Immunosuppressive agents for organ transplantation

3. ETIOLOGY & PATHOPHYSIOLOGY

  • In the most severe form of Candida infection, the organisms disseminate hematogenously and form microabscesses and small macroabscesses in major organs.
  • Although the exact mechanism is not known, Candida probably enters the bloodstream from mucosal surfaces after growing to large numbers as a consequence of bacterial suppression by antibacterial drugs and breaches in the integrity of the mucosal barrier.
  • Alternatively, in some instances, the organism may enter the bloodstream from the skin via central venous catheters.
  • A change from the blastospore stage to the pseudohyphal and hyphal stages is generally considered integral to Candida's penetration into tissue.
  • However, C. glabrata and C. auris can cause life-threatening infection, even though they do not transform into pseudohyphae or hyphae.
  • Adherence to both epithelial and endothelial cells is thought to be the first step in invasion and infection; several adhesins have been identified as well as a mucosal toxin, candidalysin.
  • Biofilm formation also is considered important in pathogenesis.
  • Numerous reviews of cases of hematogenously disseminated candidiasis have identified the predisposing factors or conditions associated with disease (Table 222-1).
  • Several genes that are involved in the pathogenesis of other Candida species—such as those responsible for biofilm formation, proteinases, lipases, phospholipases, hydrolases, adhesins, secreted aspartyl proteases, and transporters involved in azole resistance—are also present in C. auris.
  • Unlike other Candida species, several C. auris strains exhibit aggregate-forming properties in vivo, which may enable immune evasion.
  • In addition, C. auris shows a unique tolerance to high temperature and saline concentrations and can grow optimally at up to 42°C and in a 10% saline concentration, making it possible to exist and persist in harsh environments.
  • Furthermore, C. auris has significant affinity for abiotic surfaces such as plastic materials and medical devices, as well as human skin and nasal and ear cavities, which may account for its persistent colonization capabilities.
  • The C. auris–specific adhesin surface colonization factor 1 (SCF1) was recently identified as a key fungal factor governing biofilm formation, colonization of skin and medical devices, and virulence during invasive infection.
  • Innate immunity is the most important defense mechanism against hematogenously disseminated candidiasis, and the neutrophil is the most potent component of this defense.
  • Macrophages also play an important host defense role.
  • On the other hand, interleukin (IL) 17–producing innate and adaptive lymphoid cells contribute significantly to defense against mucocutaneous candidiasis as evidenced by several monogenic disorders of IL-17 receptor signaling that manifest with chronic mucocutaneous candidiasis (CMC).
  • Although many immunocompetent individuals have antibodies to Candida, the role of these antibodies in defense against the organism is not clear.
  • Multiple genetic polymorphisms in host immune-related genes that predispose to both disseminated and focal candidiasis have been identified and may contribute to patient susceptibility.

3.1 C. auris Unique Traits

  • Unique tolerance to high temperature and saline concentrations
  • Can grow optimally at up to 42°C
  • Can grow in a 10% saline concentration
  • Significant affinity for abiotic surfaces
  • Persistent colonization capabilities
  • C. auris–specific adhesin surface colonization factor 1 (SCF1)
  • Aggregate-forming properties in vivo
  • Immune evasion

4. CLINICAL FEATURES

  • Mucocutaneous Candidiasis
  • Thrush is characterized by white, adherent, painless, discrete or confluent patches in the mouth, on the tongue, or in the esophagus, occasionally with fissuring at the corners of the mouth.
  • This form of disease caused by Candida can also occur at points of contact with dentures (called "denture sore mouth").
  • Organisms are identifiable in gram-stained scrapings from lesions.
  • Approximately half of patients with CMC have associated endocrine abnormalities either in the setting of gain-of-function mutations in STAT1 or in the context of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome.
  • This syndrome is due to mutations in the autoimmune regulator (AIRE) gene and is most prevalent among Finns, Iranian Jews, and Sardinians.
  • Conditions that usually follow the onset of the disease include hypoparathyroidism, adrenal insufficiency, autoimmune thyroiditis, autoimmune hepatitis, autoimmune pneumonitis, alopecia, pernicious anemia, intestinal malabsorption, and primary hypogonadism.
  • In addition, dental enamel dysplasia, vitiligo, nail dystrophy, asplenia, and calcification of the brain and tympanic membranes may occur.
  • Patients with CMC rarely develop hematogenously disseminated candidiasis, reflecting their intact neutrophil function.
  • Vulvovaginal candidiasis is accompanied by pruritus, pain, and vaginal discharge, which is usually thin but may contain whitish "curds" in severe cases.
  • In contrast to oral thrush, HIV is not considered a major risk factor for vulvovaginal candidiasis.
  • Instead, many women who receive antibiotics, particularly β-lactams, may develop vulvovaginal candidiasis.
  • A subset of patients with recurrent vulvovaginitis may have a deficiency in the surface expression of Dectin-1, encoded by CLEC7A, a major recognition factor for β-glucan on the surface of Candida and/or in the downstream adaptor molecule CARD9, which ultimately increases the propensity for recurrent mucocutaneous (including vaginal) infections.
  • Other Candida skin infections include paronychia, a painful swelling at the nail–skin interface; onychomycosis, a fungal nail infection rarely caused by this genus; intertrigo, an erythematous irritation with redness and pustules in the skin folds; balanitis, an erythematous-pustular infection of the glans penis; erosio interdigitalis blastomycetica, an infection between the digits of the hands or toes; folliculitis, with pustules developing most frequently in the area of the beard; perianal candidiasis, a pruritic, erythematous, pustular infection surrounding the anus; mastitis; and diaper rash, a common erythematous, pustular perineal infection in infants.
  • Generalized disseminated cutaneous candidiasis, another form of infection that occurs primarily in infants, is characterized by widespread eruptions over the trunk, thorax, and extremities.
  • The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 222-1) indicate a high probability of dissemination to multiple organs as well as the skin.
  • While the lesions are seen predominantly in immunocompromised patients treated with cytotoxic drugs, they may also develop in patients without neutropenia.
  • CMC is a heterogeneous infection of the hair, nails, skin, and mucous membranes that persists despite intermittent antifungal therapy.
  • The onset of disease usually comes in infancy or within the first two decades of life, but in rare cases, it occurs in later life.
  • The condition may be mild and limited to a specific area of the skin or nails, or it may take a severely disfiguring form (Candida granuloma) characterized by exophytic outgrowths on the skin.
  • CMC is usually associated with specific immunologic dysfunction; most frequently reported is a failure of lymphocytes to secrete or respond to type-17 cytokines following stimulation by Candida antigens in vitro.
  • A subset of the affected patients has mutations in the IL-17 receptors IL-17RA or IL-17RC, its adaptor molecule ACT1 (TRAF3IP2), or, more often, in STAT1.
  • Deeply Invasive Candidiasis
  • Deeply invasive Candida infections may or may not be due to hematogenous seeding.
  • Deep esophageal infection may result from penetration by organisms from superficial esophageal erosions; joint or deep-wound infection from contiguous spread of organisms from the skin; kidney infection from catheter-initiated ascending spread of organisms through the urinary tract; infection of intraabdominal organs and the peritoneum from perforation of the gastrointestinal tract; and gallbladder infection from retrograde migration of organisms from the gastrointestinal tract into the biliary drainage system.
  • However, more commonly, deeply invasive candidiasis results from hematogenous seeding of various organs as a complication of candidemia.
  • Once the organism gains access to the intravascular compartment (either from the gastrointestinal tract or, less often, from the skin through the site of an indwelling intravascular catheter), it may spread hematogenously to a variety of deep organs.
  • The brain, chorioretina (Fig. 222-2), heart, and kidneys are most commonly infected and the liver and spleen are less commonly affected in nonneutropenic hosts (but most often involved in neutropenic patients).
  • In fact, nearly any organ can become involved, including the endocrine glands, pancreas, heart valves (native or prosthetic), skeletal muscle, joints (native or prosthetic), bones, and meninges.
  • Candida organisms can also spread hematogenously to the skin and cause classic macronodular lesions (Fig. 222-1).
  • Frequently, painful muscular involvement is evident beneath the area of affected skin.
  • Chorioretinal involvement and skin involvement are highly significant since both findings are associated with a very high probability of abscess formation in multiple deep organs as a result of generalized hematogenous seeding.
  • Ocular involvement (Fig. 222-2) may require specific treatment (e.g., partial vitrectomy or intraocular injection of antifungal agents) to prevent permanent blindness.
  • An ocular examination is indicated for patients with candidemia, whether or not they have ocular manifestations.
  • C. auris–associated candidemia can be life-threatening, with a crude mortality rate of 30–60%.
  • Invasive infections are similar to those of other Candida species and are most frequently associated with recent surgical procedures, immunosuppression, invasive devices such as catheters or various support or drainage tubes, and extended hospital stays.
  • In the majority of invasive infections, C. auris has been isolated from the blood, but invasion of the kidney or spleen, and its recovery from cerebrospinal, bile, peritoneal, and pleural fluids demonstrate its invasiveness and dissemination potential.

4.1 Chronic Mucocutaneous Candidiasis (CMC)

  • Heterogeneous infection of the hair, nails, skin, and mucous membranes
  • Persists despite intermittent antifungal therapy
  • Onset usually in infancy or within the first two decades of life
  • Rarely occurs in later life
  • May be mild and limited to a specific area of the skin or nails
  • May take a severely disfiguring form (Candida granuloma)
  • Associated with specific immunologic dysfunction
  • Failure of lymphocytes to secrete or respond to type-17 cytokines
  • Mutations in IL-17 receptors IL-17RA or IL-17RC
  • Mutations in adaptor molecule ACT1 (TRAF3IP2)
  • Mutations in STAT1
  • Associated endocrine abnormalities
  • Hypoparathyroidism
  • Adrenal insufficiency
  • Autoimmune thyroiditis
  • Autoimmune hepatitis
  • Autoimmune pneumonitis
  • Alopecia
  • Pernicious anemia
  • Intestinal malabsorption
  • Primary hypogonadism
  • Dental enamel dysplasia
  • Vitiligo
  • Nail dystrophy
  • Asplenia
  • Calcification of the brain and tympanic membranes

5. DIFFERENTIAL DIAGNOSIS

  • Distinguishing colonization from infection is a major challenge.
  • Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection.
  • Candida isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter.
  • Despite extensive research into both antigen and antibody detection systems, there is currently no widely available and validated diagnostic test to distinguish patients with inconsequential seeding of the blood from those whose positive blood cultures represent hematogenous dissemination to multiple organs.
  • Many studies have examined the utility of the β-glucan test; at present, its greatest utility is its negative predictive value (~90%).
  • Meanwhile, the presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.
  • Despite extensive diagnostic tests for hematogenous dissemination, such as polymerase chain reaction and T2 technology, no test is fully validated or widely available at present.
  • Matrix-assisted laser desorption–ionization–time-of-flight mass spectrometry (MALDI-TOF MS) is now being used extensively for detection and speciation and is useful for the correct diagnosis of C. auris.
  • C. auris can be misdiagnosed in the microbiology laboratory, often leading to inappropriate treatment and delay in the implementation of appropriate infection control measures.
  • Preliminary testing by culturing the fungus and examination of colony morphology may help in the initial identification, but this must be confirmed with more advanced diagnostic methods.
  • Features such as budding yeast morphology, absence of hyphal growth or germ tubes, and growth at 40–42°C (unlike other Candida species) on CHROMagar that may appear white, pink, red, or purple should raise suspicion for C. auris (Fig. 222-3).
  • Several advanced molecular techniques accurately identify C. auris strains and therefore are being used for the follow-up testing and confirmation of the specimens that failed to be identified by traditional methods.

5.1 Colonization vs. Infection

  • Recovery of Candida from sputum, urine, or peritoneal catheters
  • Indicates mere colonization rather than deep-seated infection
  • Candida isolation from the blood of patients with indwelling intravascular catheters
  • May reflect inconsequential seeding of the blood
  • Growth of the organisms on the catheter

6. INVESTIGATIONS & DIAGNOSIS

  • The diagnosis of Candida infection is established by visualization of pseudohyphae or hyphae on wet mount (saline and 10% KOH), tissue Gram stain, periodic acid–Schiff stain, or methenamine silver stain in the presence of inflammation.
  • Absence of organisms on hematoxylin-eosin staining does not reliably exclude Candida infection.
  • The most challenging aspect of diagnosis is determining which patients with Candida isolates have hematogenously disseminated deep-organ seeding.
  • However, because there is no reliable way to distinguish benign candidemia from deep-organ infection, and antifungal drugs less toxic than amphotericin B are available, antifungal treatment for candidemia—with or without clinical evidence of deep-organ involvement—has become the standard of practice.
  • In addition, if an indwelling intravascular catheter is present, it is best to remove or replace the device whenever feasible.
  • Moreover, an infectious disease consultation is recommended as it has been associated with improved patient outcomes.
  • C. auris can be misdiagnosed in the microbiology laboratory, often leading to inappropriate treatment and delay in the implementation of appropriate infection control measures.
  • Preliminary testing by culturing the fungus and examination of colony morphology may help in the initial identification, but this must be confirmed with more advanced diagnostic methods.
  • For example, features such as budding yeast morphology, absence of hyphal growth or germ tubes, and growth at 40–42°C (unlike other Candida species) on CHROMagar that may appear white, pink, red, or purple should raise suspicion for C. auris (Fig. 222-3).
  • Several advanced molecular techniques accurately identify C. auris strains and therefore are being used for the follow-up testing and confirmation of the specimens that failed to be identified by traditional methods.
  • Matrix-assisted laser desorption–ionization–time-of-flight mass spectrometry (MALDI-TOF MS) is now being used extensively for detection and speciation and is useful for the correct diagnosis of C. auris.
  • Table 222-2 outlines the typical decision-making steps in the diagnosis of C. auris by using different methods.
  • A suspicious C. auris specimen is usually sent to a regional reference laboratory for further testing and confirmation of C. auris.

Table 1 — Table 222-1 Well-Recognized Factors and Conditions Predisposing to Hematogenously Disseminated Candidiasis

Factor/Condition
Antibacterial agents
Indwelling intravenous catheters
Hyperalimentation fluids
Indwelling urinary catheters
Parenteral glucocorticoids
Respirators
Severe burns
Myeloperoxidase deficiency
CARD9 deficiency (central nervous system)
Neutropenia
Low birth weight (neonates)
Diabetes
Abdominal and thoracic surgery
Cytotoxic chemotherapy
Immunosuppressive agents for organ transplantation

Table 2 — Table 222-2 Typical Decision-Making Steps in the Diagnosis of C. auris

NO. METHOD DATABASE/SOFTWARE INITIAL FINDING CONFIRMATION
1. Bruker Biotyper MALDI-TOF RUO libraries C. auris C. auris
1. Bruker Biotyper MALDI-TOF CA System library C. auris C. auris
1. bioMérieux VITEK MS MALDI-TOF RUO library C. auris C. auris
1. bioMérieux VITEK MS MALDI-TOF IVD library (v3.2) C. auris C. auris
1. bioMérieux VITEK MS MALDI-TOF Older IVD libraries C. haemulonii C. auris possible: Needs further workup
1. bioMérieux VITEK MS MALDI-TOF Older IVD libraries C. lusitaniae C. auris possible: Needs further workup
1. bioMérieux VITEK MS MALDI-TOF Older IVD libraries No identification C. auris possible: Needs further workup
2. bioMérieux VITEK MS MALDI-TOF IVD library (v3.2) C. auris C. auris
3. VITEK 2 YST Software version 8.01 C. auris C. auris confirmed
3. VITEK 2 YST Software version 8.01 C. haemulonii C. auris possible: Needs further workup
3. VITEK 2 YST Software version 8.01 C. duobushaemulonii C. auris possible: Needs further workup
3. VITEK 2 YST Software version 8.01 Candida spp. not identified C. auris possible: Needs further workup
3. VITEK 2 YST Older versions C. haemulonii C. auris possible: Needs further workup
3. VITEK 2 YST Older versions C. duobushaemulonii C. auris possible: Needs further workup
3. VITEK 2 YST Older versions Candida spp. not identified C. auris possible: Needs further workup
4. API 20C Rhodotorula glutinis, if characteristic red color absent C. auris possible: Needs further workup
4. API 20C C. sake C. auris possible: Needs further workup
4. API 20C Candida spp. not identified C. auris possible: Needs further workup
5. API ID 32C C. intermedia C. auris possible: Needs further workup
5. API ID 32C C. sake C. auris possible: Needs further workup
5. API ID 32C Saccharomyces kluyveri C. auris possible: Needs further workup
6. BD Phoenix C. catenulata C. auris possible: Needs further workup
6. BD Phoenix C. haemulonii C. auris possible: Needs further workup
6. BD Phoenix Candida spp. not identified C. auris possible: Needs further workup
7. MicroScan C. lusitaniae No hyphal growth present Can rule out C. lusitaniae, C. guilliermondii, and C. parapsilosis.
7. MicroScan C. guilliermondii
7. MicroScan C. parapsilosis
7. MicroScan C. lusitaniae Hyphal growth present Possibly C. lusitaniae, C. guilliermondii, C. parapsilosis, or C. auris: Needs further workup
7. MicroScan C. guilliermondii
7. MicroScan C. parapsilosis
7. MicroScan C. famata C. auris possible: Needs further workup
7. MicroScan Candida spp. not identified C. auris possible: Needs further workup
8. RapID Yeast Plus C. parapsilosis → Test on corneal agar No hyphal growth present Can rule out C. parapsilosis. C. auris possible: Needs further workup
8. RapID Yeast Plus C. parapsilosis → Test on corneal agar Hyphal growth present Possibly C. parapsilosis or C. auris: Needs further workup
8. RapID Yeast Plus Candida spp. not identified C. auris possible: Needs further workup
9. GenMark ePlex BCID-FP Panel C. auris C. auris confirmed

Table 3 — Table 222-3 Treatment of Mucocutaneous Candidal Infections

DISEASE PREFERRED TREATMENT ALTERNATIVES
Cutaneous Topical azole Topical nystatin
Oral fluconazole (150 mg) or ibrexafungerp (300 mg twice daily for 1 day) or azole cream or suppository
Vulvovaginal Oral fluconazole (150 mg) or ibrexafungerp (300 mg twice daily for 1 day) or azole cream or suppository Nystatin suppository
Oral (thrush) Fluconazole tablets (100–200 mg/d) Clotrimazole trashes, nystatin
Fluconazole tablets (100–200 mg/d) or itraconazole solution (200 mg/d)
Esophageal Fluconazole tablets (100–200 mg/d) or Caspofungin, itraconazole solution (200 mg/d) micafungin, or amphotericin B

Table 4 — Table 222-4 Agents for the Treatment of Disseminated Candidiasis

AGENT ROUTE OF ADMINISTRATION DOSE COMMENT
Amphotericin B deoxycholate IV only 0.5–1.0 mg/kg daily Mostly replaced by lipid formulations
Amphotericin B lipid formulations IV only 3.0–5.0 mg/kg daily Not approved as primary therapy by the U.S. Food and Drug Administration, but used commonly because they are less toxic than amphotericin B deoxycholate
Liposomal (AmBiSome, Abelcet) IV only 3.0–5.0 mg/kg daily
Lipid complex (ABLC) IV only 3.0–5.0 mg/kg daily
Colloidal dispersion (ABCD) IV only 3.0–5.0 mg/kg daily Associated with frequent infusion reactions
Posaconazole IV and oral 300 mg/d (IV) 200 mg tid (oral) Approved for prophylaxis
Fluconazole IV and oral 400 mg/d Most commonly used
Voriconazole IV and oral 400 mg/d Multiple drug interactions, visual hallucinations, fluorosis, phototoxicity Approved for candidemia in nonneutropenic patients
Caspofungin IV only 50 mg/d
Anidulafungin IV only 100 mg/d
Micafungin IV only 100 mg/d
Rezafungin IV only 400 mg loading dose, 200 mg once weekly thereafter

Table 5 — Table 222-5 Typical MICs of Available Antifungal Drugs for C. auris

DRUG TENTATIVE RESISTANCE BREAKPOINT MIC 50 MIC 90 MIC 99
Amphotericin B ≥2 0.06–8 0.5–1 2–4
Fluconazole ≥32 0.12–≥64 ≥64 ≥64
Itraconazole N/A 0.032–2 0.06–0.5 0.25–1
Voriconazole N/A 0.032–16 0.5–2 2–8
Posaconazole N/A 0.015–16 0.016–0.5 0.125–2
Isavuconazole N/A 0.015–4 0.125–0.25 0.5–2
Caspofungin ≥2 0.03–16 0.25–1 1–2
Anidulafungin ≥4 0.015–16 0.125–0.5 0.5–1
Micafungin ≥4 0.015–8 0.125–0.25 0.25–2

6.1 C. auris Diagnostic Methods

  • Bruker Biotyper MALDI-TOF
  • bioMérieux VITEK MS MALDI-TOF
  • VITEK 2 YST
  • API 20C
  • API ID 32C
  • BD Phoenix
  • MicroScan
  • RapID Yeast Plus
  • GenMark ePlex BCID-FP Panel

7. MANAGEMENT & TREATMENT

  • The treatment of mucocutaneous candidiasis is summarized in Table 222-3.
  • All patients with candidemia are treated with a systemic antifungal agent.
  • A certain percentage of patients, including many of those who have candidemia associated with an indwelling intravascular catheter, probably have "benign" candidemia rather than deep-organ seeding.
  • However, because there is no reliable way to distinguish benign candidemia from deep-organ infection, and antifungal drugs less toxic than amphotericin B are available, antifungal treatment for candidemia—with or without clinical evidence of deep-organ involvement—has become the standard of practice.
  • In addition, if an indwelling intravascular catheter is present, it is best to remove or replace the device whenever feasible.
  • Moreover, an infectious disease consultation is recommended as it has been associated with improved patient outcomes.
  • The drugs used for the treatment of candidemia and suspected disseminated candidiasis are listed in Table 222-4.
  • Various lipid classes of amphotericin B, four echinocandins, the azoles fluconazole and voriconazole, and in some instances, the newer triazole posaconazole are used; no agent within a given class has been clearly identified as superior to the others.
  • Most institutions choose an agent from each class on the basis of their own specific microbial epidemiology, strategies to minimize toxicities, and cost considerations.
  • An echinocandin is the first choice of treatment.
  • The U.S. Food and Drug Administration (FDA) recently approved the use of echinocandins the new-generation echinocandin rezafungin for the treatment of candidemia and invasive candidiasis in adult patients; rezafungin has a prolonged half-life, which allows for once-weekly 200-mg dosing following a 400-mg front-loading dose.
  • Echinocandin treatment continues until sensitivities or speciation is determined.
  • In stable patients, many centers then switch to fluconazole if a sensitive strain is identified and there is no evidence of hematogenous dissemination.
  • For hemodynamically unstable or neutropenic patients, initial treatment with echinocandins is warranted, and once the clinical response has been assessed and the pathogen specifically identified, the regimen can be altered according to the sensitivities.
  • At present, the vast majority of C. albicans isolates are sensitive to fluconazole.
  • Fluconazole Isolates of C. glabrata and C. krusei are less sensitive to fluconazole and more sensitive to polyenes and echinocandins.
  • C. parapsilosis is less sensitive to echinocandins in vitro; however, this lesser sensitivity is considered clinically insignificant.
  • Posaconazole has been approved for prophylaxis, including against Candida, in neutropenic patients.
  • Itraconazole is rarely used for Candida nowadays, and isavuconazole is not recommended for this indication.
  • Antifungal drug resistance is one of the hallmarks of C. auris infections.
  • Some C. auris strains have multidrug resistance with elevated minimal inhibitory concentrations (MICs) to all three major antifungal classes—azoles, echinocandins, and polyenes—resulting in limited treatment options.
  • A CDC study reported antifungal resistance in C. auris strains obtained from 54 patients in India, Pakistan, South Africa, and Venezuela: 93% were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% of the tested strains were resistant to two antifungal classes, and, alarmingly, 4% of the tested strains were resistant to all three classes of antifungal drugs.
  • A 2023 CDC report indicated that rates of C. auris echinocandin resistance tripled in 2021 compared to the prior 2 years.
  • Almost all C. auris strains that have been identified have elevated MICs for fluconazole with variable susceptibilities to other triazoles (Table 222-5), associated with mutations in ERG11-encoded lanosterol demethylase and/or overexpression of drug transporters/efflux pumps.
  • Due to the high rates of azole resistance among C. auris strains, echinocandins is recommended as first-line therapy for C. auris infection.
  • By contrast, the CDC discourages the use of antifungal drugs for the treatment of colonization of C. auris in the absence of invasive or bloodstream infection.
  • A history of patient travel or residence in a health care or nursing facility with a known C. auris infection should prompt screening for C. auris.

7.1 Treatment Duration

  • The recommended duration of therapy is 2 weeks beyond the last positive blood culture and the resolution of signs and symptoms of infection.

8. PROGNOSIS & COMPLICATIONS

  • C. auris–associated candidemia can be life-threatening, with a crude mortality rate of 30–60%.
  • Invasive infections are similar to those of other Candida species and are most frequently associated with recent surgical procedures, immunosuppression, invasive devices such as catheters or various support or drainage tubes, and extended hospital stays.
  • In the majority of invasive infections, C. auris has been isolated from the blood, but invasion of the kidney or spleen, and its recovery from cerebrospinal, bile, peritoneal, and pleural fluids demonstrate its invasiveness and dissemination potential.

8.1 Mortality Rates

  • C. auris–associated candidemia
  • Crude mortality rate of 30–60%

9. SPECIAL CONSIDERATIONS

  • C. auris was first identified in 2009 from the ear drainage of a patient with an ear infection in Japan.
  • However, subsequent retrospective analysis of Candida strain collections identified the earliest known C. auris strain to date back to 1996 in South Korea.
  • Notably, whole genome sequencing analysis of C. auris strains from South Asia, East Asia, South America, South Africa, and Iran found that although strains within each geographic region are closely related to each other, they are distinct compared to strains from other geographic regions.
  • These findings indicate that C. auris emerged independently in multiple geographic locations around the same time; the epidemiologic reasons for this emergence remain poorly understood but may relate to the increasing use of antifungal drugs and climate change.
  • The presence of a central venous catheter and/or other invasive Candida medical devices and recent residence in nursing homes are major risk factors for C. auris colonization and infection.
  • Screening of selected patients who are in a hospital or nursing home where C. auris has been cultured and are at risk for dissemination from a colonization site may help in implementing effective infection control measures.
  • Hand hygiene with an alcohol-based hand sanitizer is recommended when hands are not visibly soiled, in which case washing with soap and water is preferred.
  • Identifying the source of contamination, if possible, and using an Environmental Protection Agency (EPA)-registered hospital-grade disinfectant effective against Clostridioides difficile spores are desirable.
  • If a patient develops an invasive or bloodstream infection, it is recommended that the health care facility informs the CDC, or a similar agency in other countries, and adheres to recommendations for infection control, including isolation of patients (contact or enhanced barrier precautions), use of proper personal protective coverings, enforcement of hospital environment hygiene, and communicating with other health care facilities if the patient is being transferred.
  • C. auris shows a unique tolerance to high temperature and saline concentrations and can grow optimally at up to 42°C and in a 10% saline concentration, making it possible to exist and persist in harsh environments.
  • Furthermore, C. auris has significant affinity for abiotic surfaces such as plastic materials and medical devices, as well as human skin and nasal and ear cavities, which may account for its persistent colonization capabilities.
  • The C. auris–specific adhesin surface colonization factor 1 (SCF1) was recently identified as a key fungal factor governing biofilm formation, colonization of skin and medical devices, and virulence during invasive infection.
  • Innate immunity is the most important defense mechanism against hematogenously disseminated candidiasis, and the neutrophil is the most potent component of this defense.
  • Macrophages also play an important host defense role.
  • On the other hand, interleukin (IL) 17–producing innate and adaptive lymphoid cells contribute significantly to defense against mucocutaneous candidiasis as evidenced by several monogenic disorders of IL-17 receptor signaling that manifest with chronic mucocutaneous candidiasis (CMC).
  • Although many immunocompetent individuals have antibodies to Candida, the role of these antibodies in defense against the organism is not clear.
  • Multiple genetic polymorphisms in host immune-related genes that predispose to both disseminated and focal candidiasis have been identified and may contribute to patient susceptibility.
  • Low birth weight (neonates) is a predisposing factor for hematogenously disseminated candidiasis.

9.1 Neonates

  • Low birth weight (neonates) is a predisposing factor for hematogenously disseminated candidiasis.

10. KEY PEARLS & CLINICAL TRAPS

  • C. auris is an emerging multidrug-resistant pathogen designated an urgent threat by CDC (2019) and critical priority by WHO (2022).
  • Echinocandins are the first choice of treatment for disseminated candidiasis.
  • C. auris exhibits unique tolerance to high temperature (up to 42°C) and saline concentrations (10%).
  • Candidemia treatment duration is 2 weeks beyond the last positive blood culture and resolution of signs and symptoms.
  • CMC is associated with monogenic disorders of IL-17 receptor signaling (e.g., STAT1, IL-17RA/RC mutations).
  • C. auris strains can be resistant to all three major antifungal classes (azoles, echinocandins, polyenes).
  • Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection.
  • The presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.
  • For C. auris, echinocandin treatment continues until sensitivities are determined.
  • C. auris was first identified in 2009 from the ear drainage of a patient with an ear infection in Japan.

WHAT TO LOOK FOR — DIAGNOSTIC CLUES

  • The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 222-1) indicate a high probability of dissemination to multiple organs as well as the skin.
  • While the lesions are seen predominantly in immunocompromised patients treated with cytotoxic drugs, they may also develop in patients without neutropenia.
  • The presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.
  • C. auris shows a unique tolerance to high temperature and saline concentrations and can grow optimally at up to 42°C and in a 10% saline concentration, making it possible to exist and persist in harsh environments.
  • Furthermore, C. auris has significant affinity for abiotic surfaces such as plastic materials and medical devices, as well as human skin and nasal and ear cavities, which may account for its persistent colonization capabilities.
  • Features such as budding yeast morphology, absence of hyphal growth or germ tubes, and growth at 40–42°C (unlike other Candida species) on CHROMagar that may appear white, pink, red, or purple should raise suspicion for C. auris (Fig. 222-3).
  • Several advanced molecular techniques accurately identify C. auris strains and therefore are being used for the follow-up testing and confirmation of the specimens that failed to be identified by traditional methods.

10.1 C. auris Clues

  • Unique tolerance to high temperature and saline concentrations
  • Can grow optimally at up to 42°C
  • Can grow in a 10% saline concentration
  • Significant affinity for abiotic surfaces
  • Persistent colonization capabilities
  • C. auris–specific adhesin surface colonization factor 1 (SCF1)
  • Aggregate-forming properties in vivo
  • Immune evasion

WHAT EXCLUDES THE DIAGNOSIS

  • Recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection.
  • Candida isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter.
  • Despite extensive research into both antigen and antibody detection systems, there is currently no widely available and validated diagnostic test to distinguish patients with inconsequential seeding of the blood from those whose positive blood cultures represent hematogenous dissemination to multiple organs.
  • Many studies have examined the utility of the β-glucan test; at present, its greatest utility is its negative predictive value (~90%).
  • Absence of organisms on hematoxylin-eosin staining does not reliably exclude Candida infection.

10.2 Colonization vs. Infection

  • Recovery of Candida from sputum, urine, or peritoneal catheters
  • Indicates mere colonization rather than deep-seated infection
  • Candida isolation from the blood of patients with indwelling intravascular catheters
  • May reflect inconsequential seeding of the blood
  • Growth of the organisms on the catheter

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Macronodular skin lesions associated with hematogenously disseminated candidiasis

Caption: FIGURE 222-1 Macronodular skin lesions associated with hematogenously disseminated candidiasis. Candida organisms are usually but not always visible on histopathologic examination. The fungi grow when a portion of the biopsied specimen is cultured. Therefore, for optimal identification, both histopathology and culture should be performed. (Image courtesy of Dr. Noah Craft and the Victor Newcomer collection at UCLA, archived by Logical Images, Inc.; with permission.) — Figure 222-1: Macronodular skin lesions associated with hematogenously disseminated candidiasis. Candida organisms are usually but not always visible on histopathologic examination. The fungi grow when a portion of the biopsied specimen is cultured.

Figure 2

Hematogenous Candida endophthalmitis

Caption: FIGURE 222-2 Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms. Lesions of this type may progress to cause extensive vitreal inflammation and eventual loss of the eye. Partial vitrectomy, combined with IV and possibly intravitreal antifungal therapy, may be helpful in controlling the lesions. (Image courtesy of Dr. Gary Holland; with permission.) — Figure 222-2: Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms.

Figure 3

Hematogenous Candida endophthalmitis

Caption: FIGURE 222-2 Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms. Lesions of this type may progress to cause extensive vitreal inflammation and eventual loss of the eye. Partial vitrectomy, combined with IV and possibly intravitreal antifungal therapy, may be helpful in controlling the lesions. (Image courtesy of Dr. Gary Holland; with permission.) — Figure 222-3 Panel A: Candida mixed culture showing C. glabrata (purple), C. tropicalis (navy blue), and C. auris (white, circled in red).

Figure 4

Hematogenous Candida endophthalmitis

Caption: FIGURE 222-2 Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms. Lesions of this type may progress to cause extensive vitreal inflammation and eventual loss of the eye. Partial vitrectomy, combined with IV and possibly intravitreal antifungal therapy, may be helpful in controlling the lesions. (Image courtesy of Dr. Gary Holland; with permission.) — Figure 222-3 Panel B: C. auris showing multiple colony morphologies.

Figure 5

Hematogenous Candida endophthalmitis

Caption: FIGURE 222-2 Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms. Lesions of this type may progress to cause extensive vitreal inflammation and eventual loss of the eye. Partial vitrectomy, combined with IV and possibly intravitreal antifungal therapy, may be helpful in controlling the lesions. (Image courtesy of Dr. Gary Holland; with permission.) — Figure 222-3 Panel C: C. auris after Salt SAB Dulcitol Broth enrichment.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.