1672 PART 5 Infectious Diseases

is characterized by widespread eruptions over the trunk, thorax, and

extremities. The diagnostic macronodular lesions of hematogenously

disseminated candidiasis (Fig. 216-1) 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 T lymphocytes to secrete type-17 cytokines

in response to stimulation by Candida antigens in vitro. A subset of

the affected patients has mutations in the IL-17 receptor, its adaptor

molecule ACT1 (TRAF3IP2), or, more often, in STAT1, resulting in an

insufficiency of IL-17 and IL-22 production.

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, chronic

active hepatitis, autoimmune pneumonitis, alopecia, juvenile-onset

pernicious anemia, intestinal malabsorption, and primary hypogonadism. In addition, dental enamel dysplasia, vitiligo, nail dystrophy,

asplenia, and calcification of the tympanic membranes may occur.

Patients with CMC rarely develop hematogenously disseminated candidiasis, reflecting their intact neutrophil function.

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 catheterinitiated 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.

TABLE 216-1 Well-Recognized Factors and Conditions Predisposing to

Hematogenously Disseminated Candidiasis

Antibacterial agents

Indwelling intravenous catheters

Hyperalimentation fluids

Indwelling urinary catheters

Parenteral glucocorticoids

Severe burns

CARD9 deficiency (central nervous

system)

Abdominal and thoracic surgery

Cytotoxic chemotherapy

Immunosuppressive agents for organ

transplantation

Respirators

Myeloperoxidase deficiency

Neutropenia

Low birth weight (neonates)

Diabetes

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 significantly

greater 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.

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, TH17 lymphocytes

contribute significantly to defense against mucocutaneous candidiasis

as evidenced by several monogenic disorders of interleukin (IL) 17

receptor signaling that manifest with chronic mucocutaneous candidiasis

(CMC) (see “Clinical Manifestations,” below). 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.

■ CLINICAL MANIFESTATIONS

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. The

occurrence of thrush in a young, otherwise healthy-appearing person

should prompt an investigation for underlying HIV infection. More

commonly, thrush is seen as a nonspecific manifestation of severe

debilitating illness. 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 may develop vulvovaginal candidiasis. A subset of patients with recurrent vulvovaginitis may have a

deficiency in the surface expression of Dectin-1, 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,

FIGURE 216-1 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.)

1673CHAPTER 216 Candidiasis

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. 216-2), 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. 216-1). 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. 216-2) may require specific treatment (e.g.,

partial vitrectomy or intraocular injection of antifungal agents) to

prevent permanent blindness. An ocular examination is indicated

for all patients with candidemia, whether or not they have ocular

manifestations. C. auris 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. C. auris-associated candidemia can

be life-threatening, with a crude mortality rate of 30–60%.

■ DIAGNOSIS

The diagnosis of Candida infection is established by visualization of

pseudohyphae or hyphae on wet mount (saline and 10% KOH), tissue

Gram’s stain, periodic acid–Schiff stain, or methenamine silver stain in

the presence of inflammation. Absence of organisms on hematoxylineosin staining does not reliably exclude Candida infection. The most

challenging aspect of diagnosis is determining which patients with

Candida isolates have hematogenously disseminated candidiasis. For

instance, recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection,

and 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 is usually 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 could raise suspicion for

C. auris (Fig. 216-3).

FIGURE 216-2 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.)

A B C

FIGURE 216-3 C. auris colony morphology and color on CHROMagar plates. A. Candida mixed culture: culture of C. glabrata (purple), C. tropicalis (navy blue), and C. auris

(white, circled in red). B. C. auris showing multiple colony morphologies. C. C. auris after Salt SAB Dulcitol Broth enrichment. (From CDC: Identification of Candida auris.

2019. Available at: www.cdc.gov/fungal/candida-auris/recommendations.html.)

1674 PART 5 Infectious Diseases

TABLE 216-2 Typical Decision-Making Steps in the Diagnosis of C. auris

NO. METHOD DATABASE/SOFTWARE INITIAL FINDING ã CONFIRMATION

1. Bruker Biotyper

MALDI-TOF

RUO libraries C. auris C. auris

CA System library C. auris C. auris

2. bioMérieux VITEK MS

MALDI-TOF

RUO library C. auris C. auris

IVD library C. auris C. auris

Older IVD libraries

C. haemulonii C. auris possible: Needs further workup

C. lusitaniae C. auris possible: Needs further workup

No identification C. auris possible: Needs further workup

3. VITEK 2 YST Software version 8.01 C. auris C. auris confirmed

C. haemulonii C. auris possible: Needs further workup

C. duobushaemulonii C. auris possible: Needs further workup

Candida spp. not identified C. auris possible: Needs further workup

Older versions C. haemulonii C. auris possible: Needs further workup

C. duobushaemulonii C. auris possible: Needs further workup

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

C. sake C. auris possible: Needs further workup

Candida spp. not identified C. auris possible: Needs further workup

5. BD Phoenix C. catenulata C. auris possible: Needs further workup

C. haemulonii C. auris possible: Needs further workup

Candida spp. not identified C. auris possible: Needs further workup

6. MicroScan C. lusitaniae

No hyphal growth present

Can rule out C. lusitaniae, C.

guilliermondii, and C. parapsilosis.

C. auris possible: Needs further workup

C. guilliermondii

C. parapsilosis

C. lusitaniae

Hyphal growth present

Possibly C. lusitaniae,

C. guilliermondii, C. parapsilosis, or

C. auris: Needs further workup

C. guilliermondii

C. parapsilosis

C. famata C. auris possible: Needs further workup

Candida spp. not identified C. auris possible: Needs further workup

7. RapID Yeast Plus C. parapsilosis → Test on

corneal agar

No hyphal growth present Can rule out C. parapsilosis. C. auris

possible: Needs further work-up

Hyphal growth present Possibly C. parapsilosis or

C. auris: Needs further workup

Candida spp. not identified C. auris possible: Needs further workup

8. GenMark ePlex

BCID-FP Panel

C. auris C. auris confirmed

IVD, in vitro diagnostic; RUO, research use only.

Source: Adapted from CDC: Identification of Candida auris. 2019. Available at: www.cdc.gov/fungal/candida-auris/recommendations.html

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. MALDI-TOF equipment with upgraded libraries, such as

Bruker Biotyper MALDI-TOF (CA System library version claim 4

or research use only [RUO] libraries versions 2014 [5627] and more

recent), and using the bioMérieux VITEK MALDI-TOF MS (IVD v3.2

or RUO libraries with Saramis Ver 4.14 database and Saccharomycetaceae update), are the most common methods of C. auris identification.

Other supplemental MALDI-TOF databases, such as MicrobeNet, that

include additional C. auris strains from the four phylogenetic clades

(i.e., South Asian, East Asian, South American, and South African) also

can be used for the identification of C. auris strains. Sequencing of the

D1–D2 region of the 28s rDNA or the internal transcribed region (ITS)

of rDNA can also correctly identify C. auris. Recently, an automated,

qualitative nucleic acid multiplex in vitro diagnostic test by GenMark

called ePlex Blood Culture Identification Fungal Pathogen (BCID-FP)

Panel was approved by the U.S. Food and Drug Administration for

C. auris testing. Also, several polymerase chain reaction–based detection methods have been reported to identify C. auris in various specimens. Table 216-2 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.

TREATMENT

Candida Infections

MUCOCUTANEOUS CANDIDA INFECTION

The treatment of mucocutaneous candidiasis is summarized in

Table 216-3.

CANDIDEMIA AND SUSPECTED HEMATOGENOUSLY

DISSEMINATED CANDIDIASIS

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 deeporgan seeding. However, because there is no reliable way to distinguish benign candidemia from deep-organ infection, and because

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.

1675CHAPTER 216 Candidiasis

In addition, if an indwelling intravascular catheter is present, it is

best to remove or replace the device whenever feasible.

The drugs used for the treatment of candidemia and suspected

disseminated candidiasis are listed in Table 216-4. Various lipid

formulations of amphotericin B, three echinocandins, the azoles

fluconazole and voriconazole, and in some instances, the newer

triazoles—posaconazole and isavuconazole—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

now considered the first choice of treatment if there is concern

for resistance, which will be the case in nearly all hospitals. 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 broader-spectrum

agents is desirable; these drugs include polyenes, echinocandins,

or later-generation azoles such as voriconazole. 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.

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, and isavuconazole has not been approved for this indication to date.

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 recent 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 2 antifungal classes, and,

alarmingly, 4% of the tested strains were resistant to all 3 classes of

antifungal drugs. Almost all C. auris strains that have been identified have elevated MICs for fluconazole with variable susceptibilities to other triazoles (Table 216-5), 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,

the use of 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 healthcare or nursing facility with a known

TABLE 216-3 Treatment of Mucocutaneous Candidal Infections

DISEASE PREFERRED TREATMENT ALTERNATIVES

Cutaneous Topical azole Topical nystatin

Vulvovaginal Oral fluconazole (150 mg) or

azole cream or suppository

Nystatin suppository

Oral (thrush) Clotrimazole troches Nystatin, fluconazole

Esophageal Fluconazole tablets (100–200

mg/d) or itraconazole solution

(200 mg/d)

Caspofungin, micafungin,

or amphotericin B

TABLE 216-4 Agents for the Treatment of Disseminated Candidiasis

AGENT ROUTE OF ADMINISTRATION DOSEa COMMENT

Amphotericin B deoxycholate IV only 0.5–1.0 mg/kg daily Mostly replaced by lipid formulations

Amphotericin B lipid formulations 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

Azolesb

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

Approved for candidemia in nonneutropenic patients

Echinocandins Broad spectrum against Candida species; approved for disseminated

candidiasis; less toxic than amphotericin B formulations

Caspofungin IV only 50 mg/d

Anidulafungin IV only 100 mg/d

Micafungin IV only 100 mg/d

a

For loading doses and adjustments in renal failure, see Pappas PG et al: Clinical practice guidelines for the management of candidiasis: 2016 update by the Infectious

Diseases Society of America. Clin Infect Dis 62:e1, 2016. The recommended duration of therapy is 2 weeks beyond the last positive blood culture and the resolution of signs

and symptoms of infection. b

Although ketoconazole is approved for the treatment of disseminated candidiasis, it has been replaced by the newer agents listed in this table.

Posaconazole has been approved for prophylaxis in neutropenic patients and for oropharyngeal candidiasis.

TABLE 216-5 Typical MICs of Available Antifungal Drugs for C. auris

DRUG

TENTATIVE

RESISTANCE

BREAKPOINTSa

MIC RANGE, lg/mL

MIC MIC50 MIC90

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

a

Tentative resistance breakpoints per CDC (www.cdc.gov/fungal/candida-auris/

c-auris-antifungal.html).

Abbreviations: MIC, minimum inhibitory concentration; N/A, not available.

Source: Adapted from CDC: Antifungal Susceptibility Testing and Interpretation.

2019. Available at: www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html

1676 PART 5 Infectious Diseases

outbreak of C. auris infection, as well as drug susceptibility data of

identified strains, act as a guide for the effective choice of treatment

of invasive and bloodstream infections. C. auris is known to develop

antibiotic resistance during treatment. Therefore, the emergence of

antifungal resistance should be closely monitored with follow-up cultures and repeat susceptibility testing. Antibiotic stewardship should

be implemented to ameliorate the risk of development of drug resistance. Patients may remain colonized with C. auris during or after the

successful treatment of invasive C. auris infection. Therefore, infection control measures should be implemented throughout patient

care. Table 216-6 outlines CDC-recommended echinocandin doses

for the initial antifungal treatment for C. auris infections.

In cases of echinocandin resistance, liposomal amphotericin B

(5 mg/Kg/d) can be considered. For neonates and infants (<2 months

old), amphotericin B deoxycholate (1 mg/Kg/d) treatment can be

initiated. If this fails, liposomal amphotericin B (5 mg/Kg/d) can be

given. In very severe cases, if all treatment options fail, echinocandins

per CDC recommendations can be given (Table 216-6). Other considerations for C. auris infection management can be referenced from

the 2016 Infectious Diseases Society of America (IDSA) Clinical

Practice Guideline for the Management of Candidiasis.

Some generalizations exist regarding the management of specific

Candida infections. Recovery of Candida from sputum is almost

never indicative of underlying pulmonary candidiasis and does not

by itself warrant antifungal treatment. Similarly, Candida in the

urine of a patient with an indwelling bladder catheter may represent

colonization only, rather than bladder or kidney infection. However,

the threshold for systemic treatment is lower in general in severely

ill patients in this category since it is impossible to distinguish colonization from lower or upper urinary tract infection. If the isolate

is C. albicans, most clinicians use oral fluconazole rather than a

bladder washout with amphotericin B, which was more commonly

used in the past. Caspofungin has been used with success; although

echinocandins are poorly excreted into the urine, they may be an

option, especially for non-albicans isolates. The doses and duration

are the same as for disseminated candidiasis. The significance of

the recovery of Candida from abdominal drains in postoperative

patients is unclear, but again, the threshold for treatment is generally low because most of the affected patients have been subjected

to risk factors predisposing them to disseminated candidiasis. In

addition, there has been a considerable increase in the recognition

and diagnosis of intraabdominal candidiasis.

Removal of the infected valve and long-term antifungal administration constitute appropriate treatment for Candida endocarditis.

Although definitive studies are not available, patients usually are

treated for weeks with a systemic antifungal agent (Table 216-4)

and then given chronic suppressive therapy for months or years

(sometimes indefinitely) with an oral azole (usually fluconazole at

400–800 mg/d).

Hematogenous Candida endophthalmitis is a special problem

requiring ophthalmologic consultation. When lesions are expanding or are threatening the macula, an IV polyene combined with

flucytosine (25 mg/kg four times daily) has been the regimen

of choice, although comparative studies with other regimens

have not yet been reported. As more data on the newer triazoles

(e.g., voriconazole) and the echinocandins become available, new

strategies involving these agents are developing, although it is

important to note that echinocandins exhibit low penetration

in ocular tissue. Of paramount importance is the decision to

perform a partial vitrectomy. This procedure debulks the infection

and can preserve sight, which may otherwise be lost due to vitreal

scarring. All patients with candidemia should undergo ophthalmologic examination because of the relatively high frequency of

this ocular complication (up to 15–20% in some case series). This

examination can detect a developing eye lesion early in its course;

in addition, identification of a lesion signifies a probability of ~90%

of deep-organ abscesses and may prompt prolongation of therapy

for candidemia beyond the recommended 2 weeks after the last

positive blood culture. Although the basis for the consensus is

a very small data set, the recommended treatment for Candida

meningitis is a polyene (Table 216-4) plus flucytosine (25 mg/kg

four times daily). Development of Candida meningoencephalitis

in an otherwise immunocompetent individual should raise suspicion for deficiency in the C-type lectin receptor adaptor molecule

CARD9 and should prompt genetic testing to rule out this monogenic disorder. Successful treatment of Candida-infected prosthetic

material (e.g., an artificial joint) nearly always requires removal of

the infected material followed by long-term administration of an

antifungal agent selected on the basis of the isolate’s sensitivity and

the logistics of administration.

■ PROPHYLAXIS

The use of antifungal agents to prevent Candida infections has been

controversial, but some general principles have emerged. Most centers

administer prophylactic fluconazole (400 mg/d) to recipients of allogeneic hematopoietic stem cell transplantation. High-risk liver transplant

recipients are also given fluconazole prophylaxis in most centers. The

use of prophylaxis for neutropenic patients has varied considerably from

center to center; many centers that elect to give prophylaxis to this population use either fluconazole (200–400 mg/d) or a lipid formulation of

amphotericin B (AmBisome, 1–2 mg/d). Caspofungin (50 mg/d) also has

been recommended. Some centers have used itraconazole suspension

(200 mg/d). Posaconazole (200 mg three times daily) has been approved

by the U.S. Food and Drug Administration for prophylaxis in neutropenic patients; it is gaining in popularity and may replace fluconazole.

Prophylaxis is sometimes given to surgical patients at very high

risk for candidiasis. The widespread use of prophylaxis for nearly all

patients in general surgical or medical intensive care units is not—and

should not be—a common practice for three reasons: (1) the incidence

of disseminated candidiasis is relatively low, (2) the cost–benefit ratio is

suboptimal, and (3) increased resistance with widespread prophylaxis

is a valid concern.

Prophylaxis for oropharyngeal or esophageal candidiasis in

HIV-infected patients is not recommended unless there are frequent

recurrences.

■ FURTHER READING

Lionakis MS, Edwards JE jr: Candida species, in Mandell, Douglas,

and Bennett’s Principles of Infectious Diseases, 9th ed. JE Bennett et al

(eds). Philadelphia, Elsevier, 2020, pp 3087-3102.

Pappas PG et al: Invasive candidiasis. Nat Rev Dis Primers 62:e1, 2018.

Proctor DM et al: Integrated genomic, epidemiologic investigation

of Candida auris skin colonization in a skilled nursing facility. Nature

Medicine 27:1401, 2021.

Tsai SV et al: Burden of candidemia in the United States, 2017. Clin

Infect Dis 71:e449, 2020.

TABLE 216-6 List of CDC-Recommended Echinocandin Doses for the

Treatment of C. auris Infections

DRUG ADULTS

CHILDREN

(>2 MONTHS)

INFANTS

(<2 MONTHS)

Caspofungin Loading dose

70 mg IV, then

50 mg IV daily

Loading dose 70 mg/m2

 per

day IV, then 50 mg/m2

 per

day IV

25 mg/m2

 per

day  IV

Anidulafungin Loading dose

200 mg IV, then

100 mg IV daily

Not approved for use in

children

Not approved

for use in

children

Micafungin 100 mg IV daily 2 mg/kg per day IV with

option to increase to 4 mg/

kg per day IV in children

40 kg

10 mg/kg per

day IV

Source: Adapted from CDC: Treatment and Management of Infections and

Colonization. 2019.

Available at: www.cdc.gov/fungal/candida-auris/c-auris-treatment.html

1677CHAPTER 217 Aspergillosis

Aspergillosis is the collective term used to describe all disease entities caused by any one of ~50 pathogenic and allergenic species of

Aspergillus. Only those species that grow at 37°C can cause invasive

infection, although some species without this ability can cause allergic

syndromes. Each common pathogenic species is actually a complex

of many species (many of them cryptic) but is referred to as a single

species here for simplicity. A. fumigatus is responsible for most cases

of invasive aspergillosis, almost all cases of chronic aspergillosis, and

most allergic syndromes. A. flavus is more prevalent in some hospitals

and causes a higher proportion of cases of sinus infections, cutaneous

infections, and keratitis than A. fumigatus. A. niger can cause invasive

infection but more commonly colonizes the respiratory tract and

causes external otitis. A. terreus causes only invasive disease, usually

with a poor prognosis. A. nidulans occasionally causes invasive infection, primarily in patients with chronic granulomatous disease (CGD).

■ EPIDEMIOLOGY AND ECOLOGY

Aspergillus has a worldwide distribution, most commonly growing

in decomposing plant materials (i.e., compost) and in bedding. This

hyaline (nonpigmented), septate, branching mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth.

Aspergilli are found in indoor and outdoor air, on surfaces, and in

water from surface reservoirs. Daily exposures vary from a few to

many millions of conidia; high numbers of conidia are encountered in

hay barns and other very dusty environments. The required size of the

infecting inoculum is uncertain; however, only intense exposures (e.g.,

during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease—acute community-acquired

pulmonary aspergillosis—in healthy immunocompetent individuals.

Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection.

High-efficiency particulate air (HEPA) filtration is often protective

against infection; thus, HEPA filters should be installed and monitored

for efficiency in operating rooms and in areas of the hospital that house

high-risk patients.

The incubation period of invasive aspergillosis after exposure is

highly variable, extending in documented cases from 2 to 90 days.

Thus, community acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial

acquisition is also common. Outbreaks usually are directly related to a

contaminated air source or construction in the hospital.

Global aspergillosis incidence and prevalence have been estimated

(Table 217-1). The frequency of different manifestations of aspergillosis varies considerably with geographic location; most notably, chronic

granulomatous sinusitis is rare outside the Middle East and India.

Fungal (mycotic) keratitis is particularly common in Nepal, Myanmar,

Bhutan, and India but occurs globally. Chronic pulmonary aspergillosis follows pulmonary tuberculosis in ~6–13% of treated cases and

also mimics pulmonary tuberculosis as smear-negative or “clinically

diagnosed” tuberculosis. Aspergillus onychomycosis, usually of the

toenail, has been reported in as low as <1% and as high as 35% of cases

of onychomycosis and is more common in diabetes.

■ RISK FACTORS AND PATHOGENESIS

The primary risk factors for invasive aspergillosis are profound neutropenia, glucocorticoid use, and underlying respiratory disease; risk

increases with longer duration of these conditions. Higher doses of

glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte

dysfunction also is an important risk factor, as evidenced by aspergillosis in CGD, advanced HIV infection, and relapsed leukemia. Invasive

aspergillosis is increasingly recognized (if actively sought) in medical

intensive care units (2–5%), those with severe influenza (8–25%),

217

severe COVID-19 (13%) and patients in the hospital with chronic

obstructive pulmonary disease (COPD; 1.3–3.9%). Extracorporeal

membrane oxygenation therapy is a risk factor. Temporary abrogation

of protective responses from glucocorticoid use or compensatory

anti-inflammatory response syndrome is a significant risk factor. Many

patients have some evidence of prior pulmonary disease—typically,

a history of pneumonia or COPD. Many new immunomodulating

agents, such as infliximab and ibrutinib, increase the risk of invasive

aspergillosis, as do severe liver disease and high levels of stored iron

in bone marrow.

Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, including tuberculosis, prior

pneumothorax, or COPD. These patients are apparently immunocompetent, but natural killer and/or interleukin 12 or gamma interferon

production defects are common. Their inflammatory immune (TH1-like)

response is suboptimal, and persistent inflammation is typical. Glucocorticoids accelerate disease progression.

Allergic bronchopulmonary aspergillosis (ABPA) usually complicates asthma and cystic fibrosis. Many genetic associations indicate a

strong basis for the development of a TH2-like and “allergic” response

to A. fumigatus. Remarkably, high-dose glucocorticoid treatment for

exacerbations of ABPA almost never leads to invasive aspergillosis.

Fungal, and especially Aspergillus, sensitization is especially common

in those with poorly controlled asthma. COPD exacerbations are

linked to Aspergillus sensitization. Most patients with Aspergillus bronchitis have bronchiectasis, with or without cystic fibrosis.

Different genetic traits are associated with invasive, chronic, and

allergic aspergillosis; the majority of people probably are not at

risk for aspergillosis. Multiple gene variants appear to be necessary for susceptibility to each form of aspergillosis.

■ CLINICAL FEATURES AND APPROACH

TO THE PATIENT

(Table 217-2)

Invasive Pulmonary Aspergillosis Both the frequency of invasive disease and the pace of its progression increase with greater

degrees of immunocompromise. Invasive aspergillosis is arbitrarily

Aspergillosis

David W. Denning

TABLE 217-1 Disease Frequency and Diagnostic Sensitivity for

Different Manifestations of Aspergillosis

PARAMETER

TYPE OF DISEASE

INVASIVE CHRONIC ALLERGIC

Incidence/100,000a 0.6−16 ~10.4 ?b

Prevalence/100,000a — 1.4−126 286c

Global burdena ~850,000 ~3,000,000 ~10,000,000

Mortality rate without treatment ~100% ~50% <1%

Respiratory Diagnostic Sensitivityd

Culturee ✓ ✓-✓✓e ✓-✓✓e

Microscopy ✓ ✓ ?

Antigen ✓✓✓ ✓✓ ✓✓✓

Real-time PCR ✓✓ ✓✓ ✓✓

Blood Diagnostic Sensitivityd

Culture × × ×

Antigen ✓✓ ✓ ×

β-D-Glucan ✓✓ ✓ ?

Real-time PCR ✓✓ × ×

IgG antibody ✓ ✓✓✓ ✓✓✓

IgE antibody × ✓✓ ✓✓✓✓

a

http://www.gaffi.org/roadmap/. b

Allergic fungal disease can develop at any

age, usually in adulthood; the annual frequency with which it occurs is not

known. c

Allergic bronchopulmonary aspergillosis and severe asthma with fungal

sensitization. d

Key for sensitivity: 1 check = limited (as the text indicates, 10–30% for

culture); 2 checks = higher; 3 checks = >80%; and 4 checks = ~95%. e

High-volume

fungal culture increases sensitivity to the same level as PCR.

Abbreviation: PCR, polymerase chain reaction.