73 . Candida species — Christopher R. Fox, MD & Merle A.

Sande, MD

Essentials of Diagnosis

• Characteristic appearance of yeast and hyphae on KOH preparations.

• Formation of germ tubes in serum is presumptive diagnosis for Candida albicans.

• Cultures must be interpreted with caution because positive culture may represent
colonization rather than infection.

• Serology not useful.

General Considerations

A. Epidemiology. Candida organisms are commensal with humans and, in the

absence of alterations in host defense mechanisms, usually do not cause disease.
Candida exists as normal flora within the oral cavity, throughout the gastrointestinal
(GI) tract, in expectorated sputum, in the vagina, and in the bladder of patients with
indwelling catheters. There are >150 species within the genus Candida, although
the majority are not known to cause disease in humans. C albicans, C krusei, C
glabrata, C tropicalis, C pseudotropicalis, C guilliermondii, C parapsilosis, C
lusitaniae, and C rugosa are known human pathogens.

Candida species cause a wide spectrum of clinical diseases that range from mild,
superficial infection of the skin and mucous membranes to life-threatening,
invasive, multisystem disease. Infection with Candida requires an alteration in the
normal milieu that allows the fungus to proliferate and evade host responses.
Under correct conditions, Candida is able to infect any of the body's mucosal
surfaces, as well as the skin. Three-quarters of women report vaginal candidiasis
within their lifetime, and the incidence appears to have increased over the last 20
years. Risk factors include recent antibiotic use, pregnancy, oral contraceptive use,
diabetes, and human immunodeficiency virus (HIV) infection.

Oral thrush is another frequent manifestation of mucosal candidiasis with similar

risk factors to vaginal candidiasis. These risks include systemic disease such as HIV
infection or diabetes, inhaled or oral corticosteroid use, and neutropenia induced by
chemotherapy.

In addition to the local forms of disease described above, Candida species may
cause invasive disease with systemic manifestations and multiple infected organs.
Although once limited to the oncology ward and bone marrow transplant unit,
candidemia is now more frequent in all areas of the hospital, with Candida the
fourth most common organism reported from hospital blood cultures. Specific risk
factors for invasive disease include previous isolation of Candida from another site,
the use of antimicrobial agents, prolonged neutropenia, indwelling central
catheters, and the use of parenteral nutrition.

Although the majority of Candida infections are caused by C albicans, several non-
albicans species are emerging as important pathogens and deserve mention. C
krusei appears to be less virulent than C albicans and rarely causes disease in the
normal host. However, in those with depressed immune function, C krusei is able to
cause significant infection. Candidemia, ocular infection, endocarditis, and renal
disease all occur with some frequency. C krusei infection has important therapeutic
implications as the organism is generally resistant to fluconazole. C glabrata,
another Candida species with increasing recovery rates, usually has intermediate
resistance to fluconazole.

B. Microbiology. Candida is a fungus that exists primarily in the yeast state,

although it may be found in tissue in both yeast and mold forms. The yeast cells are
4-6 um in diameter and reproduce primarily by budding but also by sexual
reproduction. In culture, Candida forms smooth white colonies, and a presumptive
diagnosis of C albicans can be made by observing the formation of germ tubes
within 90 min of placing the organism in serum. Candida will grow on agar plates
and in routine blood culture bottles, although the lysis-centrifugation and the
BACTEC systems have increased recovery of the organism.

C. Pathogenesis. As previously mentioned, Candida is part of the normal flora in

many areas of the body and, without alteration in host defense, does not cause
disease. Factors particularly important to preventing infection are normal bacterial
flora, intact skin and mucous membranes within the GI tract, and normal cell-
mediated immunity. Alterations of any of the above mechanisms predispose to
infection. This is seen clinically as the use of antibiotics (which alter the normal
bacterial flora), maceration of the skin, GI surgery, HIV infection, and
chemotherapy-induced neutropenia, all of which increase rates of Candida infection.

Candida produces proteins expressed within the cell wall that promote binding and
adherence to epithelial cells, endothelium, platelet and fibrin clots, and plastics.
These proteins likely help the organism attach to and invade damaged mucosa and
may play a role in Candida infection in hosts with indwelling bladder and central
venous catheters. Candida species also produce proteases and phospholipases,
which may aid the organism in evading host defenses and invading mucosal
surfaces.

CLINICAL SYNDROMES

CANDIDA DERMATITIS

Clinical Findings

A. Signs and Symptoms. Skin infections with Candida are common and may
manifest in a variety of forms. Intertrigo occurs in warm, moist areas of skin, such
as under the breast, in the groin, and in the axilla. Initially pustular or vesicular,
lesions eventually become confluent to form an erythematous, macerated area of
skin with a scalloped border and satellite lesions (Box 73-1). Erosio interdigitalis
blastomycetica is similar to intertrigo but involves the areas between the fingers
and toes. Paronychia is infection of the nail bed, seen more commonly in diabetics
and people who frequently immerse their hands in water. Candida spp. may cause
onychomycosis, particularly in HIV-infected patients. Candida spp. cause a rash in
neonates in the region of diaper contact. Other common skin manifestations include
folliculitis, balanitis, perianal candidiasis, and a generalized cutaneous eruption with
widespread lesions resembling intertrigo that spread to involve the abdomen, chest,
back, and extremities.

Chronic mucocutaneous candidiasis (CMC) is an abnormality of cell-mediated

immunity that presents with recurrent infections of the skin and mucus membranes
that may progress to disfiguring lesions (Candida granulomas) despite antifungal
therapy. Symptoms usually begin in the first several years of life. CMC is associated
with autoimmune endocrine failure, particularly hypoparathyroidism and adrenal
insufficiency (polyglandular autoimmune syndrome type I), and endocrine disease
often presents years to decades after the onset of CMC.

Cutaneous lesions may be superficial evidence of disseminated candidiasis and

candidemia. Lesions are typically red or pink nodules 5-10 mm in diameter and may
be single or widespread. Lesions resembling ecthyma gangrenosum or purpura
fulminans have also been described.

B. Laboratory Findings. Candida organisms, seen as budding yeast and hyphae, may
be present on wet mount or KOH preparations of skin scrapings. Biopsy specimens
may reveal characteristic fungal elements on histology.

C. Differential Diagnosis. Candida infection of the skin and nails may be confused
with other infections, both fungal and nonfungal, as well as noninfectious conditions
such as contact or allergic dermatitis.

D. Complications. Candida infection of the skin and nails may cause discomfort and
disturb cosmetic appearance of the skin but does not usually cause long-term
sequelae. CMC may progress to cause large disfiguring lesions.

Diagnosis

Diagnosis of Candida infection involving the skin or nails is generally made by

recognition of the clinical pattern followed by demonstration of fungal elements on
a KOH preparation of skin scrapings. Candida infection may also be diagnosed by
microscopic examination of biopsy specimens. Culture of the skin should be
interpreted with caution, as the presence of Candida spp. may represent
colonization rather than infection.

Treatment

Treatment of Candida skin infections is generally straightforward. Intertrigo is

managed by decreasing moisture in infected areas and by application of topical
antifungal therapy. Nystatin cream, topical azoles (miconazole, clotrimazole), and
amphotericin B cream are all effective when applied 2-3 times daily. Paronychia
may be treated by keeping the area dry and with topical antifungal therapy.
Onychomycosis requires several months of treatment with oral azoles, such as
itraconazole, or terbenifine. Relapses may occur. Griseofulvin is not active against
Candida.

CMC is treated with oral ketoconazole or fluconazole. Transfer factor, an

immunomodulating factor composed of a cell-free leukocyte extract, was used in
the past but has fallen out of favor because of lack of efficacy. Months to years of
treatment are generally required.

ORAL CANDIDIASIS

Clinical Findings

A. Signs and Symptoms. Candida infections of the oral cavity are relatively common
and may present in several forms. Any of the forms may be asymptomatic or may
cause soreness and burning. The most common, acute pseudomembranous
candidiasis, or oral thrush, presents with multiple white patches on the tongue,
palate, and other areas of oral mucosa. These lesions may be easily removed by
scraping with a tongue blade to reveal an erythematous, irritated mucosa (Box 73-
1).

In addition to oral thrush, oral Candida infection occurs in several distinct forms.
Acute atrophic candidiasis causes erythematous mucosa found typically on the
palate and tongue, chronic atrophic candidiasis results in erythema and edema of
the mucosa of denture wearers who do not practice adequate hygiene, and angular
cheilitis causes erythema and fissuring of the corners of the mouth. Finally, Candida
leukoplakia is described as adherent white nodules on an erythematous base and
often does not respond to topical therapy. This condition also carries an increased
risk of malignant transformation.

B. Laboratory Findings. Budding yeast and hyphae may be seen on a KOH

preparation or on preparations made with para-aminosalicyclic acid (PAS) stain,
Giemsa stain, or Gram stain. Culture of oral scrapings may grow Candida species,
although this is not a specific test.

C. Differential Diagnosis. Oral candidiasis must be differentiated from bacterial and

viral infection as well as malignancy.

D. Complications. While uncomfortable for those affected, it is unclear if oral

candidiasis predisposes to Candida infection at other sites. There are reports that
Candida esophagitis may follow oral thrush, although esophagitis was not excluded
at the initial presentation in these reports. In those with oral infection and infection
at a second site, it is likely that immune system deficits allow for multiple infections
rather than spreading from the oral cavity.

Diagnosis

The diagnosis of oral Candida infection may be suspected when the characteristic
appearance of the mucosa is present and, in the case of oral thrush, when scraping
of the mucosa removes the white plaque and leaves an inflamed mucosa.
Demonstration of dimorphic fungi on KOH-, Giemsa-, Gram-, or PAS-stained oral
scrapings strongly supports the diagnosis. Culture of Candida species from oral
scrapings is not generally required, and as Candida may be part of the normal flora
of the oral cavity, positive cultures may not represent true infection.

Treatment
Generally, oral Candida infection should initially be treated with topical agents (Box
73-3). Nystatin suspension or clotrimazole troches are generally effective therapy. If
infection occurs in a denture wearer, the dentures must be removed. Once the
infection is cured, proper dental hygiene is important to prevent recurrence. Topical
antifungal creams will treat angular cheilitis.

If topical therapy fails, or in those with severe infection, systemic therapy may be
used. In patients with advanced HIV infection, itraconazole doses may require
adjustment because of achlorhydria and impaired absorption. Treatment failure
should prompt a search for other causes, such as bacterial infection or malignancy.

In those infected with HIV or with other immune deficits, frequent recurrences are
common, and maintenance therapy may be necessary. Daily treatment with topical
antifungal agents or fluconazole, 50-100 mg daily, every other day, or once weekly
may prevent recurrence. Maintenance therapy with fluconazole should be avoided if
possible because of concerns for the emergence of resistant fungal strains.

ESOPHAGEAL CANDIDIASIS

Clinical Findings

A. Signs and Symptoms. Candida infection of the esophagus can present with a
range of clinical findings (Box 73-1). Between 20 and 50% of patients may be
asymptomatic. Others will note dysphagia, odynophagia, epigastric pain, nausea
and vomiting, or hematemesis. Fever may be present. Frequently, patients will have
concurrent symptoms of oral thrush. Physical exam of patients with esophagitis
yields few clues to its diagnosis. Oral thrush is seen in the majority.

B. Imaging. Barium studies and endoscopy are both useful for diagnosis of Candida
esophagitis. The findings found with these methods are described in the diagnosis
section.

C. Differential Diagnosis. Candida esophagitis may be confused with other causes of

esophagitis, including bacterial, viral, and reflux esophagitis. Host factors (such as
the status of the immune system), clinical findings, and endoscopic appearance of
the esophagus are helpful in making this distinction, although frequently more than
one cause of esophagitis are present concurrently.

D. Complications. Complications of esophagitis relate to deep invasion and

inflammation of the mucosa. Although uncommon, perforation and strictures do
occur. In some cases, long and complex strictures are not amenable to endoscopic
dilatation and require surgical intervention. Dissemination of the fungus from the
lower esophagus and stomach may occur, especially in neutropenic patients.

Diagnosis

Radiographic techniques using barium contrast (barium swallow) and endoscopy are
useful for diagnosis of Candida esophagitis. The barium swallow has a characteristic
appearance, with a shaggy-appearing mucosa and sometimes nodules and cobble
stoning. This technique does not allow firm diagnosis, which requires histology or
culture.

Endoscopy is the preferred method of diagnosis, as it allows direct visualization of

the mucosa and biopsy of affected areas. The mucosa typically has adherent white
plaques that may be removed with the endoscope to reveal an erythematous
mucosa. Brushings of the mucosa may be prepared as for oral disease. Histologic
specimens reveal fungal elements, which are more apparent on PAS-stained and
silver-stained material than with hematoxylin-eosin staining.

Treatment

A subset of patients may be treated empirically. In those with HIV infection, oral
thrush, and mild to moderate symptoms of esophagitis, treatment with topical
agents or an azole may be warranted. If no oral thrush is present, or if treatment
fails, endoscopy should be performed to exclude other causes of disease.

As with oral thrush, topical agents may be successful in treating esophagitis (Box
73-4). If patients fail topical treatment, have severe disease, or are considered to be
at high risk for disseminated disease, systemic therapy should be used. Therapy for
10 days is generally adequate.

CANDIDA VULVOVAGINITIS

Clinical Findings

A. Signs and Symptoms. Risk factors for Candida infection of the vagina include
pregnancy, oral contraceptive use, diabetes mellitus, HIV infection, and
antimicrobial therapy, although the majority of infections occur in the absence of
these risks. Typical complaints are vulvar pruritus and vaginal discharge (Box 73-1),
although a wide range of symptoms exists. Pruritus, the most common complaint, is
often intense, and the discharge, classically described as cottage cheese-like, may
range from a thin, white, scant discharge to homogeneously thick. Odor, if present,
is mild. Other symptoms may include vulvar burning, external dysuria, vaginal
irritation and soreness, and dyspareunia. Symptoms may peak the week prior to
menses and wane with the onset of menstrual flow.

Examination may reveal discrete papular or pustular lesions of the vulva, with
erythema and swelling of the vulva and labia. The discharge is present within the
vaginal vault, and the vaginal mucosa is inflamed and may have adherent white
plaques similar to oral thrush. The cervix appears normal.

B. Laboratory Findings. The vaginal pH is normal (<4.5). Examination of a saline or

wet mount preparation of the vaginal discharge may show fungal elements and
should not reveal abundant white cells. A KOH preparation is more sensitive in
detecting the fungus, as other cellular debris is lysed. Both budding yeast and
hyphae are typically present. Culture of the vagina will usually isolate Candida,
although this must be interpreted cautiously, as Candida can be part of the vaginal
flora without causing disease.

C. Differential Diagnosis. The signs and symptoms of Candida vulvovaginitis are

relatively nonspecific, and therefore the presentation may be confused with
bacterial vaginosis, trichomoniasis, and other sexually transmitted diseases. Two or
more of these conditions may coexist.
D. Complications. Some women may develop severe, recurrent infections despite
removal of identified risk factors and antifungal therapy. Infection of the vagina is
not associated with risk of deep tissue or bloodstream invasion.

Diagnosis

The diagnosis of vulvovaginitis is typically made by history, physical examination,

and light microscopy. In women with appropriate symptoms and fungal elements on
wet mount or KOH preparation, therapy is indicated without further testing. As up to
50% of symptomatic women with culture-proven infection have negative
microscopy, vaginal culture is indicated in those patients with symptoms and no
microscopic findings. A vaginal pH >4.5 or a large number of white cells on wet
mount should prompt a search for a different or possibly coexistent process.

Treatment

Numerous agents are available for treatment of Candida vulvovaginitis in both

topical and oral preparations (Box 73-5). Among topical agents, cure rates range
from 75 to 90%, with the azole preparations (clotrimazole, miconazole, terconazole)
having slightly better efficacy than nystatin. The formulation (cream versus
suppository versus vaginal tablet) does not alter the success rate; therefore the
choice of formulation is a matter of patient preference. Currently there is a trend
toward higher doses of topical agents with shorter durations of therapy, with
success reported with even high-dose, one-time therapy. Anecdotal failure rates are
fairly high with one-dose therapy; thus this is best reserved for women with
infrequent infections and mild or moderate symptoms.

Oral azole agents are quite effective for vaginal infection and are more convenient
than topical therapy but are more expensive. Fluconazole and itraconazole single-
dose therapy are at least as effective as topical therapy.

Cure of Candida vulvovaginitis during pregnancy can be difficult, with relapses

frequently occurring. If therapy is extended to 1-2 weeks, topical antifungal therapy
is effective. Oral azoles should be avoided during pregnancy.
In women with frequent recurrent infections, therapy is often disappointing, with
symptoms recurring within weeks of withdrawal of antifungal agents. In these
women, predisposing factors such as diabetes or HIV infection should be
considered. HIV testing is appropriate in women with risk factors for HIV infection. If
fasting blood glucose values are normal, further testing for diabetes is not required.
Oral contraceptives should be discontinued if possible, although continuation of low-
dose estrogen preparations, as long as long-term antifungal therapy is used, may
be considered. Vaginal douching and treatment of the sexual partner are not
recommended. Frequently, no risk factors are identified, and prophylactic therapy is
required. The best-studied regimen with proven efficacy for prophylaxis is
ketoconazole, 100 mg daily. Toxicity, such as hepatitis, is infrequent but may occur.
Other regimens with anecdotal support include fluconazole, 100-200 mg once
weekly, and clotrimazole vaginal tablets, 500 mg once weekly.

CANDIDURIA, CANDIDA CYSTITIS & URINARY TRACT CANDIDIASIS

Introduction

The presence of Candida spp. in the urine is common and does not necessarily
represent infection. Candiduria is commonly associated with antibiotic use,
indwelling urinary catheters, and diabetes mellitus and frequently resolves if
predisposing factors can be corrected. Patients are generally asymptomatic,
although some will have symptoms similar to bacterial cystitis, with dysuria,
frequency, and urgency (Box 73-2). Urinalysis shows fungal elements and may
reveal pyuria. At cystoscopy, the mucosa of the bladder typically has an inflamed
appearance with adherent white plaques that may be removed with the scope.

Candida spp. may also cause urethritis, typically in male sexual partners of women
with vaginal Candida infection, as well as higher urinary tract infection. The upper
urinary tract and renal parenchyma may be infected from ascending infection or,
more commonly, from hematogenous spread as part of a syndrome of disseminated
candidiasis. With ascending infection, perinephric abscesses, papillary necrosis,
fungus balls, and calyceal involvement have all been described. Risk factors are
generally present and include diabetes mellitus, urinary tract obstruction, and renal
stones. With hematogenous spread, the renal parenchyma becomes studded with
multiple microabscesses.
Diagnosis

Candiduria is usually discovered when a urine culture reveals the presence of

Candida spp. The presence of pyuria generally indicates true infection if other
etiologies, such as bacterial infection, have been excluded. Infection may also be
diagnosed by demonstrating the presence of a typical appearing fungus in biopsy
specimens obtained during cystoscopy.

Of particular importance for treatment is whether candiduria represents colonization

or true infection, and whether the upper urinary tract is involved, a distinction that
can be troublesome. Those with risk factors for ascending infection (diabetes,
stones) and those at risk for disseminated disease are more likely to have upper
urinary tract infection. Computerized tomographic scans or ultrasound may reveal
microabscesses or fungus balls.

Treatment

When treating Candida infection of the urinary tract, careful consideration must be
given to whether candiduria represents colonization or true infection, and whether
the upper urinary tract is involved. Asymptomatic candiduria usually does not
require antifungal treatment, but indwelling catheters should be removed as soon
as possible. (Treatment is summarized in Box 73-6.) In the presence of pyuria,
diabetes mellitus, or renal transplantation, treatment is indicated. Oral fluconazole
is recommended as the initial agent. Bladder irrigation with amphotericin B is also
effective. Patients with candiduria should be treated prior to instrumentation of the
urinary tract.

In patients with evidence of systemic toxicity, Candida infection at other sites, risk
factors for ascending infection (structural or metabolic abnormality of the urinary
tract such as stones or diabetes), or risk factors for disseminated candidiasis (burns,
neutropenia, or GI surgery), consideration must be given to the possibility of upper
urinary tract infection or disseminated candidiasis. Upper urinary tract involvement
usually will respond to oral fluconazole, although intravenous amphotericin B is
required for infections resistant to fluconazole or unresponsive to initial fluconazole
treatment. Fungus balls and large perinephric abscesses may require surgical
intervention. Treatment of disseminated candidiasis is discussed next.

CANDIDEMIA & DISSEMINATED CANDIDIASIS

Introduction

Candidemia may present in a variety of fashions, ranging from asymptomatic to

fulminant sepsis. The candidemic patient generally has risk factors for infection,
such as malignancy, chemotherapy-induced neutropenia, organ transplantation, GI
surgery, burns, indwelling catheters, or exposure to broad-spectrum antibiotics.

Disseminated candidiasis must be assumed to be present in those with positive

blood cultures, although negative cultures do not preclude the possibility of
disseminated disease. Dissemination usually manifests with many microabscesses
involving multiple organs, especially the liver, spleen, and eye, but almost any
organ may be involved (Box 73-2).

Diagnosis

Candidemia is diagnosed by recovering Candida species in blood culture.

Candidemia may be isolated or may occur in the setting of disseminated
candidiasis. The possibility of disseminated candidiasis should be considered in any
patient with deep Candida infection, multiple sites of infection, or positive blood
cultures. Disseminated candidiasis is diagnosed by tissue culture of biopsy material
or demonstration of Candida in histologic specimens. At present, serology is
available but has false-negative and false-positive rates too high to be of use
clinically.

Treatment

The treatment of candidemia is the subject of much debate and controversy.

Because isolation of Candida from the blood carries a high morbidity and because
there is currently no method to predict which patients will not require treatment,
there is agreement that all patients with candidemia should be treated. The
standard treatment in the past has been amphotericin B, with or without 5-FC.
Currently, fluconazole appears to be a reasonable alternative, although there are
limited data comparing mortality of fluconazole-treated patients versus those
treated with amphotericin. One randomized study of candidemic patients
demonstrated fluconazole to be equally efficacious but associated with less toxicity
when compared with amphotericin.

Fluconazole may be used as initial treatment of candidemia in a stable patient (Box

73-7). If patients had been treated with fluconazole for 2 days or greater at the time
of candidemia, deteriorate on fluconazole therapy, or are unstable (hypotension,
need for mechanical ventilation, multiple comorbid factors, etc.) at the time their
candidemia is diagnosed, then treatment with amphotericin is warranted. Smaller
doses may be used if amphotericin if chosen as the initial regimen for stable
patients. Because of the potential bone marrow toxicity of 5-FC, particularly when
combined with amphotericin, the dose of 5-FC is generally reduced when part of the
treatment regimen. Treatment is generally continued until clinical improvement is
seen and for 2 weeks after the last positive blood culture.

For all patients with candidemia, the possibility of disseminated infection must be
considered. If infection with C krusei is suspected or documented, fluconazole
should not be used as initial therapy because this species has a high level of
resistance to fluconazole. C glabrata has an intermediate level of resistance, and
fluconazole therapy may be used with caution. Clinical deterioration should prompt
an early change of therapy to amphotericin. Treatment for disseminated disease
should continue until there is definite resolution of parenchymal involvement and
for 2 weeks after the last positive blood culture.

Intravenous catheters should be removed from candidemic patients if possible. In

addition, all patients with candidemia should be followed clinically for at least 3
months, as deep infection caused by hematogenous spread may not manifest
initially. Patients should be instructed to report any symptoms, which may represent
late complications, such as fever, fatigue, jaundice, visual disturbances, abdominal
pain, or bone pain.

CANDIDA ENDOCARDITIS
Introduction

Endocarditis caused by Candida species has been reported with increasing

frequency, particularly after valvular surgery. Other predisposing factors include
underlying valvular disease, concomitant bacterial endocarditis, intravenous drug
use, intravenous catheters, and chemotherapy. Aortic and mitral valves are
commonly infected. The symptoms are similar to that of bacterial endocarditis with
fever, malaise, weight loss, and signs and symptoms of embolic phenomena.
Splinter hemorrhages, Osler's nodes, Janeway lesions, hepatosplenomegaly,
hematuria, proteinuria, and pyuria may all occur. Candida has the ability to cause
large vegetations and large emboli, which may be catastrophic, and valvular lesions
may progress to cause perforation, congestive heart failure, and myocarditis (Box
73-2).

Diagnosis

Blood cultures are generally positive in Candida endocarditis, although negative

cultures may occur in up to 25% of patients. Echocardiography reveals vegetations,
which may become quite large. Transesophageal echocardiography is more
sensitive for detection of vegetations than transthoracic echocardiography. The role
of serologic tests (Candida antibodies) is uncertain, as both false positive and false
negative results occur with some frequency.

Treatment

Treatment of Candida endocarditis generally requires combined surgical and

medical therapy. Once the diagnosis is established, therapy with amphotericin B
should be initiated and the valve replaced as soon as possible (Box 73-8). Antifungal
therapy is generally required for a total of 6-10 weeks, and patients should be
monitored for a minimum of 2 years after completion of therapy because of the high
risk of relapse. For those in whom surgical treatment is not possible, such as those
too ill to survive an operation, there exist case reports of treatment success with
medical therapy alone (amphotericin B followed by fluconazole).

GI CANDIDIASIS (NONESOPHAGEAL)
Introduction

Candida species may infect any mucosal surface of the GI tract. After esophageal
candidiasis, infection of the stomach is most common. Typically, the organism is
seen infecting benign ulcers, although a diffuse mucosal form of infection
resembling thrush has been described. In the small and large bowel, ulceration and
pseudomembrane formation are common. Mucosal GI involvement may cause deep
ulcerations with resulting hemorrhage or perforation (Box 73-1).

Candida may also infect the peritoneum, liver, spleen, gallbladder, or pancreas.
Peritoneal infection is associated with peritoneal dialysis, GI surgery, and GI
perforation. Dissemination beyond the abdomen is uncommon. Involvement of the
liver, spleen, and pancreas occurs most commonly in immunocompromised hosts,
particularly with chemotherapy-induced neutropenia. Often, other manifestations of
disseminated candidiasis are present. Fungus balls may form in the gallbladder and
biliary tree and cause obstruction. Abscesses may involve the liver and spleen.

Diagnosis

Involvement of nonesophageal mucosal involvement of the GI tract is generally

diagnosed by characteristic appearance during endoscopy and by demonstration of
Candida by histology or culture of biopsy specimens. Involvement of the
peritoneum, liver, spleen, gallbladder, and pancreas may be difficult to diagnose.
Fluid returned after peritoneal dialysis may grow Candida in culture. Computer
tomography or magnetic resonance imaging may reveal splenic or hepatic
abscesses. Laparoscopy may be required for definitive diagnosis.

Treatment

Fluconazole is recommended for initial therapy of mucosal involvement in the

stomach, small intestine, or colon (Box 73-9). Amphotericin B may also be used.
Candida peritonitis may also be treated with fluconazole alone or amphotericin B
followed by fluconazole. Peritoneal dialysis catheters should be removed if possible.
For patients with a perforated viscus, prophylactic therapy is not indicated and
should be reserved for those patients with intraoperative findings consistent with
Candida infection and positive peritoneal cultures.

Involvement of the liver, spleen, gallbladder, or pancreas should be treated with

fluconazole or amphotericin followed by fluconazole. Dosages and duration of
therapy are the same as for candidemia and disseminated disease. Large abscesses
and fungus balls may require drainage or surgical removal.

OTHER CANDIDA SYNDROMES

Introduction

Candida species are capable of causing many other infectious syndromes, which will
be mentioned briefly. Infection of the respiratory tract may result in
bronchopneumonia or diffuse nodular infiltrates. Within the central nervous system
(CNS), Candida spp. may cause meningitis and parenchymal abscesses, usually as
part of a disseminated infection. Candida spp. have been described as the etiologic
agents for osteomyelitis, septic arthritis, myositis, and chostochondritis. Ocular
infection may involve any structure within the eye and is common following
hematogenous dissemination.

Diagnosis

The diagnosis of Candida infection of the lung, CNS, musculoskeletal system, or eye
generally requires demonstration of the organism by tissue culture or on histologic
examination. However, visualization of the typical well-demarcated white retinal or
vitreal lesion by funduscopic examination in the setting of positive blood cultures is
adequate for the diagnosis of Candida endophthalmitis. It should be noted that
sputum culture is generally not sufficient for diagnosis of respiratory involvement,
particularly in an intubated patient, as the organism may only be colonizing the
respiratory tract.

Treatment
Amphotericin B has been the standard treatment for Candida infection in the CNS,
eye, lung, and musculoskeletal system. Prosthetic material or other foreign bodies
should be removed, if possible. The role of 5-FC is not clear, but it may be added to
amphotericin. There is growing support for the use of the azole class, particularly
fluconazole, as treatment for deep Candida infection. While case reports of success
with fluconazole exist, there are very limited data regarding fluconazole in these
settings and virtually no data comparing fluconazole with amphotericin.

Prevention & Control of Candida Infections

Candida species are ubiquitous; thus prevention of disease is best accomplished by

elimination of risk factors as opposed to elimination of the organism (Box 73-10).
Antibiotic therapy should be focused to treat specific organisms whenever possible.
Indwelling vascular and bladder catheters should be removed as early as possible.
In the hospital environment, health care professionals should practice good hand
washing to minimize introduction of Candida infection to patients at risk.

The role of prophylactic therapy is unclear but generally not supported. Prophylactic
therapy has been shown to reduce mortality in bone marrow transplant patients but
not in any other setting. Prophylactic therapy for candidemia may be warranted in
patients' with negative blood cultures who have multiple risk factors for infection
and have isolation of Candida from multiple sites but is generally discouraged
because of concern for creating resistant organisms. Empiric therapy may also be
employed in certain settings, such as neutropenic patients who remain persistently
febrile for 7-14 days despite broad spectrum antibiotics and exclusion of other
possible causes of infection or in patients with two or more risk factors for invasive
Candida infection and isolation of Candida from sputum or urine. Fluconazole is the
preferred agent in these settings.

REFERENCES

Cormican MG, Pfaller MA: Epidemiology of candidiasis. Comp Ther 1995;21:653.

Edwards JE Jr: Candida species. In Mandell GL, Bennett JE, Dolin R: Principals and
Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.
Edwards JE Jr et al: International conference for the development of a consensus on
the management and prevention of severe candidal infections. Clin Infect Dis
1997;25:43.

Haulk AA, Sugar AM: Candida esophagitis. Adv Intern Med 1991;36:307.

Mooney MA, Thomas I, Sirois D: Oral candidosis. Int J Dermatol 1995;34:760.

Nguyen MH et al: Candida prosthetic valve endocarditis: Prospective study of six

cases and review of the literature. Clin Infect Dis 1996;22:262.

Rex JH et al: A randomized trial comparing fluconazole with amphotericin B for the
treatment of candidemia in patients without neutropenia. New Engl J Med
1994;331:1325.

Samaranayake YH, Samaranayake LP: Candida krusei: Biology, epidemiology,

pathogenicity and clinical manifestations of an emerging pathogen. J Med Microbiol
1994;41:295.

Sobel JD: Candida vulvovaginitis. Semin Dermatol 1996;15:17.

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CURRENT DIAGNOSIS & TREATMENT IN INFECTIOUS DISEASES (2001)

Section VI. Fungal Infections

73 . Candida species — Christopher R. Fox, MD & Merle A. Sande, MD

Essentials of Diagnosis