Katherine M. Knapp
Candida species are yeast forms that are ubiquitous in nature and frequent colonizers of the skin and mucous membranes in humans, although they rarely cause invasive disease in immunocompetent individuals. Candida albicansremains the most frequent cause of human candidiasis, but infections owing to other species of Candida are increasingly recognized.1-4
In addition, the incidence of infections owing to C albicans isolates that are resistant to azole antifungals is increasing.
Non-albicans species known to cause human disease include C glabrata, C guilliermondii, C keyfr (formerly C pseudotropicalis), C krusei, C lusitaniae, C parapsilosis, and C tropicalis. Candida parapsilosisis the non- albicansspecies isolated most commonly in children, and in some neonatal units has surpassed C albicans as the most commonly isolated Candida species.1,4-8 Clinicians should be aware that some species are inherently resistant to some antifungals.
Neonates and pregnant women have impaired host resistance to Candida species, as do patients with immunodeficiencies (congenital or acquired), induced immunosuppression (eg, owing to chemotherapy or corticosteroids), or debilitation (owing to trauma or surgery). Advances in health care that have decreased mortality for many conditions (eg, prematurity and malignancy) have been associated also with changes in host defense and normal flora, which have in turn led to a larger population at risk for invasive Candida infection. Preterm newborns and oncology patients frequently receive multiple and long-term courses of medications, particularly antimicrobials (altering the normal flora), and have defects in mucosal or skin barriers (eg, owing to intravascular catheters), which puts them at high risk for development of candidiasis.
In recent years, Candida species have become increasingly important causes of health-care-associated infections. These are most frequently diagnosed in children in neonatal and surgical intensive care units. Analysis of available data neither supports nor refutes cohorting or isolation rooms as effective measures to decrease transmission of Candida from colonized neonates in closed units.12
Candida species may cause disease at any body site. The anatomic site and the extent of the infection depend upon the relative immuno-competence of the host: superficial infections of skin and mucous membranes may occur in the normal host, but systemic or disseminated disease is seen only in those with impaired host defense.
Direct microscopic examination of specimens mounted in 20% potassium hydroxide (KOH) or Calcofluor will reveal budding yeast cells and/or pseudohyphae. Periodic acid–Schiff, Gomori methenamine silver nitrate, toluidine blue, and Gram stains will reveal Candida organisms. On solid media such as Sabouraud dextrose agar, Candida species appear as moist, white or cream-colored colonies with well-demarcated borders. Candida albicans will produce germ tubes when suspended in serum for a period of 1 to 4 hours, which allows for rapid presumptive identification of this Candida species. Candidaspecies are definitively identified by biochemical tests of fermentation and assimilation.
Antibody testing is not useful in diagnosis. Those who are only colonized with Candida species may have positive antibody testing, and immunocompromised patients may test falsely negative.
There are many new molecular diagnostic tests in development for diagnosis of candidiasis. At present, the β-1,3 glucan assay (testing for a component of the Candida cell wall that is not found in humans) is the only nonculture-based method approved by the Food and Drug Administration (FDA).61,62
CLINICAL MANIFESTATIONS AND TREATMENT
Oropharyngeal (Thrush) and Esophageal Candidiasis
Thrush, almost exclusively the result of C albicans, is the most common type of candidiasis in infants and children and is not uncommon in infants up to age 5 months. Thrush may be seen in older infants or children who are receiving antibiotic therapy but are otherwise healthy. Recurrent or recalcitrant thrush in children not receiving antibiotic therapy should prompt an evaluation of the immune system (see Chapter 187).
The lesions of thrush appear most commonly as pearly white patches on the dorsal and lateral aspects of the tongue, the pharynx, gingivae, and buccal mucosa. These patches coalesce into plaques that cause punctate bleeding when removed from the mucosal surface. Removal of the patches by scraping with a tongue depressor reveals an erythematous, eroded base; a KOH examination reveals ovoid yeast forms and pseudohyphae.
Thrush usually can be treated topically, with nystatin or clotrimazole. Systemic therapy may be indicated for immunocompromised patients or in cases refractory to topical therapy.20 Fluconazole is usually effective therapy in this case but there is an increasing incidence of non-albicans species and azole-resistant C albicans isolates that may require alternate therapies.
It is important to address sites that may be colonized with Candida to effectively treat thrush in infants. Nystatin may be applied to skin that has sustained contact with the infant’s mouth, such as the mother’s nipple for breast-fed infants or the fingers of infants who habitually suck them. Bottle nipples, pacifiers, or other objects with sustained contact with the infant’s mouth should be boiled after each use.
Other oropharyngeal infections include acute atrophic candidiasis (glossitis) and angular cheilosis (perlèche). Glossitis usually occurs following the use of broad-spectrum antibiotics that later the oral bacterial flora. Papillae on the dorsum of the tongue are eroded, which results in a smooth and erythematous tongue that is often painful. This condition typically resolves with discontinuation of the antibiotics. Angular cheilitits (perlèche) is characterized by painful fissuring and erythema at the corners of the mouth, due to habitual licking, although it may also be seen in individuals with iron deficiency, vitamin B12 or folate deficiency, or in children with poor oral secretion control. Treatment with topical antifungal and/or steroids are useful in persistent cases.
Esophageal candidiasis typically presents with dysphagia. Children may also have nausea or vomiting, and esophagitis may be manifested in infants by decreased oral intake. Esophagitis may occur without oropharyngeal candidiasis. Empiric therapy may be prescribed for symptomatic immunocompromised patients but in more severe or refractory cases intravenous therapy may be required (see Chapter 394 and eFig. 394.4 ).
Cutaneous candidiasis involves moist areas, such as the perineum and intertriginous areas. Candida diaper dermatitis is discussed in Chapter 367. Infants who suck their fingers may develop sucking blisters, and infection of the nails (paronychia) may also occur. Paronychia resulting from Candida species also may follow other trauma to the nail or surrounding tissue. A maculopapular rash in an immunocompromised patient with Candida infection is often associated with disseminated disease. The skin lesions that have been described in patients with hematologic malignancies are typically discrete erythematous papules measuring 0.5 to 1.0 cm in diameter, which may have a nodular center. Biopsy of the skin lesions may be necessary for definitive diagnosis, in order to exclude other infectious etiologies in an immunocompromised host.
Recurrent or persistent indolent Candidal skin infections occur in patients with chronic mucocutaneous candidiasis as discussed in Chapter 188. Infection may be controlled through use of chronic azole therapy.
Candidiasis of the Urinary Tract
The presence of Candida in voided urine specimens, is not always indicative of urinary tract infection.27 However, candiduria is frequently seen in patients with urinary tract candidiasis. Candiduria in neonates or neutropenic patients warrants further evaluation for systemic or upper urinary tract disease.28 Candiduria may be a manifestation of obstructive uropathy (“fungus balls” in the calyces), which may be seen by renal ultrasound or computed tomography. Obstructive uropathy owing to Candida species may be seen in patients with indwelling urinary catheters or who have received prolonged antibiotic therapy. Candida species may also cause renal microabscesses and papillary necrosis.
Candiduria is often asymptomatic, but Candida cystitis may present with dysuria or urethritis, similar to manifestations of bacterial urinary tract infection.29 White plaques may be seen at the urethral meatus or by cystoscopy on the bladder mucosa. Diabetics and patients with indwelling urinary catheters or receiving prolonged antimicrobial therapy are at risk for development of Candida cystitis.
Isolated candiduria can be treated with oral fluconazole. Recurrence is common, and serial urine cultures should be performed to document clearance.30 For patients with evidence of renal or other systemic Candida infection, prolonged intravenous therapy is indicated.
Vaginitis caused by C albicans occurs commonly and is not necessarily indicative of immunosuppression. Vaginal candidiasis is more frequent in women who are pregnant or taking oral contraceptives. Candida vaginitis is characterized by pruritus and a white or watery discharge. The vaginal mucosa is erythematous with white lesions like those seen in thrush. Candidiasis also may also cause papular or ulcerative lesions of the perineum. Even in sexual partners of women with vaginal candidiasis, penile lesions resulting from Candida species are uncommon.
Vaginal candidiasis may be effectively treated topically with azoles or nystatin. A single 150-mg dose of oral fluconazole has been shown to be an effective option in adolescents and adults.31,32
Candidemia and Disseminated Infection
Candidemia may represent evidence of disseminated or deep-tissue infection, result from hematogenous seeding from the gastrointestinal or urinary tract, or be a transient finding associated with an intravascular catheter. The source of the infection may be difficult to determine, and therefore candidemia should be treated aggressively with systemic antifungal therapy. Data suggest that combination therapy with an amphotericin B product and fluconazole may clear Candida species more rapidly from the bloodstream and may be more successful than mono-therapy.34,35A minimum of 14 days of antifungal therapy should be administered.
Candidemia that is intravascular and catheter related may be distinguished from other etiologies by comparison of simultaneous blood cultures drawn from all lumens of the catheter and from a peripheral stick. Candidemia may be said to be catheter related if the colony count from a culture drawn through a catheter lumen is 10 times that of a culture drawn peripherally. Catheter-related infections resulting from Candida species are associated with biofilm formation, which makes treatment very difficult without removing the catheter. It is recommended that intravascular catheters be removed immediately in all cases of catheter-related candidemia.34
In most cases of disseminated candidiasis the infection is concentrated in two or three areas, with the lungs, kidneys, liver, spleen, and brain being the organs most commonly affected. Intravenous therapy is indicated initially in all cases. Duration of treatment is prolonged (4 weeks at a minimum) and depends upon clinical response.
The risk of developing disseminated candidiasis increases with prolonged fever with neutropenia.36,37 Clinical guidelines recommend initiating empiric antifungal therapy in patients with febrile neutropenia that does not respond within 5 to 7 days of broad-spectrum antibiotic therapy.
Prophylactic antifungal therapy has been associated with decreased incidence of Candida infections in oncology patients and other at-risk populations.38-41 Fluconazole is frequently used as prophylaxis, but there is concern about widespread use of azoles being associated with an increase in azole-resistant strains.41,42
Neonates are a special population at risk of candidemia and disseminated candidiasis. Prophylactic antifungal therapy has been shown to reduce the incidence of Candida infections in very-low-birth-weight infants (< 1500 g), who are at particular risk. Empiric antifungal therapy may be considered when sepsis is suspected in neonates who are extremely premature, who have indwelling catheters, or who have been receiving broad-spectrum antibiotics.43Cutaneous lesions may also indicate systemic candidiasis: up to half of all neonates will have diffuse erythroderma or vesiculopustules.
Catheters should be removed or replaced immediately in neonates with candidemia.44,45 Delaying removal of catheters more than one day after initiating antifungal therapy is associated with increased neurodevelopmental impairment and mortality.44 Persistent candidemia occurs frequently in neonates: blood cultures may remain positive for several days after beginning antifungal therapy, and up to 10% may have fungemia for 14 or more days.44
All neonates with candidemia should be evaluated for disseminated disease.46 Central nervous system disease may occur in up to one third of neonates with candidemia. Evaluation of infected neonates should include examination and culture of cerebrospinal fluid, head ultrasound, ophthalmologic evaluation, and echocardiogram.
Respiratory Tract Candidiasis
Because Candida species are known colonizers of respiratory tract mucosa, their presence in respiratory specimen cultures does not necessarily indicate infection.
Laryngeal candidiasis has been reported in HIV-infected children and children receiving immunosuppressive chemotherapy who had oropharyngeal candidiasis and hoarseness.47,48 It has also been reported in children receiving inhaled corticosteroids. Laryngeal candidiasis should be considered in any immunosup-pressed child with a hoarse cry or voice. Laryngoscopy will reveal the typical white plaques on the vocal cords of these patients.
Pulmonary candidiasis may manifest as localized pneumonia, diffuse infiltrates, nodular lesions, abscesses, or empyema. Because recovery of Candida species from sputum or bronchial washings may signify only colonization, definitive diagnosis of pulmonary disease requires an invasive procedure such as lung biopsy to demonstrate organisms in tissue specimens.
Candida species may cause disease in any part of the heart. Two thirds of cases of fungal endocarditis are the result of Candida species.50Candida endocarditis is associated with signs and symptoms similar to those seen with sub-acute bacterial endocarditis, and blood cultures are usually sterile. Vegetations and emboli resutling from Candida infection are usually large and may occlude vessels. Candidaendocarditis is usually associated with systemic candidiasis and indwelling central venous catheters. Valvular involvement usually affects the aortic and mitral valves, and may be difficult to visualize by two-dimensional echocardiography.
Cardiac candidiasis frequently occurs with central nervous system involvement: therefore, examination of cerebrospinal fluid and performance of computed tomography or magnetic resonance imaging of the brain is indicated in all cases of cardiac candidiasis.
Candida arthritis is usually diagnosed in association with systemic candidiasis, and most commonly involves the knee. Joint infection is owing to direct inoculation or hematogenous spread, and may be associated with a contiguous osteomyelitis. Arthritis in the absence of systemic infection has been reported following prosthetic arthoplasty.52
Reported anatomic sites of Candida osteomyelitis include the spine, upper and lower extremities, ribs and costochondral junctions, mandible, and sternum.27,53 Many Candida osteomyelitis cases that have been reported were in neonates or infants younger than age 14 weeks, in whom the lower extremities are the most frequent site of involvement.54
Central Nervous System Candidiasis
Candida species may cause a wide variety of central nervous system (CNS) findings, including meningitis, vasculitis, thrombosis, mycotic aneurysm, demyelination, abscesses, nodules, and noncaseating granulomas.55 Patients with CNS candidiasis may not have neurologic findings. Candida meningitis is more frequent in preterm newborns and may present as respiratory decompensation. Blood cultures are likely to be sterile, and many patients will not have cerebrospinal fluid (CSF) findings indicative of CNS involvement.44 CNS and cardiac candidiasis frequently occur together, and therefore CSF examination and computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in all cases of suspected Candida CNS disease and in cases of cardiac candidiasis.
In one series of pediatric oncology patients, 11 of 12 cases of Candida meningitis were the result of C tropicalis, all of which were fatal.9 In that report, duration of profound neutropenia with fever, antibiotic therapy, and administration of total parenteral nutrition (TPN) were significantly associated with Candida meningitis.
The combination of an amphotericin B product and flucytosine is the recommended treatment for CNS candidiasis. The addition of flucytosine is recommended because it penetrates the CSF readily, whereas amphotericin B does not. Intraventricular administration of amphotericin B is severely toxic, and should be an option of last resort. Fluconazole and other azoles have excellent penetration into the CSF, but experience with these agents is limited for Candida meningitis.56 Fluconazole should not be used when azole-resistant Candida organisms are isolated or suspected.
Careful routine ophthalmic examination should be performed in all patients with evidence of disseminated candidiasis. Retinitis is a frequent finding in low-birth-weight neonates with disseminated candidiasis.57 The typical findings are fluffy white chorioretinal lesions that may extend to the vitreous. Patients may complain of eye pain, blurred vision, or photophobia. Severely neutropenic patients with retinal involvement may not show evidence of retinal lesions; therefore, it is vital to perform ophthalmic examination in these patients following resolution of neutropenia.58