Candida species are yeast forms that are ubiquitous in nature and frequent colonizers of human skin and mucous membranes of the gastrointestinal, respiratory, and female genital tracts. Candida species are the most common cause of human fungal infections, although they rarely cause invasive disease in the absence of mucosal barrier disruption or compromised immune systems. Only a small number of the more than 150 species of Candida that have been described are considered to be pathogenic. There are at least 15 Candida species associated with human disease, but most invasive infections are due to 5 pathogens: C albicans, C glabrata, C tropicalis, C parapsilosis, and C krusei. Historically, C albicans has accounted for the majority of invasive infections, but in more recent reports, non-albicans species have been isolated in half or more of the cases. In addition, the incidence of infections due to C albicans isolates that are resistant to azole antifungals is increasing. This changing epidemiology has implications for appropriate treatment of antifungal-resistant Candida infections.
PATHOGENESIS AND EPIDEMIOLOGY
Candida species are part of the normal human flora of the skin and mucous membranes. The incidence of colonization with Candida species depends on host characteristics such as age and overall health. Neonates are frequently colonized with Candida species, and localized oropharyngeal candidiasis (thrush) is not uncommon in this population. Hospitalized and ill children are more frequently colonized than are healthy children. Candida species have relatively low virulence factors compared to other organisms and, therefore, rarely cause disease in the normal host. For candidiasis to occur, the host must have impaired resistance to disease, the number of yeast organisms must be high, or both.
Neonates and pregnant women have impaired host resistance to Candida species, as do patients with immunodeficiencies (congenital or acquired), induced immunosuppression (due to chemotherapy or corticosteroids), or debilitation (secondary to trauma or surgery). Advances in health care that have decreased mortality for preterm newborns and oncology patients 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. These at-risk populations frequently receive multiple and long-term courses of medications, particularly antimicrobials (altering the normal flora), and have defects in mucosal or skin barriers (such as chemotherapy-induced mucositis or the presence of indwelling intravascular catheters), which puts them at high risk for development of candidiasis.
Invasive candidiasis includes candidemia and deep-seated infection. Deep-seated infection usually results from candidemia but may occur through direct inoculation (eg, leaky surgical anastomosis leading to peritonitis). Candidemia is frequently due to translocation of Candida species in the gut into the bloodstream. In patients with indwelling central venous catheters, Candida species introduced to the bloodstream from the gut or skin colonize the catheter and form a biofilm, which will then persistently release Candida into the bloodstream. Candidemia may lead to secondary infections throughout the body, which may in turn cause secondary candidemias.
Candida species are the third or fourth most common cause of healthcare-associated bloodstream infections in children in the United States. In recent pediatric studies, C albicans accounted for approximately 45% of cases. C parapsilosis is the second most common pathogen in pediatrics, accounting for 20% to 25% of bloodstream infections, in both neonates and older children.
Candidiasis may be broadly divided into 2 categories: mucocutaneous infections and invasive disease. Mucocutaneous infection includes involvement of the oropharynx, gastrointestinal tract, female genital tract, skin, and nails. Invasive disease includes candidemia and deep-seated infection due to hematogenous spread or direct inoculation.
Oropharyngeal and Gastrointestinal Tract 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.
The lesions of thrush appear most commonly as pearly white patches on the dorsal and lateral aspects of the tongue, 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.
Other oropharyngeal infections include acute atrophic candidiasis (glossitis) and angular cheilitis (perlèche). Glossitis usually occurs following the use of broad-spectrum antibiotics that alter 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 cheilitis (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 or vitamin B12 or folate deficiency or in children with poor oral secretion control. Treatment with topical antifungals and/or steroids is 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.
Although diarrhea and abdominal pain have been reported in patients with Candida species recovered from their stool, it is not clear whether symptoms are the result of Candida infection or other cause, such as effects of chemotherapy. Candida infection may play a role in typhlitis. Gastrointestinal Candida lesions are common in immunocompromised pediatric patients and are frequently found at autopsy.
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. Penile lesions due to Candida species are uncommon, even in sexual partners of women with vaginal candidiasis.
Cutaneous candidiasis involves moist areas, such as the perineum and intertriginous areas (eg, gluteal folds, neck, axillae). Infants who suck their fingers may develop sucking blisters, and infection of the nails (onychia) or around the nails (paronychia) may also occur. Paronychia resulting from Candida species also may follow other trauma to the nail or surrounding tissue. Candida is associated with chronic paronychia, characterized by swollen, erythematous, and tender nail folds, which may occur episodically. Chronic infection may lead to thickening and discoloration of the nail beds.
Candidemia and Disseminated Infection
Candidemia may represent evidence of disseminated or deep-seated 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. Most immunocompromised patients with candidemia will have disseminated disease.
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 if feasible in all cases of catheter-related candidemia.
In most cases of disseminated candidiasis, the infection is concentrated in 2 or 3 areas, with the lungs, kidneys, liver, spleen, and brain being the organs most commonly affected. Clinical manifestations will depend on the sites and extent of Candida infection.
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. Cutaneous lesions also are frequent findings in neonates with disseminated disease: up to half of all neonates have diffuse erythroderma or vesiculopustules.
All neonates with candidemia should be evaluated for disseminated disease. 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 (CSF), head ultrasound, ophthalmologic evaluation, and echocardiogram.
Hepatosplenic candidiasis is seen in patients with hematologic malignancies. Patients may have fever, abdominal pain, and elevation of liver function tests following recovery of neutropenia. Contrast-enhanced computed tomography (CT) is the usual diagnostic imaging modality and is recommended for follow-up evaluations. Biopsy of lesions is frequently nondiagnostic.
Central Nervous System Candidiasis
Central nervous system (CNS) candidiasis is usually seen with other findings of disseminated candidiasis and frequently occurs along with cardiac candidiasis. Candida species may cause a wide variety of CNS findings, including meningitis, vasculitis, thrombosis, mycotic aneurysm, demyelination, abscesses, nodules, and noncaseating granulomas. 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 CSF findings indicative of CNS involvement. All neonates with disseminated disease should have CSF examination and head ultrasound.
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. In that report, duration of profound neutropenia with fever, antibiotic therapy, and administration of total parenteral nutrition (TPN) were significantly associated with Candida meningitis.
Careful routine ophthalmic examination should be performed in all patients with candidemia or other evidence of disseminated candidiasis. Retinitis is a frequent finding in low-birth-weight neonates with disseminated candidiasis. 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. All neonates with disseminated disease should have an ophthalmologic examination.
Candida species may cause disease in any part of the heart. Two-thirds of cases of fungal endocarditis are the result of Candida species. Candida endocarditis is associated with signs and symptoms similar to those seen with subacute bacterial endocarditis, and blood cultures are usually sterile. Vegetations and emboli resulting from Candida infection are usually large and may occlude vessels. Candida endocarditis 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 2-dimensional echocardiography. Candida infection of the myocardium may manifest as nonspecific electrocardiographic findings, including QRS changes and marked T-wave changes.
Cardiac candidiasis frequently occurs with CNS involvement; therefore, examination of CSF and performance of CT or magnetic resonance imaging (MRI) of the brain are indicated in all cases of cardiac candidiasis. All neonates with disseminated disease should have an echocardiogram performed.
Respiratory Tract Candidiasis
Because Candida species are known colonizers of respiratory tract mucosa, their presence in respiratory specimen cultures does not necessarily indicate infection. Candidiasis may affect any site within the respiratory tract and may be associated with oropharyngeal candidiasis.
Laryngeal candidiasis has been reported in HIV-infected children and children receiving immunosuppressive chemotherapy who had oropharyngeal candidiasis and hoarseness. It has also been reported in children receiving inhaled corticosteroids. Laryngeal candidiasis should be considered in any immunosuppressed child with a hoarse cry or voice. Laryngoscopy will reveal the typical white plaques on the vocal cords of these patients.
Bronchial candidiasis occurs rarely and is typically associated with pulmonary parenchymal and systemic disease. Pulmonary candidiasis may manifest as localized pneumonia, diffuse infiltrates, nodular lesions, abscesses, or empyema. The clinical presentation of pulmonary disease is nonspecific, usually characterized by fever and tachypnea. 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.
In addition to causing invasive disease, Candida species within the respiratory tract may elicit an allergic response. Polysaccharide and protein extracts of C albicans have been shown to trigger exacerbations in asthmatic patients.
Candida arthritis is usually diagnosed in association with systemic candidiasis and most commonly involves the knee. Joint infection is due 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 arthroplasty.
Reported anatomic sites of Candida osteomyelitis include the spine, upper and lower extremities, ribs and costochondral junctions, mandible, and sternum. 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. The axial skeleton is more frequently involved in adults. Multifocal involvement is common, so imaging should be performed to assess for other sites of infection.
Candida peritonitis may result from peritoneal dialysis, intestinal surgery, or bowel perforation. As with other causes of peritonitis, abdominal distention, fever, and vomiting may occur. Because the clinical features cannot distinguish fungal from bacterial peritonitis, diagnosis must be made by microbiological examination and culture of peritoneal fluid. Compared to adults, pediatric dialysis patients who develop Candida peritonitis usually have more favorable outcomes. Prior antibiotic use, preceding bacterial peritonitis, and infection due to gram-negative organisms are risk factors for development of fungal peritonitis.
Candidiasis of the Urinary Tract
The presence of Candida in voided urine specimens, even at high colony counts, is not always indicative of urinary tract infection. 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. 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. 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.
Definitive diagnosis of invasive candidiasis entails isolation of Candida from a normally sterile body site or a positive tissue biopsy. Negative blood cultures do not exclude invasive disease in immunocompromised patients. The sensitivity of blood culture is about 50%. Direct microscopic examination of specimens mounted in 10% to 20% potassium hydroxide (KOH) or prepared with calcofluor white, Gram, or fluorescent antibody stains will reveal budding yeast cells and/or pseudohyphae. On solid media such as Sabouraud dextrose agar, Candida species appear as moist, white, or cream-colored colonies with well-demarcated borders. C 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. Candida species are definitively identified by biochemical tests of fermentation and assimilation.
There are many new molecular diagnostic tests for candidiasis. The most widely used of these is the β-D-glucan assay, which tests for a component of the fungal cell wall that is not present in mammalian cells. This assay does not distinguish Candida species from other fungi and is limited by the false-positive rate among patients most at risk. False-positive β-D-glucan assays may result from hemodialysis, bacterial infections, human blood products, or certain antibiotics (amoxicillin-clavulanate or piperacillin-tazobactam), among many other causes. Candida mannan combined antigen-antibody testing has been used in Europe in the diagnosis of culture-negative hepatosplenic and other invasive candidiasis. Many institutions have developed in-house polymerase chain reaction (PCR) testing for Candida. PCR studies are limited by the lack of standardized methodologies. Recently, the US Food and Drug Administration approved the T2 Candida Panel (T2 Biosystems, Lexington, MA), which detects Candida DNA by PCR and T2 magnetic resonance, which appears promising in early studies. PCR testing offers advantages over other molecular diagnostics by allowing for the potential of species identification and identification of drug resistance.
Most mucocutaneous Candida infections may be treated topically, with nystatin or azoles. Esophagitis and urinary tract infection may be treated with oral azoles. There are several intravenous antifungals available for treatment of candidemia and deep-seated candidiasis.
Initial therapy for invasive disease prior to identification/susceptibility testing of the organism should be with an echinocandin (eg, caspofungin, micafungin, anidulafungin) or an amphotericin B product (standard amphotericin B deoxycholate or lipid formulations). Echinocandins and amphotericin B are effective against most species of Candida. Fluconazole is not appropriate empiric therapy because C krusei isolates are resistant to fluconazole, and C glabrata isolates are frequently resistant. Other azoles may be considered but often are ineffective for C glabrata as well. Some isolates of C parapsilosis have decreased susceptibility to echinocandins, but this is of uncertain significance, as C parapsilosis infections have been treated effectively with echinocandins despite in vitro resistance. C lusitaniae is resistant to amphotericin B, as are some isolates of C glabrata and C krusei. Amphotericin B products and echinocandins are fungicidal, whereas fluconazole is fungistatic.
Because neonates are more likely to have meningitis as a manifestation of candidiasis, even though up to 50% will have negative blood cultures, amphotericin B deoxycholate is the treatment of choice for any neonate with disseminated disease. Flucytosine is not recommended routinely in addition to amphotericin B deoxycholate in neonates due to toxicity risks and difficulty attaining therapeutic levels, but may be considered as adjunctive therapy in recalcitrant cases. Lipid formulations of amphotericin B have been associated with poorer outcomes in neonates.
Oropharyngeal and Gastrointestinal Tract Candidiasis
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. 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 breastfed 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.
Candida esophagitis is treated with oral fluconazole in those who can tolerate oral therapy. Other oral azoles (eg, itraconazole, voriconazole, posaconazole) may be options for fluconazole-resistant Candida. Treatment should be for a minimum of 14 to 21 days. Suppressive therapy with fluconazole is recommended for patients with recurrent esophagitis.
Vaginal candidiasis may be effectively treated topically. Topical azoles (eg, miconazole, clotrimazole) are often more effective than nystatin. A single 150-mg dose of oral fluconazole has been shown to be an effective option in adolescents and adults. Oral azoles also are options for patients with recurrent or refractory vulvovaginitis.
Skin infections may usually be treated effectively with nystatin. Miconazole and clotrimazole are other commonly used options. There are many other topical antifungals available, many of which are significantly more expensive than nystatin.
Candidemia and Disseminated Infection
Treatment for uncomplicated candidemia should be for 2 weeks from the first negative blood culture, assuming resolution of clinical manifestations. 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.
Intravascular catheters should be removed as soon as feasible in neonates and nonneutropenic children with candidemia. Delaying removal of catheters more than 1 day after initiating antifungal therapy is associated with increased neurodevelopmental impairment and mortality in neonates. Prompt removal of intravascular catheters should be considered in neutropenic children. The recommendation for removal is not as strong for neutropenic patients, because candidemia is frequently due to gastrointestinal translocation and it may be difficult to adequately assess whether the infection is catheter related, and lack of intravenous access may significantly complicate primary disease therapy in these patients. It is not recommended to immediately replace a catheter over a wire at the same site. Shorter courses of antifungal treatment may be considered in patients with clearance of candidemia following catheter removal if the patient is not immunosuppressed and there is no concern about disseminated disease.
Treatment should continue until radiographic resolution of lesions. Chemotherapy and/or hematopoietic stem cell transplant does not have to be delayed due to hepatosplenic candidiasis, but antifungal treatment should continue through the periods of neutropenia, in order to prevent relapse. There is some evidence that hepatosplenic candidiasis represents an immune reconstitution syndrome, and therefore, steroids or other anti-inflammatory drugs may be appropriate in some patients, although this has not been well studied.
Central Nervous System Candidiasis
The combination of an amphotericin B product and flucytosine is the recommended treatment for CNS candidiasis, except for neonates, who should be treated with amphotericin B deoxycholate alone. The addition of flucytosine is recommended beyond the neonatal period because it penetrates the CSF readily, whereas amphotericin B does not. Flucytosine should never be used as monotherapy. 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.
Fluconazole is the recommended agent for first-line therapy in pediatric patients with Candida peritonitis related to dialysis. The dialysis catheter should be removed, but there is disagreement about the timing of removal. Data support an option of removing the catheter early, but not immediately, in order to provide peritoneal lavage with fluconazole to help prevent peritoneal adhesions.
Candidiasis of the Urinary Tract
Isolated candiduria can be treated with a 7-day course of oral fluconazole. Bladder irrigations with amphotericin B (50 μg/mL sterile water) have been used, but as this is not systemic treatment, it is not a recommended therapy. Recurrence is common, and serial urine cultures should be performed to document clearance. Urinary catheters should be removed or replaced as soon as possible in patients diagnosed with candidiasis. For patients with evidence of renal or other systemic Candida infection, prolonged intravenous therapy is indicated. Lipid formulations of amphotericin B are not recommended for urinary tract infections because of their decreased renal excretion.
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. Fluconazole prophylaxis (3–6 mg/kg/dose orally or intravenously twice weekly for 6 weeks) is recommended for extremely low-birth-weight infants (< 1000 g) in nurseries with high rates (> 10%) of invasive candidiasis. 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. Prophylactic antifungal therapy is routinely used in children undergoing hematopoietic stem cell transplantation or myelosuppressive chemotherapy.
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