Candida

Keywords

• dermatitis

• yeast

• Candida

• fungemia

• candidiasis

• prophylaxis

• amphotericin

• fluconazole

Epidemiology

Candida species are the third most common cause of bloodstream infection in premature infants. The cumulative incidence is <0.3% among infants >2,500 g birthweight admitted to the NICU. The cumulative incidence increases to 8% for infants <750 g birthweight. In addition, the incidence varies greatly by individual NICU. Among centers in the National Institutes of Health-sponsored Neonatal Research Network, the cumulative incidence of candidiasis among infants <1,000 g birthweight ranges from 2% to 28%. Colonization is associated with a significantly increased risk of future invasive Candida infection. Up to 10% of full-term infants are colonized as the result of vertical transmission from the mother at birth, with slightly higher rates of colonization in premature infants. Colonization rates increase to >50% among infants admitted to the NICU by 1 mo of age. Histamine-2 blockers, corticosteroids, and broad-spectrum antibiotics facilitate Candida colonization and overgrowth.

Significant risk factors for neonatal invasive candidiasis include prematurity, low birthweight, exposure to broad-spectrum antibiotics, abdominal surgery, endotracheal intubation, and presence of a central venous catheter.

Pathogenesis

Immunologic immaturity along with an underdeveloped layer of skin, need for invasive measures (endotracheal tubes, central venous catheters), and exposure to broad-spectrum antibiotics places preterm infants at great risk for invasive candidiasis. Premature infants are also at high risk for spontaneous intestinal perforations and necrotizing enterocolitis. Both conditions require abdominal surgery, prolonged exposure to broad-spectrum antibiotics, and total parenteral nutrition administration requiring placement of central venous catheters. Each of these factors increases the risk of invasive candidiasis by decreasing the physiologic barriers that protect against invasive infection.

Clinical Manifestations

The manifestations of neonatal candidiasis vary in severity from oral thrush and Candida diaper dermatitis (see Chapter 261.2 ) to invasive candidiasis that can manifest with overwhelming sepsis (see Chapter 261.3 ). Signs of invasive candidiasis among premature infants are often nonspecific and include temperature instability, lethargy, apnea, hypotension, respiratory distress, abdominal distention, and thrombocytopenia.

Central nervous system involvement is common and is most accurately described as meningoencephalitis. Candida infections involving the central nervous system often result in abscesses, leading to unremarkable cerebrospinal fluid parameters (white blood cell count, glucose, protein) even though central nervous system infection is present. Endophthalmitis is an uncommon complication affecting <5% of infants with invasive candidiasis. In addition, candidemia is associated with an increased risk of severe retinopathy of prematurity. Renal involvement commonly complicates neonatal invasive candidiasis. Renal involvement may be limited to candiduria or can manifest with diffuse infiltration of Candida throughout the renal parenchyma or the presence of Candida and debris within the collecting system. Due to the poor sensitivity of blood cultures for Candida , candiduria should be considered a surrogate marker of candidemia in premature infants. Other affected organs include the heart, bones, joints, liver, and spleen.

Diagnosis

Mucocutaneous infections are most often diagnosed by direct clinical exam. Scrapings of skin lesions may be examined with a microscope after Gram staining or suspension in KOH. Definitive diagnosis of invasive disease requires histologic demonstration of the fungus in tissue specimens or recovery of the fungus from normally sterile body fluids. Hematologic parameters are sensitive but not specific. Thrombocytopenia occurs in more than 80% of premature infants with invasive candidiasis, but also occurs in 75% of premature infants with Gram-negative bacterial sepsis and nearly 50% of infants with Gram-positive bacterial sepsis. Blood cultures have very low sensitivity for invasive candidiasis. In a study of autopsy-proven candidiasis in adult patients, the sensitivity of multiple blood cultures for detecting single-organ disease was 28%. Blood culture volumes in infants are often only 0.5-1 mL, making the sensitivity in this population almost certainly lower. Blood culture volume should be maximized as much as possible to increase sensitivity. Fungal-specific media can improve sensitivity when Candida is present as a coinfection with bacteria and can also decrease the time to positivity, leading to more rapid diagnosis.

Further assessment of infants in the presence of documented candidemia should include ultrasound or computerized tomography of the head to evaluate for abscesses; ultrasound of the liver, kidney, and spleen; cardiac echocardiography; ophthalmologic exam; lumbar puncture; and urine culture. These tests are necessary to determine if more than 1 body system is infected, which is commonly the case.

Prophylaxis

NICUs with a high incidence of invasive candidiasis should consider prophylaxis with fluconazole in infants <1,000 g birthweight as a cost-effective method of reducing invasive candidiasis. Twice-weekly flucon­azole at 3 or 6 mg/kg/dose decreases rates of both colonization with Candida species and invasive fungal infections. Use of this dosing strategy has not been shown to increase the frequency of infections caused by fluconazole-resistant strains, but use of an alternative antifungal class for cases of breakthrough infection is suggested.

Treatment

In the absence of systemic manifestations, topical antifungal therapy is the treatment of choice for congenital cutaneous candidiasis in full-term infants. Congenital cutaneous candidiasis in preterm infants can progress to systemic disease, and therefore systemic therapy is warranted.

Every attempt should be made to remove or replace central venous catheters once the diagnosis of candidemia is confirmed. Delayed removal has been consistently associated with increased mortality and morbidity, including poor neurodevelopmental outcomes.

Although no well-powered randomized, controlled trials exist to guide length and type of therapy, 21 days of systemic antifungal therapy from the last positive Candida culture is recommended in infants. Antifungal therapy should be targeted based on susceptibility testing. Amphotericin B deoxycholate has been the mainstay of therapy for systemic candidiasis and is active against both yeast and mycelial forms. Nephrotoxicity, hypokalemia, and hypomagnesemia are common, but amphotericin B deoxycholate is better tolerated in infants than in adult patients. C. lusitaniae , an uncommon pathogen in infants, is often resistant to amphotericin B deoxycholate. Liposomal amphotericin is associated with worse outcomes in infants and should be used only when urinary tract involvement can reliably be excluded. Fluconazole is often used instead of amphotericin B deoxycholate for treatment of invasive neonatal Candida infections because of its effectiveness and low incidence of side effects. It is particularly useful for urinary tract infections, obtaining high concentrations in the urine. A loading dose should be given to obtain therapeutic serum concentrations in a timely manner. Fluconazole is inactive against all strains of C. krusei and some isolates of C. glabrata. Additionally, in centers where fluconazole prophylaxis is used, another agent, such as amphotericin B deoxycholate, should be used for treatment. The echinocandins have excellent activity against most Candida species and have been used successfully in patients with resistant organisms or in whom other therapies have failed. Several studies have described the pharmacokinetics of antifungals in infants ( Table 261.1 ).

Prognosis

Mortality following invasive candidiasis in premature infants has been consistently reported to be around 20% in large studies but can be as high as 50% in infants <1,500 g birthweight. Candidiasis is also associated with poor neurodevelopmental outcomes, chronic lung disease, and severe retinopathy of prematurity.