Candida

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Chapter 226 Candida

P. Brian Smith, Daniel K. Benjamin, Jr.

Candidiasis encompasses many clinical syndromes that may be caused by several species of Candida. Invasive candidiasis (Candida infections of the blood and other sterile body fluids) is a leading cause of infection-related mortality in hospitalized immunocompromised patients.

Candida exists in 3 morphologic forms: oval to round blastospores or yeast cells (3-6 mm in diameter); double-walled chlamydospores (7-17 mm in diameter), which are usually at the terminal end of a pseudohypha; and pseudomycelium, which is a mass of pseudohyphae and represents the tissue phase of Candida. Pseudohyphae are filamentous processes that elongate from the yeast cell without the cytoplasmic connection of a true hypha. Candida grows aerobically on routine laboratory media but can require several days of incubation.

C. albicans accounts for most human infections, but C. parapsilosis, C. tropicalis, C. krusei, C. lusitaniae, C. glabrata, and several other species are commonly isolated from hospitalized children. C. albicans forms a germ tube when suspended in rabbit or human serum and incubated for 1-2 hr; a rapid germ tube test should therefore be performed before further identification tests are conducted. Thereafter, differentiation and susceptibility testing are important owing to increasing frequency of fluconazole resistance. The other clinically important Candida species can be identified within 48 hr on the basis of biochemical test results.

Treatment of invasive Candida infections is complicated by the emergence of non-albicans strains. Amphotericin B deoxycholate is inactive against approximately 20% of strains of C. lusitaniae. Fluconazole is useful for many Candida infections but is inactive against all strains of C. krusei and 5-25% of strains of C. glabrata. Susceptibility testing of these clinical isolates is recommended.

226.1 Neonatal Infections

P. Brian Smith, Daniel K. Benjamin, Jr.

Candida is a common cause of oral mucous membrane infections (thrush) and perineal skin infections (Candida diaper dermatitis) in newborn infants (Chapter 658). Rare presentations include congenital cutaneous candidiasis, caused by an ascending infection into the uterus during gestation, and invasive fungal dermatitis, a postnatal infection skin infection resulting in positive blood cultures. Invasive candidiasis is a common infectious complication in the neonatal intensive care unit (NICU) because of improved survival of the extremely preterm infants.

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 12% for infants <750 g birthweight. In addition the incidence varies greatly by individual NICU. In the National Institutes of Health–sponsored Neonatal Research Network, the cumulative incidence of candidiasis among infants <1,000 g birthweight is 2.4-20.4%.

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 preterm infants. Colonization rates increase to >50% among infants admitted to the NICU by 1 mo of age. H₂ blockers and broad-spectrum antibiotics facilitate Candida colonization and overgrowth.

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

Pathogenesis

The immune system of premature infants has deficiencies in chemotaxis, cytokine production, phagocytosis, and production of type-specific antibodies. These immune defects combined with an underdeveloped layer of skin, need for invasive measures (endotracheal tubes, central venous catheters), and exposure to broad-spectrum antibiotics place preterm infants at great risk for invasive candidiasis. Preterm 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 administration requiring placement of central venous catheters. Each of these factors increases the risk of invasive candidiasis.

Clinical Manifestations

The manifestations of neonatal candidiasis vary in severity from oral thrush and Candida diaper dermatitis (Chapter 226.2) to invasive candidiasis that can manifest with overwhelming sepsis (Chapter 226.3). Signs of invasive candidiasis among preterm neonates are often nonspecific and include temperature instability, lethargy, apnea, hypotension, respiratory distress, abdominal distention, and hyperglycemia or hypoglycemia.

Central nervous system (CNS) involvement is common and is more accurately described as meningoencephalitis. Candida infections involving the CNS often result in abscesses leading to unremarkable cerebrospinal fluid parameters (white blood cell count, glucose, protein) in the presence of CNS infection. Endophthalmitis is an uncommon complication affecting <5% of neonates 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. 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. Although thrombocytopenia occurs in >80% of preterm infants with invasive candidiasis, thrombocytopenia also occurs in 75% of preterm 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 neonates are typically only 0.5-1 mL, making the sensitivity in this population almost certainly lower.

Assessment of neonates 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.

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. No well-powered randomized, controlled trials exist to guide length and type of therapy.

Systemic antifungal therapy should be administered for 21 days from the last positive Candida culture. 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 neonates than in adult patients. C. lusitaniae, an uncommon pathogen in neonates, is resistant to amphotericin B deoxycholate. Fluconazole is very useful for treatment of invasive neonatal Candida infections, especially urinary tract infections. Fluconazole is inactive against all strains of C. krusei and some isolates of C. glabrata.

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