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. 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 226-1).

Table 226-1 DOSING OF ANTIFUNGAL AGENTS IN INFANTS* AND NUMBER OF SUBJECTS <1 YR OF AGE STUDIED WITH REPORTED PHARMACOKINETIC PARAMETERS

DRUG INFANTS STUDIED SUGGESTED DOSE
Amphotericin B deoxycholate 15 1 mg/kg/day
Amphotericin B lipid complex 28 5 mg/kg/day
Liposomal amphotericin B 17 5 mg/kg/day
Amphotericin B colloidal dispersion 0 5 mg/kg/day
Fluconazole 55 12 mg/kg/day
Micafungin† 48 10 mg/kg/day
Caspofungin‡ 22 50 mg/m2/day
Anidulafungin‡,§ 0 1.5 mg/kg/day

* Voriconazole dosing has not been investigated in the nursery.

† Micafungin has been studied in infants <120 days of life at this dosage. Dosing for older infants should be 4-8 mg/kg.

‡ Caspofungin and anidulafungin should generally be avoided, because dosing sufficient to penetrate brain tissue has not been studied.

§ The formulation for anidulafungin contains alcohol and should generally be avoided in premature infants; an alcohol-free formulation is undergoing clinical investigation in 2009-2011.

Prognosis

Mortality following invasive candidiasis in premature infants has been consistently reported to be around 20% in large studies. Candidiasis is also associated with poor neurodevelopmental outcomes, chronic lung disease, and severe retinopathy of prematurity.

Bibliography

Baley JE, Meyers C, Kliegman RM, et al. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr. 1990;116:791-797.

Benjamin DKJr, Smith PB, Arrieta A, et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharm Ther. 2010;87:93-99.

Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother. 1989;33:1989-1993.

Heresi GP, Gerstmann DR, Reed MD, et al. The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants. Pediatr Infect Dis J. 2006;25:1110-1115.

Kotwani RN, Gokhale PC, Bodhe PV, et al. A comparative study of plasma concentrations of liposomal amphotericin B (L-AMP-LRC-1) in adults, children and neonates. Internat J Pharm. 2002;238:11-15.

Neely M, Jafri HS, Seibel N, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009;53:1450-1456.

Saez-Llorens X, Macias M, Maiya P, et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother. 2009;53:869-875.

Smith PB, Walsch TJ, Hope W, et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr Infect Dis J. 2009;28:412-415.

Wade KC, Wu D, Kaufman RM, et al. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother. 2008;52:4043-4049.

Wurthwein G, Groll AH, Hempel G, et al. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother. 2005;49:5092-5098.

226.2 Infections in Immunocompetent Children and Adolescents

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

Oral Candidiasis

Oral thrush is a superficial mucous membrane infection that affects approximately 2-5% of normal newborns. C. albicans is the most commonly isolated species. Oral thrush can develop as early as 7-10 days of age. The use of antibiotics, especially in the 1st year of life, can lead to recurrent or persistent thrush. It is characterized by pearly white, curdish material visible on the tongue, palate, and buccal mucosa. Oral thrush may be asymptomatic or can cause pain, fussiness, and decreased feeding, leading to inadequate nutritional intake and dehydration. It is uncommon after 1 yr of age but can occur in older children treated with antibiotics. Persistent or recurrent thrush with no obvious predisposing reason, such as recent antibiotic treatment, warrants investigation of an underlying immunodeficiency, especially vertically transmitted HIV infection.

Treatment of mild cases might not be necessary. When treatment is warranted, the most commonly prescribed antifungal agent is nystatin. For recalcitrant or recurrent infections, a single dose of fluconazole may be useful. In breast-fed infants, simultaneous treatment of infant and mother with topical nystatin or oral fluconazole may be indicated.

Diaper Dermatitis

Diaper dermatitis is the most common infection caused by Candida (Chapter 658) and is characterized by a confluent erythematous rash with satellite pustules. Candida diaper dermatitis often complicates other noninfectious diaper dermatitides and often occurs following a course of oral antibiotics.

A common practice is to presumptively treat any diaper rash that has been present for >3 days with topical antifungal therapy such as nystatin, clotrimazole, or miconazole. If significant inflammation is present, the addition of hydrocortisone 1% may be useful for the 1st 1-2 days, but topical corticosteroids should be used cautiously in infants because the relatively potent topical corticosteroid can lead to adverse effects. Frequent diaper changes and short periods without diapers are important adjunctive treatments.

Ungual and Periungual Infections

Paronychia and onychomycosis may be caused by Candida, although Trichophyton and Epidermophyton are much more common causes (Chapter 655). Candida onychomycosis differs from tinea infections by its propensity to involve the fingernails and not the toenails, and by the associated paronychia. Candida paronychia often respond to treatment consisting of keeping the hands dry and using a topical antifungal agent. For ungual infections, a short course of systemic azole therapy may be necessary.

Vulvovaginitis

Vulvovaginitis is a common Candida infection of pubertal and postpubertal female patients (Chapter 543). Predisposing factors include pregnancy, use of oral contraceptive, and use of oral antibiotics. Prepubertal girls with Candida vulvovaginitis usually have a predisposing factor such as diabetes mellitus or prolonged antibiotic treatment. Clinical manifestations can include pain or itching, dysuria, vulvar or vaginal erythema, and an opaque white or cheesy exudate. More than 80% of cases are caused by C. albicans.

Candida vulvovaginitis can be effectively treated with either vaginal creams or troches of nystatin, clotrimazole, or miconazole. Oral therapy with a single dose of fluconazole is also effective.

226.3 Infections in Immunocompromised Children and Adolescents

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

Etiology

C. albicans is the most common cause of invasive candidiasis among immunocompromised pediatric patients and is associated with higher rates of mortality and end-organ involvement than are non-albicans species.

Clinical Manifestations

HIV-Infected Children

Oral thrush and diaper dermatitis are the most common Candida infections in HIV-infected children. Besides oral thrush, 3 other types of oral Candida infections can occur in HIV-infected children: atrophic candidiasis, which manifests as a fiery erythema of the mucosa or loss of papillae of the tongue; chronic hyperplastic candidiasis, which presents with oral symmetric white plaques; and angular cheilitis, in which there is erythema and fissuring of the angles of the mouth. Topical antifungal therapy may be effective, but systemic treatment with fluconazole or itraconazole is usually necessary. Symptoms of dysphagia or poor oral intake can indicate progression to Candida esophagitis, requiring systemic antifungal therapy. In HIV patients, esophagitis can also be caused by cytomegalovirus, HSV, reflux, or lymphoma; Candida is the most common cause, and Candida esophagitis can occur in the absence of thrush.

Candida dermatitis and onychomycosis are more common in HIV-infected children. These infections are generally more severe than they are in immunocompetent children and can require systemic antifungal therapy.

Cancer and Transplant Patients

Fungal infections, especially Candida and Aspergillus infections, are a significant problem in oncology patients with chemotherapy-associated neutropenia (Chapter 171); the risk of these infections increases after 5 days of neutropenia and fever. Accordingly, empirical antifungal therapy is usually added to the antimicrobial regimen, if fever and neutropenia persist for ≥5 days. The triazoles and echinocandins have similar efficacy and improved safety profiles compared with either amphotericin B deoxycholate or lipid-complex formulations of amphotericin.

Bone marrow transplant recipients have a much higher risk of fungal infections because of the dramatically prolonged duration of neutropenia. Fluconazole prophylaxis decreases the incidence of candidemia in bone marrow transplant recipients. The echinocandins (anidulafungin, caspofungin, micafungin) and voriconazole have been successfully used as monotherapy or in combination with each other and amphotericin B deoxycholate. The use of myelopoietic colony-stimulating factor affects the duration of neutropenia after chemotherapy and is associated with decreased risk for candidemia. When Candida infection occurs in this population, the lung, spleen, kidney, and liver are involved in >50% of cases.

Solid organ transplant recipients are also at increased risk for superficial and invasive Candida infections. Studies in liver transplant recipients demonstrate the utility of antifungal prophylaxis with amphotericin B deoxycholate, fluconazole, voriconazole, or caspofungin.

Catheter-Associated Infections

Central venous catheter infections occur most often in oncology patients but can affect any patient with a central catheter (Chapter 172). Neutropenia, use of broad-spectrum antibiotics, and parenteral alimentation are associated with increased risk for Candida central catheter infection. Treatment requires removing or replacing the catheter and a 2-3 wk course of systemic antifungal therapy.

Diagnosis

The diagnosis is often presumptive in neutropenic patients with prolonged fever because positive blood fungal cultures occur only in a minority of patients who are later found to have disseminated infection. If isolated, Candida grows readily on routine blood culture media, with ≥90% of positive cultures identified within 72 hr.

Treatment

Echinocandins are favored for moderately or severely ill children; fluconazole is acceptable for those infected with susceptible organism and less critically ill; amphotericin B products are also acceptable. Fluconazole is not effective against C. krusei and some isolates of C. glabrata. Amphotericin B deoxycholate is inactive against approximately 20% of strains of C. lusitaniae, and therefore susceptibility testing should be performed for all strains (Table 226-2).

Table 226-2 DOSING OF ANTIFUNGAL AGENTS IN CHILDREN >1 YEAR OF AGE FOR TREATMENT OF INVASIVE DISEASE

DRUG SUGGESTED DOSAGE
Amphotericin B deoxycholate 1 mg/kg/day
Amphotericin B lipid complex 5 mg/kg/day
Liposomal amphotericin B 5 mg/kg/day
Amphotericin B colloidal dispersion 5 mg/kg/day
Fluconazole 12 mg/kg/day
Voriconazole 7 mg/kg every 12 hr
Micafungin* 4-8 mg/kg/day
Caspofungin† 50 mg/m2/day
Anidulafungin 1.5 mg/kg/day

* Use adult dosages in children >8 yr of age.

† Loading doses should be used for caspofungin and anidulafungin: 70 mg/m2 and 3.0 mg/kg, respectively.

Bibliography

Aslam S, Hernandez M, Thornby J, et al. Risk factors and outcomes of fungal ventricular-assist device infections. Clin Infect Dis. 2010;50:664-671.

Kuse ER, Chetchotisakd P, Arns de Cunha C, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomized double-blind trial. Lancet. 2007;369:1519-1526.

Neely M, Jafri HS, Seibel N, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009;53:1450-1456.

Plantinga TS, van der Velden JFM, Ferwerda B, et al. Early stop polymorphism in human DECTIN-1 is associated with increased Candida colonization in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2009;49:724-732.

Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:2472-2482.

Seibel N, Schwartz C, Arrieta A, et al. Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005;49:3317-3324.

226.4 Chronic Mucocutaneous Candidiasis

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

Chronic mucocutaneous candidiasis is a group of heterogeneous immune disorders with a primary defect of T-lymphocyte responsiveness to Candida. Endocrinopathies (hypoparathyroidism, Addison disease), hyperimmunoglobulin E syndrome (Job syndrome), autoimmune disorders, HIV, and inhaled corticosteroid use are associated with chronic mucocutaneous candidiasis (Chapter 119). Although the underlying immune disorders are varied, the presentations of chronic mucocutaneous candidiasis are usually similar. Symptoms can begin in the 1st few months of life or as late as the 2nd decade of life. The disorder is characterized by chronic and severe Candida skin and mucous membrane infections. Patients rarely develop systemic Candida disease. Topical antifungal therapy can provide limited improvement early in the course of the disease, but systemic courses of azoles are usually necessary. The infection usually responds temporarily to treatment but is not eradicated and recurs.

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