Diagnosis and Management of Candidemia and Invasive Candidiasis in Neonates and Children

Systemic infections with Candida species affect the most vulnerable neonates, infants and children. Neonates born prematurely, children with hematologic malignancies, children undergoing hematopoietic stem cell or organ transplantation, children with abdominal surgery and/or critically ill children admitted to an intensive care unit, and those with specific inborn errors of immunity, are at the highest risk to develop candidemia and invasive candidiasis (IC).1 The clinical presentation of candidemia is indistinguishable from bacterial bloodstream infections. Specific risk factors and clinical characteristics associated with neonatal candidemia are very low birth-weight (<1000 g), receiving broad-spectrum antibiotics and/or parenteral nutrition, abdominal surgery, thrombocytopenia and occurrence in the 3rd week of life. For infants and children, chemotherapy-induced neutropenia and mucositis, receiving prolonged broad-spectrum antibiotics and abdominal surgery are among the well-known risk factors.2,3 Incidence of neonatal IC (including candidemia) ranges between 0.5% and 2% in high-income countries and between 1.5% and 6.3% in low- and middle-income countries (LMICs), with higher rates in low birth weight and premature neonates (birth weight ≤ 1500 g and/or gestational age ≤ 28 weeks).3,4 Overall case-fatality rates range from 9% to 40% with higher rates in LMICs. Rates for pediatric candidemia are lower compared with those for neonates and range between 0.25 and 2.6/100,000 population, with a mortality rate of 10%–15%.1,5,6 Candida albicans and C. parapsilosis are the predominant species causing IC in neonates and children, followed by C. tropicalis, C. glabrata and C. krusei. Alarming is the change in the global fungal epidemiology with a rise in infections caused by C. auris, a multidrug-resistant Candida species, especially in neonates in LMICs, and an increase in fluconazole-resistant C. parapsilosis.4,7,8 To allow for timely guidance for the best management approach, global guidelines for the diagnosis and management of candidiasis have recently been published.9 Below, we have summarized the key recommendations for the management of candidemia and IC in neonates and children. INVASIVE CANDIDIASIS IN CHILDREN Diagnosis Blood cultures and cultures, direct microscopy and histologic examination of tissue samples are the gold standard for diagnosing candidemia and IC, respectively. Nevertheless, the sensitivity of blood cultures is low (40% positive in IC), and the median time to positivity is 2–3 days.10 Molecular detection methods are only moderately recommended due to lack of standardization and limited capacity for species differentiation. A negative polymerase chain reaction (PCR) test, though, may rule out IC with a high degree of certainty.11 The commercially available T2Candida panel automatically identifies 5 Candida species (albicans, parapsilosis, tropicalis, glabrata and krusei) directly from whole blood based on multiplex PCR and T2 magnetic resonance detection. Two pediatric studies have shown a good sensitivity (80%–100%) and specificity (94.1%–97.1%).12,13 Together with a significantly shorter time to obtaining a result (mean 3.7 ± 0.7 hours vs. 125.5 ± 20.8 hours), the T2 Candida panel has promise in optimizing the diagnosis of pediatric candidemia. β-D-glucan testing in pediatric patients has been shown to have a very poor positive predictive value (3%) with a sensitivity of 9.1% and specificity of 85.4% and is therefore not recommended to be used for the diagnosis of pediatric candidiasis.12 Imaging techniques, such as computed tomography or magnetic resonance imaging, are valuable to diagnose involvement of individual organs depending on clinical signs and symptoms. Prolonged candidemia (eg, > 3 days) can result in metastatic foci of infection in abdominal organs, the endocardium, and the eyes. Screening by echocardiography and ophthalmological examination is therefore recommended. Chronic disseminated candidiasis (eg, hepatosplenic candidiasis) is a phenotype of IC observed in children with leukemia, clinical characterized by persistent fever after neutrophil recovery, abdominal pain and increased alkaline phosphatase and gamma-glutamyl transferase.14 Blood cultures are often negative with characteristic lesions detected by CT imaging of the liver, spleen and/or kidneys.15 Prophylaxis Only limited data are available in the pediatric setting, and recommendations are mainly derived from adult studies. Fluconazole prophylaxis (12 mg/kg/d, max 400 mg) may be considered for pediatric intensive care unit patients at high risk for IC and for high-risk liver and small bowel/pancreas transplant patients.9 Children with acute myeloid leukemia, high-risk or recurrent acute lymphatic leukemia and those undergoing allogeneic hematopoietic stem cell transplantation should receive antifungal prophylaxis with coverage for molds unless the institutional incidence of mold infections is very low. Posaconazole is the recommended antifungal agent in these patient populations. If oral azoles are contraindicated due to drug–drug interactions (eg, vincristine) or not tolerated, caspofungin or liposomal amphotericin B are alternative options.9 Treatment The management principles of IC are similar for neonates, children and adults and include timely targeted antifungal therapy, removal of indwelling intravascular catheters and other prosthetic devices, alongside surgical source control as appropriate.9 Antifungal therapy for candidemia is typically continued for 14 days after clearance of Candida from the bloodstream, defined by 2 negative blood cultures.9 Clearance of infectious foci in specific organs and resolution of clinical signs and symptoms will determine the duration of treatment in tissue IC, including central nervous system (CNS) candidiasis. For Candida endocarditis, the minimum treatment duration is 12 weeks.9 An echinocandin or liposomal amphotericin B is strongly recommended as first-line treatment, with the echinocandins providing a better safety profile.9 For CNS candidiasis, liposomal amphotericin B with/without flucytosine is recommended due to limited exposure of echinocandins in the CNS. For Candida endocarditis in the presence of a prosthetic valve, liposomal amphotericin B with/without flucytosine is preferred.9 First-line treatment with fluconazole might be considered in azole-naïve patients and in places with low fluconazole-resistant IC. Fluconazole is an attractive antifungal for switching to oral therapy in patients infected with fluconazole-susceptible Candida isolates. INVASIVE CANDIDIASIS IN NEONATES Diagnosis The diagnosis of neonatal IC remains challenging. Clinical presentation is often indistinguishable from late-onset bacterial sepsis. Blood cultures remain the gold standard diagnosis, but their sensitivity might be reduced in neonates due to the limited blood volumes available for culture.3 Among nonculture-based methods, PCR-based methodologies are potentially of clinical value. In a case–control study, PCR performed on blood and serum demonstrated a sensitivity and specificity of 87.5% and 81.6%, respectively, for the diagnosis of neonatal IC.16 The role of the T2 Candida platform in neonates remains to be defined and might be challenging, as a minimum of 2 mL of blood is needed for this assay. Similarly to older children, the use of serum beta-D-glucan testing in neonates is not recommended. Whereas a meta-analysis estimated sensitivity and specificity values of 89% (80–94%) and 60% (54–66%), respectively, using a threshold of 80 pg/mL17; the optimal cutoff value remains poorly defined with higher baseline levels in neonates compared with older children and adults.18 While beta-D-glucan measurement in cerebrospinal fluid may assist in the diagnosis of Candida meningoencephalitis, further studies are required before its use can be recommended.19 Positive urine cultures in neonates require careful interpretation. Neonates with candiduria show morbidity and mortality rates like those with candidemia; thus, a positive urine culture in a high-risk neonate should be considered as clinically significant as a positive blood culture.20Candida meningoencephalitis develops in 15% of preterm infants with candidemia.21 Other commonly affected organs include the heart (5%), kidneys (5%) and eyes (3%).21 Once candidemia is diagnosed, further evaluation for disseminated infection is indicated. Recommended investigations include lumbar puncture for cerebrospinal fluid analysis and culture, dilated ophthalmologic examination, echocardiography, abdominal ultrasound and neuroimaging.3,9 Prophylaxis In institutions with a neonatal IC incidence >2% and low fluconazole-resistance rates, fluconazole prophylaxis is strongly recommended for high-risk preterm neonates (ie, extremely low birth weight <1000 g).9 Of note, recommendations for neonatal antifungal prophylaxis are based on the epidemiology of high-income countries. Recent studies have shown that in LMIC settings, the clinical risk profile is different.4,22 Fluconazole can be administered in various dosing regimens for the first 6 weeks of life or until discharge. Prophylaxis with fluconazole has been shown to significantly reduce neonatal IC rates in high-risk preterm infants.23 It is generally well tolerated and appears to have minimal impact on antifungal resistance.24 Nystatin is recommended as an alternative and might be considered in neonatal settings with high incidences of fluconazole-resistance.25 Alternative preventive strategies, such as oral lactoferrin (alone or combined with Lactobacillus species) until day 30 of life, are moderately recommended, although the supporting evidence remains limited.9 Treatment First-line treatment options with comparable efficacy include amphotericin B deoxycholate, liposomal amphotericin B, and the echinocandins micafungin and caspofungin.9 Nephrotoxicity due to amphotericin B formulations is less frequently observed compared with older children and adults. Fluconazole is a suitable alternative for neonates without prior azole exposure and in settings with a low level of fluconazole resistance. Pharmacokinetic studies support the higher dosages recommended for fluconazole and micafungin in neonates and have shown that to achieve adequate exposures in the CNS.26,27 Despite the favorable CNS penetration of fluconazole and the supportive pharmacokinetic animal data for micafungin, evidence for its use in hematogenous Candida meningoencephalitis is still limited.9 Evidence for the combined use of amphotericin B and flucytosine to treat neonatal Candida meningoencephalitis is derived from the clinical trials in cryptococcal meningitis.28 Therapeutic drug monitoring of flucytosine is required due to the risks of bone marrow suppression, hepatic and renal toxicity.9 Obstructive renal fungal bezoars may need local irrigation with amphotericin B deoxycholate via nephrostomies in addition to systemic treatment with fluconazole or amphotericin B deoxycholate.29 CONCLUSIONS Timely management of pediatric and neonatal candidemia and IC remains challenging, due to the nonspecific clinical presentation, indistinguishable from bacteremia and severe bacterial infections. Recognizing the neonate or child being at risk of developing IC is a first step in allowing timely diagnostic work-up and treatment.2 Different clinical risk profiles globally for developing neonatal candidemia or IC require adaptation of preventive management strategies to ensure protection of the most vulnerable neonates. Standard infection prevention and control (IPC) measures, such as hand hygiene, central-line care bundles and environmental cleaning, remain the most cost-effective interventions to prevent healthcare-associated infections, including those caused by Candida spp.9,30 Enhanced IPC measures are indicated when resistant Candida species are detected and when a cluster of cases is identified. Outbreaks of neonatal IC with fluconazole-resistant Candida species are increasingly being reported, especially in LMICs.31 Specific guidance for IPC measures against IC has been targeted to the multidrug-resistant C. auris, but those recommendations are relevant generally for IC caused by other Candida species.9 Conventional direct microscopy and culture-based methods are still the mainstay of diagnosis. Lack of resources for identification to species level and performance of antifungal susceptibility, particularly in LMICs, negatively impacts the outcome of neonatal and pediatric candidemia and IC.22 Access to the first-line recommended antifungals and therapeutic drug monitoring is a challenge in many parts of the world, contributing to increased morbidity and mortality among pediatric and neonatal patients. The aim of the global guideline for the diagnosis and management of candidiasis,9 summarized for the neonatal and pediatric population in this concise review, is to support the provision of best-practice multidisciplinary care for patients across the world. This global guideline provides a valuable management tool to be adapted to local settings.