Invasive Candidiasis In Neonates Research Articles

Changes in the incidence of candidiasis in neonatal intensive care units.

Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time. We examined data from 709,325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year. We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750-999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010. The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.

ESCMID guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.

Invasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin ± Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.

Results From a Prospective, International, Epidemiologic Study of Invasive Candidiasis in Children and Neonates

Candida species are the third most common cause of pediatric health care-associated bloodstream infection in the United States and Europe. To our knowledge, this report from the International Pediatric Fungal Network is the largest prospective, multicenter observational study dedicated to pediatric and neonatal invasive candidiasis. From 2007 to 2011, we enrolled 196 pediatric and 25 neonatal patients with invasive candidiasis. Non-albicans Candida species predominated in pediatric (56%) and neonatal (52%) age groups, yet Candida albicans was the most common species in both groups. Successful treatment responses were observed in pediatric (76%) and neonatal patients (92%). Infection with Candida parapsilosis led to successful responses in pediatric (92%) and neonatal (100%) patients, whereas infection with Candida glabrata was associated with a lower successful outcome in pediatric patients (55%). The most commonly used primary antifungal therapies for pediatric invasive candidiasis were fluconazole (21%), liposomal amphotericin B (20%) and micafungin (18%). Outcome of pediatric invasive candidiasis was similar in response to polyenes (73%), triazoles (67%) and echinocandins (73%). The most commonly used primary antifungal therapies for neonatal invasive candidiasis were fluconazole (32%), caspofungin (24%) and liposomal amphotericin B (16%) and micafungin (8%). Outcomes of neonatal candidiasis by antifungal class again revealed similar response rates among the classes. We found a predominance of non-albicans Candida infection in children and similar outcomes based on antifungal class used. This international collaborative study sets the foundation for large epidemiologic studies focusing on the unique features of neonatal and pediatric candidiasis and comparative studies of therapeutic interventions in these populations.

Neonatal invasive candidiasis in Tunisian hospital: incidence, risk factors, distribution of species and antifungal susceptibility

The aim of our study was to assess epidemiological features of neonatal invasive candidiasis in Farhat Hached hospital of Sousse, Tunisia, including incidence, risk factors, mortality, species distribution and antifungal susceptibility. Laboratory data from 1995 to 2010 and medical records of 127 invasive candidiasis cases were reviewed. We tested the susceptibility of 100 Candida sp isolates by using ATB fungus(®) 3 and to fluconazole by using E-test(®) strips. A total of 252 cases of neonatal invasive candidiasis occurred over the study period. The incidence increased 1.8-fold from 1995 to 2006 and decreased fourfold from 2007 to 2010. Candida albicans was the predominant species up to 2006 and a shift in the species spectrum was observed with increase of the non-albicans species mainly C. parapsilosis. The agreement between the ATB Fungus(®) and the E-test(®) for determining fluconazole susceptibility was high. All tested isolates were susceptible to fluconazole, flucytosine, amphotéricine B and voriconazole and the itraconazole resistance rate was 5%. The mortality rate was 63%. The invasive candidiasis incidence increased from 1995 to 2006 and decreased from 2007 to 2010. The spectrum of Candida species and the lack of fluconazole-resistant strains argue for the usefulness of fluconazole as an empiric treatment.

Investigation of a Cluster ofCandida albicansInvasive Candidiasis in a Neonatal Intensive Care Unit by Pulsed-Field Gel Electrophoresis

Nosocomial invasive candidiasis (IC) has emerged as a major problem in neonatal intensive care units (NICUs). We investigated herein the temporal clustering of six cases of neonatal IC due to Candida albicans in an NICU. Eighteen isolates obtained from the six neonates and two isolates from two health care workers (HCWs) working at the same unit and suffering from fingers' onychomycosis were genotyped by electrophoretic karyotyping (EK) and restriction endonuclease analysis of genomic DNA by using Sfi I (PFGE-Sfi I). PFGE-Sfi I was more effective in discriminating between temporally related isolates. It showed that (i) both HCWs had specific strains excluding them as a source of infections in neonates. (ii) Isolates collected from three neonates were identical providing evidence of their clonal origin and the occurrence of a horizontal transmission of C. albicans in the unit. (iii) The three remaining neonates had specific strains confirming that the IC cases were coincidental. (iv) Microevolution occurred in one catheter-related candidemia case. Our results illustrate the relevance of the molecular approach to investigate suspected outbreaks in hospital surveys and the effectiveness of PFGE-Sfi I for typing of epidemiologically related C. albicans isolates.

Efficacy of CG3R6TAT Nanoparticles Self-Assembled from a Novel Antimicrobial Peptide for the Treatment of Candida albicans Meningitis in Rabbits

Background: Candidal meningitis is a common clinical manifestation of invasive candidiasis in neonates. The aim of this study was to evaluate the in vivo antifungal efficacy of CG₃R₆TAT nanoparticles, novel core-shell structures self-assembled from cationic antimicrobial peptides, in a rabbit model of candidal meningitis. Methods: In vitro activity of CG₃R₆TAT nanoparticles against Candida albicans was assessed by determining the minimum inhibitory concentration and kill-time curves. In vivo, intravenous treatment with CG₃R₆TAT nanoparticles (n = 6; 0.25 mg/kg/day) or fluconazole (n = 6; 100 mg/kg/day) began 3 days after infection and continued for 11 consecutive days; the efficacy was assessed following 11 days of treatment by yeast counting in cerebrospinal fluid (CSF), the leukocyte concentrations in CSF and the histopathology of brain parenchyma. Results: At a concentration three times higher than the minimum inhibitory concentration (8.1 µmol/l), the nanoparticles complete- ly sterilized C. albicans after 5 h of incubation. In addition, there was a significant reduction in fungal counts and leukocyte concentrations in the CSF from rabbits treated with CG₃R₆TAT nanoparticles or fluconazole versus those from untreated control rabbits (p < 0.05, ANCOVA). The median number of days of treatment required to sterilize CSF cultures was 8.5 days for CG₃R₆TAT nanoparticle therapy (p = 0.022, vs. control) and 9.7 days for fluconazole therapy (p > 0.05, vs. control). The histopathologic severity of rabbits was significantly attenuated after CG₃R₆TAT treatment (p = 0.001, vs. control). Conclusion: This study suggests that CG₃R₆TAT nanoparticles may be a promising therapeutic agent for candidal meningitis.

Candidoses invasives en réanimation néonatale

In the USA, the incidence of invasive candidiasis in neonates is respectively 0.3% of infants over 2500 g and up to 20% of infants less than 1000 g. Their incidence is increasing. Two populations of newborn infants are particularly vulnerable: the premature infants and newborn infants with severe neonatal digestive diseases. Fifty percent of infants hospitalized in NICU are colonized with Candida at the end of the first week of hospitalization; a direct relationship exists between the importance of colonization and the invasive infection risk. C. albicans is the species most often responsible for invasive candidiasis in the newborn. These infections represent the third cause of related-catheter infection in the USA. Mortality rate in neonates linked to this disease is 20 to 50%; morbidity primarily concerns brain and lungs. Neonatal invasive candidiasis risk factors are known and a primary prevention is possible. The diagnosis of neonatal invasive candidiasis is difficult and often delayed because of a polymorphic clinical expression. Empiric and preemptive treatment are based on the use of amphotericin B. Prophylactic treatment using fluconazole of newborns with birth weight ≤ 1000 grams and/or gestational age ≤ 27 weeks gestation is recommended by the American Academy of Paediatrics and the Infectious Diseases Society of America. A better knowledge of French epidemiological data in this area would improve both the diagnosis and therapeutic management of this disease.

Invasive candidiasis in neonates and children

Invasive candidiasis is associated with high morbidity and mortality in neonates and children. The incidence of invasive candidiasis is greater in children than in adults and is particularly high in neonates. Main risk factors are multiple antibiotics, central venous catheters, parenteral nutrition, immunodepression, low birth weight, fungal colonization, and necrotizing enterocolitis. Successful management of IFIs relies on early recognition and rapid initiation of effective treatment.

Neonatal Invasive Candidiasis in Spain. An epidemiological study from the “Grupo de Hospitales Castrillo”

Introduction: Invasive fungal infections, especially Candidemia have emerged as an increasing problem among high risk neonates because of their immature host defenses, frequent exposure to invasive diagnostic and therapeutic procedures, and prolonged hospital stay. Objective: to assess the epidemiology of neonatal invasive candidiasis in our country (Spain). Patients and methods: The data of neonatal invasive candidiasis (NIC) were obtained from a prospective multicenter epidemiological study of nosocomial neonatal sepsis in VLBW infants (birth weight Results: In a total of 7,101 admissions to the neonatal units of the participating hospitals, 2,152 nosocomial sepsis were reported (30.3%), 195 of them were candidemias (2.75%). The incidence of candidemia was significantly higher in tertiary care (referral) hospitals as compared with non-referral hospitals (4.26% vs 1.03%). In relation to the etiology of nosocomial sepsis, Candida spp was the third more frequently isolated pathogen (9.0%) after S. epidermidis (49.8%) and Klebsiella (11.0%). In 96% of infants with candidemia 4 or more risk factors were reported. C. parapsilosis was the pathogen most frequently recovered (42%) followed by C. albicans (38.5%), C. tropicalis (6.15%) and C. glabrata (4.6%). The most frequently antifungal treatment used was liposomal amphotericin B (76.8% of cases) followed of fluconazol (11%). In five infants treatment was not started. The average treatment length was 18 days (range 1-59). Overall mortality rate was 24.1 % and was higher the mortality associated to C. albicans and C. tropicalis (33.0%) compared to C. parapsilosis (17.5%). Prophylactic fluconazol was not used in any hospital. Any isolated Candida species showed resistance to amphotericin B, 3.9% to 5-fluocytosine and 0.9% to fluconazol. Conclusions: Candida spp is a frequently isolated pathogen in nosocomial neonatal sepsis and with a high associated mortality. C. parapsilosis is the most frequently isolated species in our country. All isolated Candida species were sensitive to amphotericin B.

Population Pharmacokinetics of Fluconazole in Young Infants

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Outcomes Attributable to Neonatal Candidiasis

The incidence of candidiasis has increased in neonatal intensive care units, and invasive candidiasis is associated with significant morbidity and mortality. However, few data exist on outcomes directly attributable to neonatal candidiasis. We estimated the incidence of systemic candidiasis in hospitalized neonates within the United States and determined the attributable mortality, length of hospital stay, and associated costs. We used the 2003 Kid's Inpatient Database from the Healthcare Cost and Utilization Project. Systemic candidiasis and comorbidities were defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Neonates with uncomplicated births and neonates who died within the first 3 days of life were excluded. We used propensity score methods to balance covariates between the neonates with and neonates without candidiasis. Attributable outcomes were calculated between propensity score-matched neonates with and neonates without candidiasis. Because of the known confounding effect of birth weight, we performed separate propensity score analyses for extremely low birth weight (ELBW) neonates (i.e., neonates weighing < 1000 g). The overall incidence of invasive candidiasis in neonates is 15 cases per 10,000 neonatal admissions (95% confidence interval [CI], 13-16 cases per 10,000 neonatal admissions). ELBW neonates with invasive candidiasis were 2 times more likely to die (odds ratio, 2.2; 95% CI, 1.4-3.5) than propensity-matched ELBW neonates without candidiasis. The propensity score-adjusted mortality rate attributable to candidiasis among ELBW neonates was 11.9%. Candidiasis in ELBW infants was not associated with an increase in length of hospital stay but was associated with a mean increase in total charges of $39,045 (95% CI, $1374-$76,715). Among infants with a birth weight > or = 1000 g, those who had candidiasis did not experience a significant increase in mortality, compared with infants without candidiasis. However, the propensity score-adjusted length of stay and charges attributable to candidiasis among neonates with a birth weight > or = 1000 g were 16 days (95% CI, 8-24 days) and $122,302 (95% CI, $80,457-$164,148), respectively. Invasive candidiasis is associated with a significantly increased risk of death and excess hospital charges in ELBW neonates and with excess hospital stay and excess hospital charges in neonates with a birth weight > or = 1000 g.

173 Fungal Colonization of Newborn in Neonatal Intensive Care Unit: A Prospective Study

Background. Invasive candidiasis in neonates has become an increasing problem over the past decade in Neonatal Intensive Care Units (NICUs) in the world; it is a relatively common cause of late onset sepsis associated with a high mortality. Risk factors are preterm babies who require invasive diagnostic and aggressive therapeutic procedures, prior antibiotic therapy, congenital abnormalities, gastrointestinal tract diseases, necrotizing enterocolitis and anatomical abnormalities requiring surgery. Prior colonization is the major risk factor for candidemia. Methods. To determine the rate of colonization, risk factors and the possible modes of acquisition of Candida spp. In neonates in NICU, we conducted a prospective cohort study including 48 successive admissions at NICU of Pediatric University Hospital, Sarajevo, during 3 months. Samples (mucocutaneous swabs, urine, stool, blood) were obtained weekly until the time of discharge or death (one infant enrolled in the study exited). Care health worker hands were cultured weekly (55 samples). Results. Candida spp. from various body sites samples were isolated in 7 patients (rate of colonization 14,8%) while 7 samples of health workers hands were positive for C. spp (14,5%). Patients colonizated or infected by Candida spp. In our study were or very preterm newborns (3/7) or compromised term newborns (4/7), with congenital abnormalities (2/7) or gastrointestinal surgical interventions (2/7). Two very preterm neonates were colonized early from the birth, which indicates possible vertical transmission. In other 5 patients, colonization occurred more lately, after at least 15 days stay in NICU, which indicates nosocomial transmission as a predominant mode of acquisition. Among 10 positive patterns from different body sites, Candida albicans was isolated in 6 cases; other 4 cases were C. glabrata (2/10), C. krusei (1/10) and C. famata (1/10). Conclusions. Rather than focusing on methods of identifying of pregnant women with vaginal Candida colonization, attention should be directed to high risk neonates and infection control measures including hands washing by health care workers.

Caspofungin Therapy of Neonates With Invasive Candidiasis

Invasive candidiasis is an increasing problem in neonatal intensive care units worldwide and is an important cause of morbidity, mortality and prolongation of hospital stay. Despite administration of amphotericin B, invasive candidiasis in neonates is sometimes complicated by persistent fungemia and refractory invasive candidiasis. The problem has been augmented by the increasing prevalence of non-albicans species that often are resistant to fluconazole and to amphotericin B. The population consisted of 1 term and 9 premature neonates with invasive candidiasis caused by Candida albicans (n = 4), Candida parapsilosis (n = 3), Candida tropicalis (n = 2) and Candida glabrata (n = 1). Despite initial therapy with deoxycholate amphotericin B, blood cultures remained positive in all patients for 13-49 days. Invasive candidiasis progressed to meningitis and enlarging renal Candida bezoars in the kidney of one patient and an enlarging atrial vegetation in another. Another patient developed severe hypokalemia refractory to potassium supplementation. Two of the C. albicans and all of the non-albicans Candida isolates were resistant to fluconazole; the C. glabrata isolate was resistant to amphotericin B. Amphotericin B was discontinued and caspofungin initiated in all patients in a dosage of 1 mg/kg/d for 2 days followed by 2 mg/kg/d. All positive blood cultures cleared between 3 and 7 days after initiation of caspofungin, the atrial vegetation resolved and the renal Candida bezoars disappeared. Renal and hepatic function tests did not show any values above normal throughout caspofungin therapy. There were no attributable clinical adverse events during the administration of caspofungin in any of the patients. Caspofungin was effective, safe and well-tolerated as an alternative therapy for persistent and progressive candidiasis in those neonates who were unresponsive to or intolerant of deoxycholate amphotericin B.

Neonatal invasive candidiasis: a prospective multicenter study of 118 cases.

A prospective multicenter study was conducted to assess the epidemiology of neonatal invasive candidiasis in Spain. In a total of 20,565 admissions to the 27 participating neonatal units over an 18-month period, systemic candidiasis was diagnosed in 118 (0.57%) neonates. Candida species were isolated from the blood in 79 infants, from the urine in 33, and from the cerebrospinal fluid in 4; in 2 cases, histologic evidence of deep tissue candidiasis was found at autopsy. Very-low-birth-weight (VLBW) infants (< or = 1500 g) showed a significantly higher incidence of systemic candidiasis (4.8%) than infants weighing > 1500 g (0.2%) ( p < 0.001). Candida albicans was the most frequent species (52.5%) followed by C. parapsilosis (23.7%), and C. tropicalis (7.6%). Only seven infants were treated with amphotericin B (initial dose 0.18 +/- 0.3 mg/kg, maximal daily dose 1.7 +/- 0.9 mg/kg) but treatment was stopped in three of them (43%) due to nephrotoxicity. Liposomal amphotericin B was given to 81 neonates and amphotericin B lipid complex to 29. There were no differences in mortality rate and in the incidence of adverse effects in relation to treatment with liposomal amphotericin B or amphotericin B lipid complex. The mortality rate was 10.2% and all deaths occurred in the VLBW cohort with candidemia.