Overview
Invasive candidiasis in neonates is a serious and relatively common cause of late onset sepsis associated with a high mortality. A review of the first 26 cases reported in the English literature up to 1984 reported a mortality rate of 54% [1128]. More recent data from the (A):NICHD Neonatal Research Network centers reported a death rate of 28.1% in the neonates with fungemia [2170].
Premature neonates and particularly low birth weight infants require invasive diagnostic and aggressive therapeutic interventions, many of which increase the risk factors for developing Candida infections (see below). In addition the immaturity of the immune system specially among preterm neonates, which mainly involves T-cells and neutrophils, further predisposes this population to infections [2439]. Indeed, the anti-Candida activity of lung macrophages in neonates has been shown to be reduced [211, 770].
Neonatal candidiasis can be subdivided into two categories:
- Catheter-related candidemia
- Disseminated or invasive candidiasis
Catheter-related candidemia refers to infants with central vascular catheters in place and candidemia that resolves rapidly after catheter removal and initiation of therapy. Disseminated or invasive candidiasis refers to persistent candidemia if a catheter was in place and removed, and/or the isolation of Candida from other normally sterile body sites. However, as in adults, there are no clinical criteria or diagnostic tests that allow a differentiation of these two groups at presentation [351].
Up to 75% of cases of neonatal candidiasis present with infection of two or more organs. Unifocal osteomyelitis, meningitis, and renal candidiasis are the most common presentations, otherwise infection of any combination of blood, kidneys, meninges, heart, eye, bones, or joints [1128].
A distinctive form of cutaneous candidiasis that may become invasive and that is known as (A):Congenital Candidiasis is discussed separately below.
Epidemiology
The incidence of invasive candidiasis in neonatal care units ranges between 1.6 and 4.5% [164, 708, 1128]. More recent data from the NICHD Neonatal Research Network centers on late-onset sepsis in very low birth weight neonates, has reported that fungal pathogens explain 9% of all bloodstream infections [2170].
Neonates may acquire Candida by vertical or nosocomial transmission [1885, 2346]. In vertical transmission, acquisition may occur either during gestation or at the time of delivery. In both cases an ascending route from the mother’s vagina is involved. Vaginal candidiasis occurs frequently among pregnant women, especially in the last trimester. Rates as high as 56% have been reported [771].
Candida carriage rates among neonates vary between 30 to 60% [1720]. Interestingly as gestational age falls, the rates of candidal colonization appear to rise [2088]. Acquiring Candida does not always translate into systemic infection, but previous colonization is a required step before the occurrence of invasive candidiasis.
Candidal nosocomial acquisition is being recognized as a very important form of transmission in the neonatal ICU (NICU) [1885]. Indeed, important outbreaks of candidemia in NICU have been identified [709, 731, 1880]. Such colonization is actually a general phenomenon: hand carriage rates among health workers in seven SICU across the USA have been found to be of around 30% [1871].
Risk Factors For Neonatal Candidiasis
| Risk factors | Comments | References |
|---|---|---|
| Classic (also described in adults) | ||
| Use of multiple antibiotics | Length of antibiotic treatment is as important as the spectrum of the regimen used | [2392] |
| Central venous catheters | [2392] | |
| Parenteral hyperalimentation and intravenous fat emulsion | [2392] | |
| Colonization with Candida and/or previous episode of mucocutaneous candidiasis | [710, 1720, 1978] | |
| Risk factors unique to this age group | ||
| Low birth weight | ~ 90% of affected neonates are very low birth weight (<1500 gr) | [710] |
| Endotracheal tubes and tracheostomies | Many neonates have some type of respiratory insufficiency | [2392] |
| Peripheral venous catheters | Leibovitz, 1992 #512] | |
| Congenital malformations, GI malformations and congenital heart diseases are the most frequent | Most frequently seen in infants > 2,500 gr at birth with prolonged NICU hospitalization | [1862] |
| Gastrointestinal tract diseases | Necrotizing enterocolitis and anatomical abnormalities requiring surgery | [710] |
Neonatal Candidiasis and Candida species
Initial reports on neonatal candidiasis consistently found Candida albicans to be responsible for the majority of cases [351, 710]. However, similar to change of the epidemiologic patterns that has been observed in adults, a changing spectrum of species is being noted among neonates. This change is characterized by a progressive decrease in the rate of isolation of Candida albicans and an emergence of non-albicans species [731, 1871]. Unlike the situation with adults however, it is Candida parapsilosis that is becoming the most prevalent species. In some centers it has replaced C. albicans as the most frequent species [1327].
| Reference | Place | N | Frequency (%) for each Candida species | ||||
|---|---|---|---|---|---|---|---|
| C. albicans | C. tropicalis | C. glabrata | C. parapsilosis | Others | |||
| [710] | USA | 16 | 88 | 0 | 0 | 12 | 0 |
| [351] | USA | 30 | 73 | 13 | O | 10 | 1(1) |
| [1315] | Israel | 25 | 71 | 0 | 0 | 4 | 25 (2) |
| [1327] | USA
1 center |
35 | 26 | 3 | 0 | 68 | 3 |
| [1871] | USA | 35 | 63 | – | 6 | 29 | 3 |
- One case of C. lusitaniae
- One case of C.krusei
Clinical Manifestations
The classic clinical picture of systemic candidiasis in neonates is indistinguishable from bacterial sepsis [164]. All of the following signs may be seen:
- Temperature instability
- Hypotension
- Respiratory deterioration and apnea
- Abdominal distension
- Guaiac positive stools
- Carbohydrate intolerance
Among these, respiratory dysfunction and apnea were the most common presenting signs in large series, being present in about 70% of cases [2284].
A significant proportion of neonates will present simultaneously with localized signs of candidal infection at one or more other sites:
- Skin and mucous membranesMucocutaneous candidiasis in neonates may present with the classic thrush, diaper rash and/or any variety of this erythematous rash with papules and/or pustules affecting usually wet cutaneous surfaces [710]. Skin abscesses have also been described [1315]. However, the most common presentation is perineal candidiasis [710]. It is important to emphasize that even when any of these forms of mucocutaneous candidiasis may precede the appearance of systemic disease, this is not a pathognomonic or required condition. Prospective evaluation of this association has found that 44% of neonates with invasive candidiasis never developed skin lesions [710]. However, the same analysis did demonstrate that neonates who developed mucocutaneous candidiasis had a higher risk of developing later deep organ Candidal infection [710].
Two unique varieties of neonatal candidal skin diseases are:
- (A):Cutaneous Congenital Candidiasis
- Invasive Fungal Dermatitis. This recently described skin disorder [1977] affects extremely low birth weight neonates. Characteristic ulcerative and erosive lesions with extensive crusting are seen. Even when other fungal pathogens have been implicated in this entity, Candida spp. are responsible for about 70% of cases [1977]. More than half of these Candida-related skin infections were associated with the occurrence of invasive candidiasis. Authors describing this picture and others have postulated that immature skin becomes in these cases the portal of entry for Candida [1516, 1977].
- Central nervous systemAmong neonates Candida meningitis is one of the most common manifestations of invasive candidiasis [164, 433, 708]. Up to 64 percent of neonates dying with invasive candidiasis have CNS involvement and more than 2/3 of these babies have positive (A):CSF cultures at some point in their disease [708].
Neurologic clinical manifestations in this particular population are few and related to increased intracranial pressure (buldging fontanelle and splitting sutures). Instead, general signs of sepsis and progressive clinical deterioration are commonly found [708]. In other words, Candida meningitis usually presents as part of the syndrome of invasive or disseminated candidiasis. Therefore, a physician dealing with sepsis in a high risk neonate, should suspect Candida meningitis if Candida spp. is recovered from the blood, urine or other site suggestive of heavy colonization [708].
Candida meningitis carries a high rate mortality and for survivors a high incidence of severe sequelae (hydrocephalus, psychomotor retardation, and aqueductal stenosis) [433].
- EyesThe use of fundoscopic exam has been recommended as a tool for early diagnosis of invasive disease. The only prospective study evaluating neonates with either candidemia or CSF positive for Candida found an incidence of Candida endophthalmitis of 50% [162].
- HeartCandidal endocarditis has been found to be the second most common form of endocarditis in this age group [506, 1662]. Clinically, classic findings are expected, including cardiac murmurs, petechiae, skin abscesses, arthritis, hepatomegaly and splenomegaly [506]. Right-sided intracardiac fungal masses can manifest with heart failure or even with pulmonary fungal embolism [1128] [867, 1472].
- KidneysCandidal UTI is the most frequent cause of urinary tract infection in the (A):NICU [1787]. About half of these babies are found to have concomitant candidemia [1787]. In addition, this population is particularly predisposed to suffer renal candidiasis, which refers to renal (A):fungus balls or renal fungal abscesses. Between 35 to 42% of neonates hospitalized at NICU with candiduria will have renal candidiasis, and the large majority of these cases are indeed fungus balls [330, 1787]. Unilateral or bilateral renal obstruction may occur [330, 1787]. Renal insufficiency could be the first clinical manifestation of invasive candidiasis [2336].
- Bones and JointsCandida spp. have been repeatedly listed among the three most common agents causing neonatal arthritis [507, 1689, 1807]. Warmth and fusiform swelling of the lower extremities in combination with radiographic evidence of osteolysis and cortical bone erosion are the expected findings in cases of candidal osteomyelitis and/or arthritis in the neonate [2375, 2396].
Specific Diagnostic Strategies
For general concepts on diagnostic procedures please review our (A):general discussion of the diagnosis of invasive candidiasis. However, for the most part the concepts discussed in that page come from data on adult populations.
Invasive candidiasis in neonates is different in that the recovery rate of cultures seems to be higher and localized manifestations more frequent [1128]. Johnson et. al analyzed 31 cases of invasive candidiasis in infants and reported the following most frequent sites from where Candida was isolated [1128]:
| Sites | Recovery rate |
|---|---|
| CSF | 52% |
| Urine | 48% |
| Blood | 45% |
| Bones/Joins | 26% |
| Eye | 23% |
| Lung | 13% |
| Peritoneum | 13% |
Despite these data, at least 20% of babies with evidence of candidal deep organ infection at autopsy were culture negative during life in one study [1128].
In conclusion, a positive culture for Candida spp. recovered from an infant at high risk to develop invasive candidiasis should never be disregarded. In addition, Candida spp. always should be considered in the differential diagnosis of sepsis in the neonate, particularly late onset sepsis [473]. A thorough evaluation to rule out disseminated candidal infection in infants with this syndrome should be done routinely by:
- completing a microbiological evaluation of blood, urine, and CSF
- a clinical evaluation of the retina [162]
- an echocardiographic evaluation of the heart
- a renal ultrasound [644, 1264]
Some authors advocate performing serial ultrasound. Bryant et. al. studied 41 infants with candiduria hospitalized at NICU and found that the time to develop abnormalities detectable by ultrasound was 8 to 39 days from the detection of candiduria [330]. If clinical evidence of arthritis or osteomyelitis is present, then a complete skeletal survey and synovial or bone aspiration should be included in the assessment [320].
Therapies
For general concepts on therapeutic strategies please review the discussion of (A):therapy of invasive candidiasis. Most data for the treatment of any form of invasive candidiasis in children and neonates has been extrapolated from studies in older patients.
The ways in which neonates differ in terms of relevant strategies are increasingly appreciated. Important differences on the pharmacokinetics but particularly on the toxicity profile of available antifungal agents have been demonstrated. As we will discuss, the both classic but toxic antifungal agents, amphotericin B and 5-fluorocytosine, cause minimal side effects in neonates and the combination of these two agents for the treatment of neonatal candidiasis has been extensively used and advocated [164, 630, 708, 1128, 1315, 2392].
- Amphotericin B
Initial reports on the use of amphotericin B in neonates were somewhat alarming. In particular, the report by Baley et al. implicated this agent in a high mortality rate in 10 infants with invasive candidiasis and caused skepticism among neonatologists [163, 2284]. However, confounding factors such as previous renal insufficiency and the simultaneous use of other nephrotoxic agents were not considered [2284].Johnson et al. did not find a single case of significant renal toxicity with amphotericin B in a group of 21 infants (birth weight < 1,500 grams) with neonatal candidiasis treated with this agent [1128]. In addition, the classic infusion-related side effects, fever, chills, nausea and vomiting are especially seen in this population [630, 1128, 2376]. And even when amphotericin B is known to inhibit erythropoietin production, anemia has not been described as a significant finding among babies treated with this drug [351, 1346].Indeed, the use of amphotericin B alone for the treatment of neonatal candidiasis has been advocated by some authors, in view of the lack of an intraveneous formulation of 5-fluorocytosine and the immaturity of the (A):GI tract in neonates [351]. A retrospective analysis of such approach revealed that transient azotemia, elevations in serum creatinine and hypoalkemia occurred in about half of cases, but all these complications were satisfactorily managed with short interruptions of therapy or adjustment in dosing intervals. In addition, a comparison of the mortality rate of these infants treated without 5-fluorocytosine with the one reported by authors using the classic combination revealed they were similar or even lower [351].
- 5-fluorocytosine
Johnson et al. also emphasized the lack of cases of either bone marrow or liver toxicity when using 5-fluorocytosine for the treatment of neonatal candidiasis. They used doses of between 20 to 200 mg/kg/day [1128]. Many other reports reviewing this topic have favored the combined use of this agent with amphotericin B [164, 708, 1128, 1315, 2392]. - Fluconazole
Limited data on the use of fluconazole in this population has been published. Most of the data are from anecdotal reports [245, 1078, 1258, 1521, 1617, 2329, 2330, 2348]. More recently a single randomized study compared fluconazole with amphotericin B for the treatment of 23 infants with neonatal candidiasis [619]. However, a heterogeneous group of babies was included. Single stool culture positive for Candida was accounted as a criteria for invasive candidiasis in one case. Therefore, no major conclusions can be made from this study [619]. There is no doubt that fluconazole deserves further evaluation.
In conclusion, amphotericin B alone or in combination with 5-fluorocytosine remains the standard of care for neonatal candidiasis. The optimal duration of therapy is unknown. However, it is recommended to complete a minimun of 10 to 15 mg/kg of amphotericin B in cases of uncomplicated catheter-related candidemia and between 25 to 30 mg/kg total for patients with invasive disease. When using 5-fluorocytosine, 100 mg/kg/day given in four equal doses is recommended [351].
Congenital Candidiasis
Congenital candidiasis is a rare clinical entity in which intrauterine Candida infection becomes manifest at birth. Congenital candidiasis is not related to vaginal delivery, premature rupture of membranes, prematurity, maternal age, duration of labor or parity [639, 1985]. Intrauterine contraceptive devices have been frequently associated with this condition [513, 563, 2426]. Two forms of disease have been described [1842]:
- Congenital cutaneous candidiasis
In this case an extensive skin rash becomes manifest within the first 12 hours of life [1985]. A macular erythema that may evolve from a pustular, papular or vesicular phase finally results in extensive desquamation [851, 1985]. Paronychia and dystrophy of the nail plates have been also described [112, 1877]. The most commonly affected areas include the trunk, neck, face and extremities [1985]. These cutaneous lesions usually resolve spontaneously or after short courses of oral nystatin [50, 1985]. - Congenital systemic candidiasis
In certain cases, the picture may evolve to an invasive infection and death, particularly in very low birth weight infants [1127]. This form of the disease has a high mortality rate. Importantly, at least half of the cases do not develop the cutaneous phase previously described [1124]. Pneumonia with respiratory distress is the most common presentation of systemic or invasive candidiasis [477, 851, 1124, 2426]. Other presentations include candidal meningitis, candiduria and/or candidemia.
Diagnosis
Direct smear or culture of gastric aspirate, meconium, scrapings of skin vesicles or cord lesion can all be positive for Candida spp. Microscopic and even macroscopic examination of the placenta may disclose fungal chorioamnionitis [2426]. Elevated leukocyte count with an increase in immature forms or persistent hyperglycemia are other frequently encountered findings [513, 2426].
Therapy
Systemic antifungal therapy with amphotericin B is warranted in infants with skin lesions suggestive of congenital cutaneous candidiasis and respiratory distress [1422]. See above our discussion of the unique aspects of (A):antifungal selection in the neonate.