Congenital candidiasis is uncommon and may occur as an isolated skin infection or in conjunction with systemic fungal disease. In one series of cases of chorioamnionitis, Candida
was isolated from the fetal surface of the placenta in only 0.8% of infections (313
chorioamnionitis and congential infection has been associated with the presence of an intrauterine contraceptive device in about 25% of cases, probably due to heavy fungal colonization (107
). Congenital fungal infection was first described in term infants who presented with pustules, vesicles, skin abscesses, and an erythematous maculopapular rash of the trunk and extremities, at times leading to desquamation (42
). Subamniotic fungal abscesses form beadlike discrete yellow plaques on the umbilical cord or placenta. Histologic evaluation of the placenta demonstrates hyphae, microabcsesses, and granulomas and is often helpful in identifying the cause of these skin manifestations.
Congenital candidiasis is more commonly associated with systemic spread and worse outcome in preterm than in term neonates. For this reason, term infants with congenital candidiasis should be evaluated for an immunodeficiency. Early reviews demonstrate that half of the patients were preterm infants and that without systemic therapy, these patients, as well as full-term infants with pneumonia, died (107
). Whyte et al. described similar findings for 18 cases of histopathologic Candida
chorioamnionitis, with 15 leading to neonatal infection (all in infants with birth weight of <2,000 grams), and for 12 cases at <28 weeks' gestation (501
). VLBW infants with congenital Candida
infection are more likely to present with severe infection, such as pneumonia and widespread dermatitis with focal areas of superficial erosion and desquamation (226
). The autopsy findings for the three infants who died within 1 h of birth demonstrated a diffuse pneumonitis with budding yeast in the airways, middle ear, stomach, and syncytial giant cells as well as pseudohyphae in the esophagus and stomach, all suggesting a contiguous spread of Candida
along mucosal surfaces. In another early review, only 5 of 27 cases occurred in infants for whom the rupture of membranes occurred >12 h prior to delivery; therefore, the congenital infection may occur via intact membranes, a break in the amniotic membranes, or a large inoculum present once the membranes had ruptured or at delivery (107
can infect and penetrate human fetal and chick chorioallantoic membranes, but animal studies have shown that it cannot pass through the placental barrier (79
More recently, 63 cases of congenital cutaneous candidiasis (1960 to 1997) were reviewed (105
). Since all cases diagnosed in the first 6 days of life were considered, there may have been overlap with postnatally acquired mucocutaneous infection (see below). Twenty-seven infants (43%) had birth weight of >2,500 g, 21 (33%) had birth weight between 1,000 and 2,500 g, and 15 (24%) had birth weight of less than 1,000 g. Infants with diffuse burn-like erythematous macular dermatitis with skin exfoliation were more likely to have blood, urine, or CSF involvement (9 of 12 infants) compared to a papulopustular rash at any gestational age (105
). ELBW infants with congenital cutaneous candidiasis had a greater risk of invasive fungal infection (10 of 15) and mortality, although only one-third of these patients received systemic therapy (105
). In full-term infants, this infection was unlikely to disseminate. A more descriptive diagnosis of congenital cutaneous candidiasis would be a skin rash in the first 2 days of life with or without placental histology.
Fungal sepsis. Candida
accounts for approximately 12% of LONS in VLBW infants (Table ) (37
). In most centers, the incidence of fungal sepsis among VLBW infants ranges from 2 to 6.8% and is inversely proportional to gestational age and birth weight (30
). The incidence of fungal sepsis among preterm infants has increased considerably over the last two decades. In a single-center study (1989 to 1998) of VLBW infants, the incidence increased from 3.8% in 1989 to 6.8% in 1998 (302
). The Neonatal Network, reporting on over 13,000 VLBW infants, showed that the proportion of LONS caused by fungi increased from 9% in 1991 to 1993 to 12% in 1998 to 2000, while the associated mortality increased from 28 to 32% (451
). This increase may be due to the survival of smaller and sicker preterm infants exposed to invasive therapies for long periods.
In a multicenter study of six NICUs from 1993 to 1995, the incidence of fungal sepsis was 0.26% (3 of 1,139) in infants with birth weight of >2,500 g, 3.1% (29 of 926) in infants with birth weight of <1,500 g, and 5.5% (23 of 421) in infants with birth weight of < 1,000 g (402
). A later five-NICU retrospective cohort study of ELBW infants (1994 to 1998) demonstrated a higher incidence of fungal sepsis of 10% (136 of 1,372) (M. G. Karlowicz, J. L. Rowen, M. L. Barnes-Eley, B. L. Burke, M. L. Lawson, C. M. Bender, K. E. Shattuck, M. Horgan, and W. L. Albritton, Abstract, Pediatr. Res. 51:
301A, 2002). This is similar to the results of a single-center study of 1,407 ELBW infants, which showed an increase in fungal sepsis from 1.0% in 1981 to 1985 to 9.9% in 1991 to 1995 (266
). In the five-NICU study, the incidence of fungal sepsis increased linearly with decreasing gestational age: from 3% at 28 weeks to 28% at 23 weeks (Karlowicz et al., abstract, 2002). There was also considerable interinstitution variability in incidence of fungal sepsis, ranging from 4 to 14%.
(i) Risk factors.
Risk factors for fungal sepsis overlap with those for fungal colonization, as discussed previously (43
) (Fig. ). In two multicenter studies, lower gestational age (<28 weeks), birth weight (<1,000 g), and cephalosporin or carbapenem use were the strongest risk factors for fungemia after multivariate analysis (43
). Multiple-site fungal colonization (two or more sites) is also a risk factor for invasive fungal infection, with each additional site increasing the risk by a factor of 3 (95% CI, 1.4 to 6.8) (246
). In a multicenter study in which rectal colonization cultures were performed for 76% of preterm infants, univariate analysis demonstrated prior colonization as a risk factor for fungal sepsis, but multivariate analysis controlling for birth weight and abdominal surgery demonstrated that prior rectal colonization was not a risk factor (402
). Other single sites may have greater sensitivity, such as endotracheal and stool cultures compared to swabs of the rectum. In two smaller studies of VLBW infants, each with five cases of fungal sepsis, Candida
was isolated from endotracheal and stool cultures of all patients prior to the onset of fungal sepsis (362
). Bloodstream fungal infection often is preceded by colonization, but it may also occur in the absence of colonization via direct seeding of the bloodstream from infected catheters, infusates, feedings, or feeding tubes (215
Some studies have found differences between colonizing and infecting Candida
species. Studies have reported multisite C. albicans
colonization, at the same time as C. glabrata
sepsis was diagnosed in preterm neonates (215
). In another study, one infant with C. albicans
rectal colonization developed C. dubliniensis
). This may be due to undetected colonization with multiple fungi or may indicate that bloodstream infection occurred from another source.
Vascular catheters create a unique surface for proliferation of microorganisms, with a matrix of coagulation factors, including platelets and fibrinogen, that favor fungal adherence. Parenteral nutrition is often given through these catheters, providing a substrate for growth (433
species tend to form biofilms on catheter surfaces that shield the organism from the host immune response and from antifungal drugs (6
). For this reason, removal of central vascular catheters is recommended for any preterm infant with candidemia in order to eradicate the infection as rapidly as possible and reduce the risk for deep-seated infection (46
Hyperglycemia may increase the risk of fungal sepsis by providing a substrate for proliferation and by upregulating the expression of genes responsible for pathogenicity (180
). In one study of 370 VLBW infants, 7 of 12 infants with fungal sepsis were hyperglycemic and required insulin therapy (32
). Sepsis in VLBW infants may result in insulin resistance and hyperglycemia; therefore, high serum glucose levels may be secondary to sepsis in addition to being a risk factor for fungal proliferation.
(ii) Candida species causing fungal sepsis.
In three large multicenter studies of LONS in VLBW infants, C. albicans
and C. parapsilosis
were the most common species causing candidemia (303
). These studies cover the periods of 1991 to 1993 (n
= 6,911, 12 centers, United States), 1995 to 1998 (n
= 5,555, 28 centers, Israel), and 1998 to 2000 (n
= 6,215, 15 centers, United States). In these studies, fungal sepsis due to C. albicans
occurred in 51, 23, and 48% of cases, respectively, whereas C. parapsilosis
was the cause in 26, 17, and 34%. In the 1995 to 1998 study, one NICU reported using amphotericin B as empiric therapy for evaluation of LONS in all NICU patients, which may select for Candida
species other than C. albicans
and C. parapsilosis
The prevalence and species distribution of Candida
appears to be similar in adult ICU and NICU patients. A study comparing Candida
species in seven surgical ICUs (SICUs) and six NICUs between 1993 and 1995 described an incidence of fungal sepsis of 9.8 per 1,000 admissions and 0.99 per 1,000 patient-days in SICU patients and 12.3 per 1,000 admissions and 0.64 per 1,000 patient-days for NICU patients (381
). The Candida
species causing bloodstream infections in the SICU patients included C. albicans
(48%), C. glabrata
(24%), C. tropicalis
(19%), C. parapsilosis
(7%), and other Candida
species, (2%). Comparatively, in the NICU the distribution for fungal sepsis was C. albicans
(63%), C. parapsilosis
(29%), C. glabrata
(6%), and other Candida
species (3%). The species variations may reflect differences in empiric or prophylaxis practices.
Although C. albicans
and C. parapsilosis
are the predominant Candida
species in VLBW infants, an increasing number of other Candida
species have been isolated recently, with C. glabrata
being one the more common emerging species. Features of neonatal C. glabrata
sepsis were compared to those of C. albicans
and C. parapsilosis
sepsis in a two-center retrospective review from 1991 through 1998 (Table ) (131
). Of all cases of candidemia in the two centers, 15.5% were due to C. glabrata.
This high incidence of C. glabrata
could not be attributed to the use of fluconazole for prophylaxis or treatment of fungal infection in these patients, since this agent was rarely used during or before the study period in these units. Interestingly, C. glabrata
sepsis occurred in patients with a significantly higher gestational age and birth weight compared to sepsis with non-glabrata Candida
species. While the clinical presentation of C. glabrata
infection was somewhat less severe, the number of positive blood cultures and the incidence of meningitis, UTI, and NEC were not significantly different, indicating that C. glabrata
is capable of causing invasive disease in preterm infants. Also of note in this study, five of the six patients with birth weight of >1,500 g who developed fungemia had a history of gastrointestinal surgery (two had NEC with subsequent short-gut syndrome, two had jejunal atresia, and one had gastroschisis), further demonstrating this important association in higher-birth-weight infants.
Comparison of C. albicans, C. parapsilosis, and C. glabrata sepsisa
(v) End-organ dissemination.
At the time fungal infection is clinically apparent, the organisms have often disseminated from the blood, urine, or CSF to adhere to and proliferate in body fluids, tissues, and organs. Candida
species can cause endocarditis, endophthalmitis, dermatitis, peritonitis, osteomyelitis, and septic arthritis, and fungal abscesses may form in the CNS, kidneys, liver, spleen, skin, bowel, and peritoneum (Fig. ). Fungal end-organ dissemination has been noted since the earliest reports of Candida
sepsis in neonates (201
). In an early review (1972 to 1982) of 31 VLBW infants with invasive fungal infection, dissemination occurred to the bones or joints (26%), eyes (23%), lungs (13%), skin (10%), heart (6%), and peritoneum (3%) (227
). More than one organ system was involved in 21 of these cases. The high prevalence of end-organ dissemination in earlier studies of neonatal fungal sepsis reflects prolonged periods of fungemia, since most of the diagnoses were made late or by autopsy. A meta-analysis of studies reporting fungal end-organ dissemination in neonates, spanning both older and more recent practices from 1979 to 2002, found that the median prevalence was 5% for cardiac vegetations or thrombi, 3% for endophthalmitis, 5% for renal involvement, and 4% for CNS abscesses (45
). In a more recent study (1989 to 1999) of 86 cases of fungal sepsis in neonates, cardiac vegetations or thrombi occurred in 15.2%, endophthalmitis occurred in 6%, renal involvement occurred in 4.5%, and liver abscesses occurred in 3% (352
). Dissemination may be higher in lower-birth-weight infants. In a 1988 to 1995 study examining 46 ELBW infants with fungal sepsis or meningitis, fungal abscesses of the CNS were found in 13 patients (28%) (149
Chapman and Faix (80
) have reported increased fungal end-organ dissemination with persistently positive blood cultures for more than 7 days (1981 to 1999). In a more recent review (1989 to 1999), Noyola et al. also found that infants with candidemia for more than 5 days were more likely to demonstrate ophthalmologic, renal, or cardiac abnormalities than those with a shorter duration of candidemia (352
). However, when amphotericin B was given and central vascular catheters were removed within 2 days of the first positive blood culture, outcomes such as end-organ dissemination and mortality were not decreased (352
). With improved blood culture methods, the majority of blood cultures grow Candida
within 2 days. One study of neonates demonstrated that isolation of fungus in blood cultures occurred at 37 ± 14 h, with 97% of blood cultures positive by 72 h if the patient was not exposed to antifungal therapy (414
) and 91% positive with antifungal exposure.
(a) Endocarditis and infected vascular thrombi. Candida
endocarditis has been found in 5.5 to 15.2% of cases of fungal sepsis, with equal prevalence for C. albicans
and C. parapsilosis.
Fungal endocarditis may be associated with higher mortality than fungemia alone (46
). Noyola et al. reported that of 11 patients with fungal endocarditis, 3 died acutely and 2 died later of unrelated complications (352
). Central vascular catheters place neonates at increased risk for endocarditis and infected vascular thrombi (319
). As discussed above, they can cause local trauma to valvular, endocardial, or endothelial tissue, creating a nidus for thrombus and infection. To minimize the risk of trauma, care must be taken to avoid placing umbilical or peripherally inserted central catheters past the superior or inferior vena cava. Removal of central vascular catheters as soon as is reasonably feasible may also reduce the risk of vascular injury, microbial colonization, and disseminated infection. In addition, prompt removal of central catheters in patients with fungal sepsis is likely to reduce the incidence of endocarditis and infected vascular thrombi.
(b) Endophthalmitis and retinopathy of prematurity
. Endophthalmitis begins as a chorioretinal lesion that gradually elevates and breaks free in the vitreous, appearing as a white fluffy ball. These solitary or multiple white lesions are most often seen in the posterior retina (zone I) and vitreous. In adults and children, the clear cell-free vitreous becomes hazy due to an influx of inflammatory cells. This vitreous reaction is more difficult to recognize in preterm infants due to the vitreous haze that is present in the first weeks of life. The most immature infants appear to be at highest risk for fungal endophthalmitis (reviewed in reference 29
). In an early study of VLBW infants, endophthalmitis occurred in four (50%) of eight cases of fungal sepsis, with excellent prognosis after prompt treatment with amphotericin B and 5-fluorocytosine (28
). More recent studies have reported a much lower incidence of retinal endophthalmitis, probably due to more rapid diagnosis, treatment, and surveillance of systemic candidemia. In a retrospective study from 1989 to 1999, 4 of 67 (6%) of preterm infants with fungal sepsis who underwent indirect ophthalmoscopy examination had endophthalmitis (352
). Severe fungal eye pathology may develop in ELBW infants with fungal sepsis. A recent report describes a 24-week-gestation infant with Candida
sepsis at 4 weeks of age who, on examination at the time fungemia was detected, had markedly immature fundi with limited vascularization. Five weeks later, despite antifungal therapy, bilateral cataract and intraocular inflammation were present, with progressive retinopathy of prematurity (ROP) and tractional retinal detachment (429
). On vitrectomy and lensectomy, an intralenticular Candida
abscess was found.
Even in the absence of visible retinal abscesses or chorioretinitis, there is some epidemiologic evidence that Candida
sepsis may predispose VLBW infants to severe ROP. Kremer first described 15 preterm infants with C. albicans
sepsis and ROP (269
). Since then, several studies have examined this association. In a study of ELBW infants, threshold ROP developed in 33% of infants (19 of 58) with a history of candidemia compared to 10% (39 of 391) without candidemia, but this was not statistically significant when controlled for gestational age (242
). Conversely, Noyola and colleagues, in a case-control study of VLBW infants <28 weeks' gestation, found that 52% of infants with candidemia (24 of 46) developed threshold ROP compared to 24% of controls without candidemia (11 of 46) (P
= 0.008) (351
). In this series, retinal detachment occurred in 10 of the candidemic patients compared to 4 of the controls (P
= 0.10) (351
). In another study of 130 ELBW infants from 1996 to 1999, controlling for gestational age, race, days receiving supplemental oxygen, and cumulative postnatal dexamethasone dose, fungal sepsis was independently associated with the need for laser therapy for ROP (OR, 8.2; 95% CI, 2.0 to 33.0) (189
). Of note, however, 13 of 14 patients with fungal sepsis had received postnatal steroids, implying that they were critically ill for prolonged periods; thus, other factors than Candida
sepsis may have contributed to the development of ROP. While the data regarding an association between fungal sepsis and ROP are conflicting, early and frequent screening for retinal pathology is recommended in VLBW infants with candidemia.
(c) Renal system and fungal infection
. Renal factors that favor Candida
growth are hypertonicity and acidity of the tubular lumen as well as a delayed renal inflammatory response. In VLBW infants, urine pH is increased in the first weeks of life due to decreased bicarbonate absorption at the proximal tubule, so that a UTI at this time may be due to local immune factors and hematogenous spread. Prematurity, antibiotic treatment, and immunosuppressive therapy are also risk factors for renal fungal infections. In six studies of VLBW infants, the incidence of fungal UTI was 2.4% among all 1,322 infants and 58.3% (28 of 48) in infants with fungal sepsis (31
). In one study of ELBW infants, the incidence of fungal UTI was 6% (3 of 50), and 1 of 8 infants with fungal sepsis had Candida
Renal abscess formation in preterm infants may occur by dissemination of candidemia or as an ascending infection with candiduria (reviewed in reference 239
). Hurley and Winner observed in animal studies that large doses (>2 × 106
organisms) of Candida
given intravenously produced systemic candidiasis, with systemic fungal lesions and renal involvement in all cases (219
). Smaller intravenous doses resulted in isolated renal infection with acute pyelonephritis and multiple cortical abscesses developing within 48 h, followed by cortical scarring 1 week later, with papillary necrosis and mycelia isolated in the tubular lumens of the medulla. Additionally, in these animals, large fungal abscesses in the renal pelvis led to obstructive nephropathy and renal failure.
Renal fungal abscess formation may complicate Candida
UTIs in preterm infants. Fungal UTI may occur alone or in conjunction with fungal sepsis. In one study, 41 (0.5%) of 8,790 neonates admitted to the NICU with median birth weight of 890 g and gestational age of 27 weeks developed candiduria (64
). Candiduria occurred in the more preterm infants, and renal abscesses developed in 36.6% of the infants with candiduria (15 of 41). These 15 patients had a median birth weight of 770 g and gestational age of 26 weeks. Initial ultrasound examinations were normal in six patients who developed renal abscesses 8 to 39 days later. This study suggests that for infants with candiduria, renal imaging studies should be performed at the time of infection and also at the end of antifungal treatment.
Renal fungal abscess formation may cause acute renal failure and long-term morbidity in preterm neonates. In the same study that is described above, Bryant et al. found that 2 of 15 preterm infants with candiduria developed acute renal failure (64
). One patient required percutaneous aspiration of the renal fungal abscess. The clinical course of the 15 cases of renal fungal abscesses included persistent renal echogenic foci at hospital discharge in 6 patients (40%), calcification in 4 (27%), partial obstruction in 2 (13%), and hydronephrosis in 2 (13%). Without antifungal treatment papillary necrosis may occur (472
(d) Central nervous system candidiasis
. CNS fungal infection may involve meningitis, ventriculitis, or abscess formation in VLBW infants (83
). In six studies from 1979 to 1994, the overall incidence of culture-proven fungal meningitis among VLBW infants was 1.6% (17 of 1,048 infants). In these studies, 36% of VLBW infants with fungal sepsis (23 of 64) had evidence of meningitis by culture or abnormal CSF indices (31
). In contrast, other studies have reported a lower incidence of fungal meningitis among preterm and term neonates with fungal sepsis, ranging from 5.7 to 22% (45
Culture of the CSF is important in diagnosing fungal meningitis in VLBW infants since CSF cell counts and chemistries may not be abnormal. In one study of 25 infants with Candida
sepsis or meningitis, spinal fluid abnormalities occurred in only 25% of infants with culture-proven Candida
). In another study of 12 VLBW infants with Candida
meningitis detected by culture, the most common CSF abnormality was low glucose (<30 mg/dl), noted in 7 of 9 tested cases, while the CSF protein level was elevated in only half of the patients (range, 30 to 480 mg/dl) (288
). CSF white blood cell counts ranged from 3 to 1030 cells/μl, with varying percentages of neutrophils and mononuclear cells in these cases of culture-proven fungal meningitis (288
Fungal abscesses of the CNS have been reported to be microscopic and not readily detectable by ultrasonography or computed tomography (193
). In a study of 46 ELBW patients with fungal sepsis and/or meningoencephalitis, only 6 of 13 patients with fungal CNS abscesses (detected by ultrasound or computed tomography or on autopsy) had abnormal results on lumbar puncture (149
). Two studies have found an association between invasive fungal infection and periventricular leukomalacia in preterm infants, possibly related to the release of cytokines which may damage the periventricular white matter (149
). These findings demonstrate the need for cranial imaging such as utrasonography in all patients with fungal sepsis, regardless of the results of CSF studies.
Outcome of invasive fungal infection. (i) Neurodevelopmental outcome.
In the largest analysis (1988 to 1994) of fungal infection and morbidity in ELBW infants, 46 infants with Candida
sepsis and/or meningoencephalitis were compared to a cohort of 470 ELBW infants without fungal sepsis (149
). Six cases were not diagnosed until autopsy. C. albicans
and C. parapsilosis
accounted for 78 and 20% of the cases, respectively. Comparing 27 Candida
-infected patients to the 303 control patients who survived and were available for analysis, there was increased severe neurodevelopmental impairment (41 and 12%, respectively; P
= 0.005), less intact neurodevelopment (41 and 65%, respectively; P
= 0.02), and a trend toward increased periventricular leukomalacia (P
= 0.06) in the Candida
-infected patients. Infected infants had more chronic lung disease (100 and 11%, respectively; P
= 0.0001) and severe ROP (stage 3 or 4) (22 and 9%, respectively; P
= 0.04). In this study, neurodevelopmental outcome was related to timing of initiation of antifungal therapy. Antifungal therapy was initiated 5.1 ± 3.0 days after blood culture was drawn for those infants who had severe disabilities or died compared to 2.1 ± 1.3 days for those who were normal or mildly impaired (P
In a smaller retrospective study of infants with birth weight of <1,250 g, neurodevelopmental outcome was assessed between 2 and 3 years of age in 14 infants who had fungal sepsis or meningitis compared to 21 matched controls (277
). The mental developmental index was similar (83 ± 20 and 90 ± 20, respectively), but the performance developmental index was lower in the patients who experienced fungal sepsis (71 ± 21 and 87 ± 18, respectively P
< 0.05). However, not all studies have demonstrated adverse neurodevelopmental outcome in preterm survivors of fungal sepsis compared with their gestational age-matched peers. In a retrospective study of VLBW infants with systemic candidiasis compared to matched controls. Baley found no difference in the mental developmental index (89 ± 16 and 83 ± 22, respectively) or the performance developmental index (91 ± 18 and 85 ± 22, respectively) scores or neurologic impairment at 2 years of age (27
Early studies reported autopsy evidence of disseminated or focal fungal disease in up to 30% of patients who died of suspected sepsis but had no growth of fungus from blood, urine, or CSF cultures prior to death (31
). More recently, with improved blood culture techniques, and with increasing awareness of the high incidence and severity of fungal sepsis among preterm infants, therapy is instituted earlier and outcome has improved. In a 1989 to 1999 review of fungal sepsis in preterm infants, only 3 (2.7%) of 110 cases of invasive fungal infection were not diagnosed until autopsy (352
All-cause mortality among VLBW infants who experienced fungal sepsis has been reported in several multicenter studies to range from 28 to 32%, compared to a mortality of approximately 7 to 9% in VLBW infants who do not have an infection during their NICU stay (303
). Mortality is higher in ELBW infants who develop fungal sepsis and has been reported at between 37 and 40% (149
), while fungal sepsis occurring after 4 weeks of life has been associated with lower mortality (133
). Studies reporting high mortality associated with Candida
sepsis generally present mortality from all causes, and it is likely that the number of deaths directly attributable to fungal infection is smaller. In the most recent VLBW NICHD study, which included 160 cases of fungal sepsis, 48% of fungus-related deaths occurred in the first 72 h and 73% occurred with 7 days from the time of blood culture. Several centers have reported, for smaller samples of patients, a lower mortality from fungal sepsis in preterm infants (131
). One study reported no mortality in 49 NICU patients with fungal sepsis, including 35 cases in VLBW infants (302
), and in another study involving 52 VLBW neonates with Candida
sepsis, only 3 patients died prior to NICU discharge and none of the deaths was directly attributed to fungal sepsis (131
A number of studies have shown that C. albicans
is associated with significantly higher mortality than are other Candida
). This was first noted by Faix in a single-center study (1980 to 1990) of 45 cases of invasive fungal infection in term and preterm infants, which demonstrated a higher associated mortality due to C. albicans
(24%) than to C. parapsilosis
). In the recent NICHD Neonatal Network survey of VLBW infants, patients with C. albicans
sepsis had a mortality of 44% compared to 16% for those with C. parapsilosis
). This may be related in part to the timing of infection, with vertically transmitted C. albicans
causing infection earlier, when the immune system is more compromised, and horizontally transmitted C. parapsilosis
causing infection in an older, more immunocompetent host.
Treatment of Candida sepsis. (i) Antifungals.
The mainstay of therapy for neonates with disseminated fungal infection remains amphotericin B deoxycholate, with some exceptions, although newer antifungal agents are under investigation for use in neonates (reviewed in references 54
, and 254
). Amphotericin B is generally better tolerated in neonates than in adults, allowing therapy to begin at 1 mg/kg without administering test doses. Liposomal amphotericin B preparations were shown to be comparable in efficacy to amphotericin B in a limited number of small neonatal trials and may be used in patients with renal impairment or toxicity from amphotericin B (54
). In adult studies, amphotericin B levels in CSF are 5 to 10% of the levels in plasma, but in one study of 13 preterm infants, concentrations in CSF were 40 to 90% of those in the plasma. In patients with meninigitis, enteral flucytosine may be added if tolerated, but resistance emerges if this drug is used as monotherapy. Animal studies have demonstrated better penetration of liposomal amphotericin than of amphotericin into CSF, although this has not been studied in preterm infants.
Several small studies have found similar efficacy of azoles compared to amphotericin B for treatment of preterm infants with fungal sepsis (118
). Of the azoles, fluconazole has undergone the most extensive study in VLBW infants. Currently, the strength of fluconazole used in preterm infants is for prophylaxis (intermittent 3-mg/kg dosing) in high-risk ELBW infants (see below). With prolonged daily treatment of fungal sepsis with azoles at doses of 6 to 12 mg/kg, resistance may develop, particularly among C. krusei
and C. glabrata
species; thus, amphotericin is generally preferred as a first-line agent for treatment of fungal sepsis in neonates. There is some concern about ophthalmologic side effects of voriconazole use in preterm infants with a developing retina, and this requires further study (171
). A new class of antifungal agents, the echinocandins, acts through noncompetitive inhibition of 1,3-β-glucan synthesis of the fungal cell wall and is licensed for use in adults. Studies are under way to determine their efficacy in pediatric and neonatal patients.
Factors to consider in deciding the duration of therapy include the species of fungus involved, whether a central line was present and was removed, number of positive blood cultures, CSF indices, and findings of the evaluation for end-organ dissemination, including echocardiogram, renal ultrasound, ophthalmologic examination, and neuroimaging studies. Generally, 2 to 4 weeks of intravenous therapy after negative cultures is recommended for treatment of candidemia in preterm neonates, with longer courses being appropriate for meningitis and deep-seated infections. Despite prolonged courses of appropriate therapy, recurrence of Candida
infection, including severe osteoarthritis, has been reported in preterm neonates (192