Candida infections in neonates: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Candida infections are common in neonates and have a broad range of clinical severity. In healthy term newborns, most candidal infections are mild (eg, oral thrush (picture 1), diaper dermatitis (picture 2A-B)). However, in preterm neonates, Candida is an important cause of invasive systemic illness that can be associated with substantial morbidity and mortality.

The epidemiology, clinical manifestations, and diagnosis of Candida infections in the neonate will be reviewed here. Related topics include:

●(See "Candida infections in neonates: Treatment and prevention".)

●(See "Unusual fungal infections in the neonate".)

●(See "Candida infections in children".)

●(See "Common problems of breastfeeding and weaning", section on 'Candidal infection'.)

EPIDEMIOLOGY

Incidence

●Superficial mucocutaneous infections (oral thrush, diaper dermatitis) – Superficial mucocutaneous Candida infections (eg, oral thrush, diaper dermatitis) are very common in newborns, with approximately 10 to 20 percent of healthy infants being affected at least once during the first few months after birth [1]. (See 'Superficial mucocutaneous infections' below and "Candida infections in children", section on 'Oropharyngeal candidiasis' and "Diaper dermatitis".)

●Invasive infection – The incidence of invasive Candida infections in neonates is approximately 5 to 10 cases per 100,000 live-born infants [2-4]. Candida species are particularly important hospital-acquired pathogens in infants admitted to the neonatal intensive care unit (NICU) [5-7]. Reported rates of invasive Candida infections in the general NICU population range from 0.5 to 2 percent [5,8-12]. The incidence varies depending on the gestational age and the birth weight of the cohort studied; the risk is greatest among preterm infants with extremely low birth weight (ELBW; <1000 g). In studies limited to ELBW infants, reported rates of invasive candidiasis range from 5 to 15 percent [5,8-11,13]. In a prospective study of >10,000 very preterm infants with late-onset sepsis, Candida accounted for 5 percent of cases [7]. (See 'Candidemia and invasive candidiasis' below.)

Risk factors for invasive candidiasis — Among neonates admitted to the neonatal intensive care unit (NICU), the following have been identified as risk factors for acquiring invasive Candia infection (table 1) [13-24]:

●Prematurity and low birth weight; the risk is highest among ELBW neonates

●Exposure to broad-spectrum antibiotics

●Presence of invasive devices (eg, central venous or arterial catheters, endotracheal tubes, urinary catheters) (see 'Compromise of epithelial barriers' below)

●Perinatal asphyxia and/or low five-minute Apgar score (<5)

●Maternal intra-amniotic infection (also called chorioamnionitis)

●Hemodynamic instability and/or shock

●Necrotizing enterocolitis

●Surgery (especially if surgical drains are in place)

●Parenteral nutrition and/or intralipid infusion

●Postnatal glucocorticoids

●Gastric acid suppressing drugs (eg, H2 blockers, proton pump inhibitors)

●Skin breakdown (see 'Compromise of epithelial barriers' below)

●High density of Candida colonization and/or multiple sites of colonization (see 'Colonization' below)

●Prolonged NICU stay

●Neutropenia

Many of these risk factors are not specific for candidiasis; they are general risk factors of hospital-acquired infections in preterm neonates.

Neonates with multiple risk factors may present with early-onset invasive Candida infection (ie, within the first seven days after birth), which may be associated with increased risk of mortality [25]. In one study, risk factors for early-onset infection included birth weight <750 g, gestational age <25 weeks, maternal chorioamnionitis, and vaginal delivery [25]. Mortality was considerably higher in neonates with early-onset compared with late-onset disease (71 versus 32 percent); however, the difference in mortality is likely accounted for, at least in part, by differences in the gestational age and birth weights of the two groups.

Trends for invasive Candida infections — The overall incidence of candidiasis in NICUs in the United States appears to be decreasing [2,12,17]. The reason for the decline is not certain. Possible explanations include increased use of fluconazole prophylaxis in at-risk ELBW infants and declining use of broad-spectrum antibiotics. Differences in these practices may also account for the variability in rates of invasive candidiasis seen across different NICUs. In one multicenter study, rates of candidiasis ranged from 2 to 20 percent among the 12 participating NICUs, and the rate directly correlated with the average number of days of antibiotic use [26]. These findings add to other studies indicating that exposure to broad-spectrum antibiotics is an important risk factor for invasive candidal infection. (See 'Risk factors for invasive candidiasis' above.)

In a multicenter study from the Pediatrix Medical Group, the overall incidence of neonatal invasive candidiasis decreased from 36 to 14 cases per 10,000 patients from 1997 to 2010 [12]. The decrease was greatest among infants with birth weights between 750 and 999 g (in whom the rate fell from 2.4 to 1.2 percent) and in those with birth weights <750 g (in whom the rate fell from 8.3 to 2.4 percent). The authors attributed the decline to reduced use of broad-spectrum antibacterial antibiotics and increased use of fluconazole prophylaxis. (See "Candida infections in neonates: Treatment and prevention", section on 'Targeted prophylaxis'.)

PATHOGENESIS

Transmission — Neonatal Candida colonization is largely the result of vertical transmission from the mother; however, horizontal transmission from health care workers or the hospital environment also plays an important role [27,28].

●Vertical transmission – Using molecular typing techniques, vertical transmission of Candida albicans, Candida parapsilosis, and Candida glabrata has been documented [27]. Heavy maternal Candida colonization or vaginitis increases the vertical transmission of the organism and neonatal colonization [27]. Breastfeeding can result in transmission of Candida from the maternal skin to the oral mucosa of the infant, especially in mothers with Candida mastitis.

In a prospective study of 76 mothers who gave birth to very low birth weight (VLBW) infants (birth weight <1500 g), maternal cultures were obtained within 24 hours of delivery, and infant cultures were obtained weekly for 12 weeks or until death or discharge [28]. C. albicans was isolated from 46 mothers (61 percent) and 27 infants (36 percent). Eighteen of the 27 infants were born to a C. albicans-colonized mother (67 percent). DNA fingerprinting demonstrated identical banding patterns in the C. albicans strains in 11 of the 13 pairs (85 percent), confirming vertical transmission.

Candida can also be transmitted through breastfeeding, as discussed separately. (See "Common problems of breastfeeding and weaning", section on 'Candidal infection'.)

●Horizontal transmission – Outbreaks of various Candida species (including C. albicans, C. parapsilosis, C. tropicalis, and C. lusitaniae) infections have been reported due to horizontal transmission from health care staff [29-31]. In particular, the primary mode of acquisition for C. parapsilosis in neonates is horizontal transmission from health care workers [29,30,32]. In one multicenter study, C. parapsilosis was the most common species cultured from the hands of health care workers [33]. Of the 2989 cultures, C. parapsilosis was recovered in 19 percent of samples and C. albicans in 5 percent. However, carriage rates did not correlate with the NICU-specific rates for colonization.

Exposure to surfaces that are contaminated by Candida species is also a potential source of horizontal transmission. Both C. albicans and C. parapsilosis can survive on glass, stainless steel, and fabrics for significant time periods (several days to as long as two weeks) [34]. In addition, contamination of medications, retrograde medication administration using multiple-use syringes, and glycerin suppository have been reported as sources of candidal infectious outbreaks [35-37]. Horizontal transmission of multidrug resistant C. auris has been reported in neonatal units in some parts of the world (eg, Bangladesh, India, China, and South America) [38].

Colonization — Candida species generally colonize the skin, gastrointestinal tract, lower female genital tract, intertriginous areas (eg, groin and armpits), and the foreskin of the uncircumcised male. As in adults and older children, colonization usually precedes invasive fungal infection. Neonates are generally infected with a clone with which they had previously been colonized [36,39].

In infants admitted to the NICU, colonization occurs in 30 to 60 percent of patients, depending on gestational age and birth weight.

In a retrospective analysis of 50 extremely low birth weight (ELBW) infants who underwent weekly surveillance fungal cultures of the skin, gastrointestinal tract, respiratory tract, and umbilicus, 62 percent were colonized with a Candida species by six weeks of age [19]. The skin and gastrointestinal tract were the first sites colonized, followed by the respiratory tract. Colonization was inversely related to gestational age.

In a study of VLBW (birth weight <1500 g) infants, approximately 27 percent of patients were colonized with a candidal species, of which one-third developed mucocutaneous candidiasis and 8 percent invasive candidal infection [36].

The level of colonization is an important factor in developing invasive disease. The greater the density of organisms, the more likely it is that the organism will penetrate the host epithelial barriers, spread to the underlying tissue, and be disseminated through the blood stream. Factors that promote gastrointestinal overgrowth, such as the use of broad-spectrum antimicrobial agents, are associated with an increased risk of Candida infection [16,19,40,41]. (See 'Risk factors for invasive candidiasis' above.)

Patients who are intubated can have colonization of their upper respiratory tract, which increases the risk of invasive candidal infection [42].

Penetration of host defense — Locally invasive and disseminated Candida infections results for penetration of the organism through the epithelial barriers at the sites of colonization. The progression from benign colonization to invasive infection depends largely on host factors.

Immature immune system — Neonates, especially preterm infants, have immature immune systems. Preterm infants have low levels of circulating maternal immunoglobulin G (IgG) because of decreased transplacental antibody transfer that occurs primarily during the latter half of the third trimester of pregnancy. Even in the presence of adequate IgG concentrations, opsonization and complement functions are reduced in preterm neonates. Neutropenia is also a common finding in premature infants with candidal infections [20]. The degree of immune compromise increases with decreasing gestational age.

Compromise of epithelial barriers — The skin and mucosal barriers in preterm neonates are immature and thin. They provide minimal protection and readily break down. In addition, neonates admitted to the NICU often require invasive procedures and devices that compromise the epithelial barrier (eg, central venous and arterial catheters, endotracheal tubes, surgical procedures) [14,41]. Clinical conditions, such as necrotizing enterocolitis or skin breakdown, that compromise the host epithelial barriers are also risk factors for candidiasis (table 1). (See 'Risk factors for invasive candidiasis' above.)

MICROBIOLOGY — The different Candida species generally are capable of producing the same clinical syndromes, although infection with Candida albicans is the most common. C. albicans accounts for approximately 60 to 75 percent of neonatal Candida infections and C. parapsilosis accounts for approximately 20 to 30 percent [2,3,5,6,15,43,44]. Other species such as C. tropicalis, C. lusitaniae, C. glabrata, C. krusei, and C. auris are far less common, together accounting for only 5 to 10 percent.

The major reason to identify the infecting Candida species is that they have different susceptibility profiles. C. glabrata and C. krusei are less susceptible to azole antifungal agents than are other species; C. lusitaniae is generally resistant to amphotericin B. C. auris is often multidrug resistant [45].

Infections caused by nonalbicans Candida species occur at a later age and are more likely to be acquired from the hospital environment [33,40]. It is unclear whether use of prophylactic fluconazole in preterm neonates increases the risk nonalbicans Candida infections [16,33,40]. It is important for NICUs to monitor the relative incidence of the different Candida species, especially in NICUs routinely using prophylactic fluconazole in ELBW neonates. (See "Candida infections in neonates: Treatment and prevention", section on 'Targeted prophylaxis'.)

CLINICAL MANIFESTATIONS — Candida infections in the neonate range from mild superficial mucocutaneous infections (eg, oral thrush (picture 1), diaper dermatitis (picture 2A-B)) to severe invasive systemic infection. Most Candida infections in newborns are acquired postnatally, with onset typically after the age of 5 to 7 days.  

Superficial mucocutaneous infections

Oropharyngeal candidiasis (thrush) — Oropharyngeal candidiasis is a common manifestation of Candida infection throughout infancy, both in preterm and healthy full-term infants.

Thrush presents as irregular white plaques with or without an erythematous base on the buccal or lingual mucosal surface of the mouth (picture 1). Most infants remain asymptomatic; however, some infants may refuse to eat because of discomfort from contact with their lesion during feeding [46]. (See "Candida infections in children", section on 'Oropharyngeal candidiasis'.)

The etiology is generally presumed to be vertical transmission of maternal colonization to the newborn. The transition from colonization to infection is mediated by a variety of factors in the newborn. (See 'Transmission' above and 'Penetration of host defense' above.)

Oropharyngeal candidiasis can be transmitted through breastfeeding, though the colonized breastfeeding infant can also be the cause of fungal mastitis [47]. (See "Common problems of breastfeeding and weaning", section on 'Candidal infection'.)

Diaper dermatitis — Candida diaper dermatitis is common in both term and preterm infants. It is characterized by an area of confluent erythema in the inguinal region, discrete erythematous papules and plaques with superficial scales, and satellite lesions (picture 2A-B). Additional details are provided separately. (See "Diaper dermatitis".)

Invasive skin infections — Invasive Candida skin infections include congenital cutaneous candidiasis (CCC) (picture 3A-B) and invasive fungal dermatitis. These are rare skin infections in neonates.

Congenital cutaneous candidiasis — CCC is a rare condition resulting from in utero or early perinatal Candida infection acquired. Risk factors for ascending infection include prolonged rupture of the membranes, presence of a uterine or cervical foreign body (eg, cervical cerclage), and a history of vaginal candidiasis [48,49]. CCC occurs more commonly in preterm than term infants, though term infants can be affected [48,50]. The risk of systemic dissemination is greatest among extremely low birth weight (ELBW; birth weight <1000 g) infants [48].

The affected infant typically presents on the first day after birth with a generalized eruption of 2 to 4 mm erythematous macules and/or papules that rest upon a 5 to 10 mm erythematous base. These lesions evolve into pustules, vesicles, or even bullae (picture 3A and picture 3B) [48,51]. The palms and soles are frequently involved. This finding helps distinguish CCC from the more common benign neonatal skin eruptions such as erythema toxicum neonatorum or miliaria, in which the palms and soles are typically spared. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Benign vesiculopustular eruptions'.)

Oral thrush may be present at birth, and yellow-white papules may be observed on the umbilical cord.

In preterm infants, the rash may have a variable presentation including widespread pustular and vesicular lesions or diffuse erythematous macular patches resembling a burn [52]. Crusting of the skin may be the presenting feature of such cases. In term infants, the skin lesions generally resolve with desquamation by the first week after birth.

Demonstration of budding yeast and pseudohyphae, usually in large numbers, on a potassium hydroxide preparation of scrapings from the skin lesions is helpful in making the diagnosis. Skin biopsy may be needed in some cases. Cultures should also be obtained of blood, urine, and cerebrospinal fluid (CSF). (See 'Diagnosis' below and 'Evaluation for extent of disease' below.)

Invasive fungal dermatitis — Invasive fungal dermatitis is a condition that is unique to preterm ELBW neonates and presents during the first two weeks after birth [53,54]. In a case series of 16 infants with this condition, postnatal steroids and hyperglycemia were risk factors; 69 percent had evidence of disseminated fungal disease [53].

The lesions vary in appearance. They include macular, papular, vesicular, or pustular lesions that are typically independent or intertriginous areas of the skin. The erosions can be extensive and sometimes involve the whole area of the abdomen or back.

Skin biopsy is diagnostic and shows Candida hyphae invading the dermis. Blood cultures should be obtained since dissemination of infection to the bloodstream is common. If candidemia is detected, the infant should undergo additional evaluation to determine the extent of infection. (See 'Candidemia and invasive candidiasis' below and 'Evaluation for extent of disease' below.)

Candidemia and invasive candidiasis — Preterm infants, particularly ELBW infants, are at increased risk for developing invasive Candida infections because of the immaturity of their immune and epithelial protection, use of invasive devices and procedures (eg, central venous catheters, endotracheal tubes. surgery), and other factors that promote increased density of candidal colonization (eg, broad-spectrum antibiotics) (table 1). (See 'Risk factors for invasive candidiasis' above.)

The clinical manifestations of candidemia and invasive candidiasis vary from minor changes in the neonate's clinical status (eg, temperature instability, increase in apnea episodes) to fulminant sepsis with multiorgan involvement. Although any organ can be involved, the most common sites are the bloodstream, urinary tract, and CNS.

Candidemia — The presentation of neonatal candidemia is generally indistinguishable from that of late-onset bacterial sepsis. Signs are nonspecific and may include lethargy, feeding intolerance, jaundice, glucose intolerance, apnea, and/or cardiorespiratory instability [46,55,56]. In the most severe cases, cardiorespiratory function is severely compromised, with multiorgan failure. The combination of persistent hyperglycemia and thrombocytopenia in ELBW infants is strongly associated with candidemia [57].

Many Candida bloodstream infections are associated with central venous catheters (CVCs). Thrombocytopenia is a common finding in CVC-associated candidemia. An infected thrombus can form on the catheter tip, which consumes platelets and can be a source of septic emboli. Removal of the infected CVC is an important component of treatment, as discussed separately. (See "Candida infections in neonates: Treatment and prevention", section on 'Treatment of confirmed infection'.)

The hallmark of candidemia is involvement of multiple organ systems, especially in ELBW infants. Infants with multiorgan failure have a poor prognosis. The finding of involvement of one organ system should prompt a thorough examination and evaluation to detect candidemia and other organ involvement (table 2). (See 'Evaluation for extent of disease' below.)

Bloodstream infection may be the primary site of infection or candidemia may occur secondarily from another primary site. In a national surveillance study that included data on nearly 2000 cases of neonatal candidemia, 86 percent were classified as primary and 14 percent were secondary [5]. Among the secondary bloodstream infections, the primary sites included the urinary tract (35 percent), gastrointestinal tract (18 percent), skin or soft tissue (15 percent), lung (13 percent), CNS (8 percent), cardiovascular system (5 percent), and other sites (5 percent).

Urinary tract infection — Candida UTI commonly accompanies candidemia, though it can occur in isolation [58-60].

The spectrum of Candida UTI in neonates ranges from Candida cystitis in infants with indwelling urinary catheters to parenchymal kidney disease from candidemia.

Clinical manifestations are nonspecific and include apnea, bradycardia, glucose intolerance, and decreased urine output. Findings specific to the kidney and/or urinary tract may be noted in some cases (eg, urinary obstruction, hypertension, or acute kidney injury) [61-64].

UTIs (with or without associated candidemia) account for approximately 50 to 60 percent of neonatal invasive Candida infections [65]. Most of these represent simple cystitis; kidney involvement occurs less commonly (approximately 5 to 10 percent of cases). However, systemic infection can occur secondarily in neonates with simple cystitis. In a cohort study that prospectively followed 30 infants diagnosed with Candida UTI without extrarenal involvement, 13 percent subsequently developed extrarenal candidiasis [66].

Risk factors for Candida UTI include the presence of an indwelling bladder catheter, congenital anomalies of the kidney and urinary tract (CAKUT), and urinary obstruction/ stasis. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

Infants diagnosed with a Candida UTI should undergo evaluation for systemic infection. including ultrasonography of the bladder and kidneys (table 2). Ultrasonography can detect kidney parenchymal infiltration, calyceal mycetoma, or fungal masses in the urinary tract. It also screens for CAKUT. (See 'Evaluation for extent of disease' below and "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)".)

Abnormalities may not be present at the initial evaluation but may become evident on subsequent ultrasound studies [59]. If the ultrasound shows abnormalities (eg, kidney parenchymal involvement or fungal mass), follow-up imaging should be obtained to assess the response to therapy and demonstrate resolution [59,67].

Central nervous system infection — CNS infection results from hematogenous spread of Candida. The most common CNS manifestation is meningitis, which occurs in approximately 10 to 20 percent of neonates with invasive candidiasis [65,68]. Candida is a particularly important pathogen in late-onset meningitis among extremely preterm neonates. In a report of 167 cases of late-onset meningitis in neonates born at 22 to 26 weeks gestation, Candida was the second most common pathogen, accounting for 23 percent of cases [69].

Ventriculitis and brain abscesses can also occur, but these are less common, occurring in approximately 4 to 5 percent of neonates with invasive candidiasis [46]. Neonates with ventricular drains or CSF shunts are at highest risk for these CNS infections.

The presentation of Candida CNS infection varies from a subacute, indolent illness, which is only identified because of a high index of suspicion, to severe illness with cardiorespiratory instability and multiorgan failure [68]. Clinical signs are generally the same as in bacterial meningitis and may include temperature instability, irritability, poor feeding, vomiting, respiratory distress, and apnea. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Clinical features'.)

In some cases, Candida CNS infection may be recognized when an intracranial abscess is seen on cranial imaging obtained for other reasons (eg, follow-up imaging for an intraventricular hemorrhage). (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis".)

CSF parameters are variable and depend on the type of CNS involvement (meningeal versus parenchymal disease). Normal CSF chemistries, cell count, and Gram stain do not exclude CNS involvement, because the inflammatory response may be limited or delayed and the inoculum of the organism may be low [68,70,71]. Definitive diagnosis is based on isolating Candida from the CSF culture. (See 'Diagnosis' below.)

Infants diagnosed with Candida CNS infection should be evaluated for other manifestations of systemic infection (table 2). (See 'Evaluation for extent of disease' below.)

Complications of CNS infection can include obstructive hydrocephalus, cerebral atrophy, and poor neurodevelopmental outcome [69].

Endocarditis — All infants diagnosed with candidemia should undergo echocardiography to evaluate for endocarditis [72]. (See 'Evaluation for extent of disease' below.)

Candida endocarditis occurs in approximately 5 percent of neonates with candidemia [65,73]. Risk factors include persistent candidemia (ie, lasting ≥5 days) and indwelling CVCs [73] The right atrium is the most common site of vegetations in neonatal Candida endocarditis [73]. (See "Infective endocarditis in children".)

Eye involvement — The term endophthalmitis refers to infection of the vitreous and/or aqueous humor. It may be endogenous, with seeding of the eye via the bloodstream, or exogenous, in which the infection is introduced into the eye via the ocular surface. In neonates, Candida endophthalmitis is almost always endogenous. Candida can also cause a less severe eye infection (chorioretinitis), in which there is minimal or no vitreous involvement. However, the term "Candida endophthalmitis" is commonly used to broadly describe both types of ocular candidiasis. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Endogenous Candida endophthalmitis'.)

Ocular candidiasis occurs in approximately 3 to 5 percent of neonates with candidemia [26,65].

Affected neonates may lack specific clinical signs and, if not treated, endophthalmitis may lead to loss of vision. Thus, all neonates with candidemia should undergo dilated eye examination (table 2). (See 'Evaluation for extent of disease' below.)

The classic ophthalmologic findings are focal, glistening, white, infiltrative, often mound-like lesions on the retina with indistinct borders (picture 4). Vitreous extension occurs occasionally and can be seen as a vitreal haze or as fluffy white lesions ("snowballs") within the vitreous (picture 5). (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Ophthalmic examination'.)

Even without clear eye involvement, candidemia may be associated with an increased risk of developing severe retinopathy of prematurity (ROP) [26,74-78]. Several studies have shown an association between candidemia and ROP requiring treatment [75,77,78]; though in one study, candidemia was not an independent risk factor for ROP after controlling for gestational age and other confounding factors [79]. Nevertheless, all neonates who develop candidemia should be evaluated by an ophthalmologist to assess for eye involvement and ROP. (See "Retinopathy of prematurity (ROP): Risk factors, classification, and screening".)

Other organ involvement — Other sites of infection may include the liver, intestines, peritoneum, bone, and joints. In addition, septic skin abscesses can be seen in patients with candidemia. Neonates diagnosed with Candida infection involving any of these sites should undergo additional evaluation, as discussed below. (See 'Evaluation for extent of disease' below.)

●Intestinal infections and peritonitis – Candida infections of the intestines and peritoneum can occur in preterm neonates with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) [80-84]. In these cases, Candida may be isolated in the blood, peritoneal fluid, or from a surgical specimen. In neonates with SIP, pathologic examination of the area of intestinal perforation area may demonstrate fungal invasion of the mucosa [81]. It is unclear whether the perforation in these cases is primarily due to Candida or if Candida secondarily invades the injured bowel wall. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis" and "Spontaneous intestinal perforation of the newborn".)

●Liver and spleen abscesses – Liver and splenic abscesses are uncommon complications of systemic invasive candidiasis in neonates, occurring in approximately 1 to 3 percent of cases [65,85,86]. Malpositioned umbilical catheters and prolonged parenteral nutrition are reported risk factors. Ultrasound may demonstrate a single or multiple focal lesions.

●Osteoarticular infections – In the neonate, Candida osteomyelitis or arthritis rarely occurs as an isolated event and typically occurs because of disseminated bloodstream infection [87-89]. The signs and symptoms of these infections caused by Candida are similar to those that occur in septic arthritis or osteomyelitis caused by bacteria (ie, swelling and decreased range of motion). (See "Hematogenous osteomyelitis in children: Clinical features and complications" and "Bacterial arthritis: Clinical features and diagnosis in infants and children".)

●Skin abscesses – Skin abscesses resulting from septic emboli can be seen in neonates with candidemia and/or endocarditis [90]. They appear as clusters of painless pustules or nodules on an erythematous base. They can be distinguished from CCC based on the timing (the lesions in CCC are present around the time of birth) and the distribution (the lesions in CCC tend to be diffuse, whereas septic emboli from candidemia typically occur in isolated focal areas in the skin). (See 'Congenital cutaneous candidiasis' above.)

To distinguish fungal from bacterial infections in these sites, the diagnosis is dependent upon isolating Candida from either the blood culture or other sample (eg, peritoneal fluid, synovial fluid, bone aspirate, surgical specimen).

EVALUATION FOR EXTENT OF DISEASE — Neonates with invasive Candida infections should undergo a thorough evaluation to determine the extent of systemic infection, which informs management decisions (table 2).

●Who to test – A full evaluation is warranted for any neonate in whom Candida has been identified in the blood, urine, or cerebrospinal flid (CSF) culture or other appropriate specimen.

Testing generally is not necessary in neonates with superficial mucocutaneous infections (eg, oral thrush, diaper dermatitis) unless there are other clinical concerns for systemic infection.

●Tests to perform – The following tests should be performed (table 2) [45,65,91]:

•Cultures of the blood, urine, and CSF

•Dilated eye examination to assess for eye involvement (see 'Eye involvement' above)

•Echocardiography to assess for vegetations (see 'Endocarditis' above)

•Ultrasound imaging of the kidney, bladder, liver, and spleen (see 'Urinary tract infection' above and 'Other organ involvement' above)

•Head ultrasound (see 'Central nervous system infection' above)

Although any organ can be involved, the most common sites are the bloodstream, urinary tract, and CNS.

DIAGNOSIS — The diagnosis of mucocutaneous candidiasis depends upon the presentation. Superficial skin and mucous membrane infections (eg, oral thrush, diaper dermatitis) are diagnosed clinically. Invasive candidiasis is diagnosed by isolating Candida in culture of a normally sterile site (blood, urine, cerebrospinal fluid [CSF]).

Oral thrush and diaper dermatitis — Oropharyngeal candidiasis (oral thrush (picture 1)) and Candida diaper dermatitis (picture 2A-B) are diagnosed clinically based on the characteristic appearance. It is usually not necessary to obtain cultures of the lesion. In refractory cases that do not respond to topical therapy, a culture may be useful to identify the Candida species and assess its susceptibility profile. (See 'Superficial mucocutaneous infections' above and "Candida infections in neonates: Treatment and prevention", section on 'Treatment of superficial mucocutaneous infections'.)

Invasive skin infections

●Invasive fungal dermatitis – Invasive fungal dermatitis may be suspected based upon the appearance of skin lesions (macular, papular, vesicular, or pustular lesions in dependent or intertriginous areas of the skin). The definitive diagnosis is confirmed by a skin biopsy with isolation or histologic identification of the organism.

●Congenital cutaneous candidiasis (CCC) – In patients with CCC, a presumptive diagnosis can be made by identifying the organism by Gram stain of the vesicular contents or by potassium hydroxide preparations of skin scrapings (picture 6). Confirmation of the diagnosis is made with isolation of the organism from a culture of the discrete lesions or swabs of the affected skin areas.

Candidemia and invasive candidiasis — Neonates with documented invasive Candida infection should undergo evaluation to determine the extent of infection. (See 'Evaluation for extent of disease' above.)

●Blood culture – The diagnosis of candidemia is made by isolating a Candida species from the blood culture (picture 7). Modern blood culture media can efficiently isolate the most common Candida species (ie, C. albicans and C. parapsilosis), usually with a time to positivity that is ≤48 hours [92-94]. If a central venous catheter is present, obtaining blood samples for cultures both through the catheter and from a peripheral vessel can help distinguish between disseminated infection and catheter-related infection. However, removal of the catheter is necessary in either scenario, as discussed separately. (See "Candida infections in neonates: Treatment and prevention", section on 'Treatment based on extent of disease'.)

●Urine culture – The diagnosis of Candida urinary tract infection (UTI) is based upon a positive urine culture (ie, >10,000 colony forming units per mL [CFU/mL] in a catheterized specimen or >1000 CFU/mL in a specimen collected by suprapubic aspiration) [58,95]. "Clean voided" bag urine samples should not be used for culture, as there is a high rate of false-positive results.

●CSF culture – The diagnosis of Candida central nervous system (CNS) infection is made by isolating a Candida species from the CSF culture. CSF parameters (eg, cell count, chemistries) are variable; normal CSF parameters do not exclude CNS involvement, because the inflammatory response may be limited or delayed.

●Other tests – Other tests that can be used to support the diagnosis of invasive fungal infections include the beta-D-glucan assay (a blood test that detects a cell wall component of many fungi) and molecular methods (eg, polymerase chain reaction [PCR]) [96,97]. However, the beta-D-glucan test does not perform well in neonates and is not specific for Candida (it can be positive in patients with other invasive fungal infections, including Aspergillus) [45,96]. PCR testing for Candida is a more sensitive and specific test [97], but it is not available in most settings. These tests are discussed in greater detail separately. (See "Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis", section on 'Nonculture methods' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

●Incidence

•Noninvasive infections (oral thrush, diaper dermatitis) – Noninvasive Candida infections (eg, oral thrush, diaper dermatitis) are very common in newborns, with approximately 10 to 20 percent of healthy infants being affected at least once during the first few months of life. (See 'Incidence' above.)

•Invasive infection – The incidence of invasive Candida infections in the general neonatal population is approximately 5 to 10 cases per 100,000 live-born infants. Reported rates of invasive Candida infections among neonates admitted to the neonatal intensive care unit (NICU) range from 0.5 to 2 percent. Among extremely low birth weight (ELBW; <1000 g) infants, the incidence is 5 to 15 percent. (See 'Incidence' above.)

●Microbiology – Candida albicans is the most common cause of Candida infections in neonates, though C. parapsilosis accounts for substantial minority (approximately 20 to 30 percent). Other species (eg, C. tropicalis, C. lusitaniae, C. glabrata, C. krusei, and C. auris) are far less common. (See 'Microbiology' above.)

●Risk factors for invasive Candida infection – Important risk factors for invasive Candida infection include prematurity (the risk increases with decreasing gestational age), exposure to broad-spectrum antibiotics, and the presence of invasive devices (eg, central venous or arterial catheters, endotracheal tubes, urinary catheters). Additional risk factors are summarized in the table (table 1). (See 'Risk factors for invasive candidiasis' above.)

●Clinical manifestations and diagnosis – The manifestations vary depending on the site and extent of infection. (See 'Clinical manifestations' above and 'Diagnosis' above.)

•Oropharyngeal candidiasis (oral thrush) appears as irregular white plaques with or without an erythematous base on the buccal or lingual mucosal surface of the mouth (picture 1). Thrush is diagnosed clinically based on its characteristic appearance. (See 'Oropharyngeal candidiasis (thrush)' above.)

•Candida diaper dermatitis is characterized by an area of confluent erythema in the inguinal region, discrete erythematous papules and plaques with superficial scales, and satellite lesions (picture 2A-B). Candida diaper dermatitis is diagnosed clinically based on its characteristic appearance. (See 'Diaper dermatitis' above and "Diaper dermatitis".)

•Invasive fungal dermatitis is a condition that is unique to ELBW infants and presents during the first two weeks after birth. The lesions vary in appearance, including macular, papular, vesicular, or pustular lesions that are typically independent or intertriginous areas of the skin. Invasive fungal dermatitis is diagnosed with skin biopsy. Dissemination of infection to the bloodstream is common. (See 'Invasive fungal dermatitis' above.)

•Congenital cutaneous candidiasis (CCC) is a rare condition that results from in utero or early perinatal infection. It typically presents on the first day after birth with a generalized maculopapular eruption (picture 3A-B). CCC is diagnosed based on isolation of the organism from a culture of the discrete lesions or swabs of the affected skin areas. (See 'Congenital cutaneous candidiasis' above.)

•Invasive candidiasis (see 'Candidemia and invasive candidiasis' above):

-Candidemia – The presentation of neonatal candidemia is indistinguishable from that of late-onset bacterial sepsis. Signs are nonspecific and may include lethargy, feeding intolerance, jaundice, glucose intolerance, apnea, and/or cardiorespiratory instability. The diagnosis is made by isolating a Candida species from a blood culture. (See 'Candidemia' above.)

-Urinary tract infection (UTI) – Candida UTI commonly accompanies candidemia, though it can occur in isolation. Clinical manifestations are generally nonspecific and similar to those of candidemia. Findings specific to the kidney and/or urinary tract may be noted in some cases (eg, urinary obstruction, hypertension, or acute kidney injury). The diagnosis of Candida UTI is based upon a positive urine culture (>10,000 colony forming units per mL [CFU/mL] in a catheterized specimen or >1000 CFU/mL in a specimen collected by suprapubic aspiration). (See 'Urinary tract infection' above.)

-CNS infection – CNS involvement, which typically manifests as meningitis, is common in infants with disseminated infection. The presentation varies from a subacute, indolent illness to severe illness with cardiorespiratory instability and multiorgan failure. The diagnosis of Candida CNS infection is made by isolating a Candida species in cerebrospinal fluid (CSF) culture. CSF parameters (eg, cell count, chemistries) are variable; normal CSF parameters do not exclude CNS involvement, because the inflammatory response may be limited or delayed. (See 'Central nervous system infection' above.)

-Other organ involvement – Other sites of infection may include the eyes, heart valves (endocarditis), liver, spleen, intestines, peritoneum, bones, and joints. Infection at these sites usually occurs from disseminated bloodstream infection. (See 'Eye involvement' above and 'Endocarditis' above and 'Other organ involvement' above.)

●Evaluation for extent of disease – Neonates who are diagnosed with invasive Candida infection should undergo a thorough evaluation to determine the extent of systemic infection (table 2). (See 'Evaluation for extent of disease' above.)