Epidemiology and risk factors for Candida infection in neonates

INTRODUCTION — Infections due to Candida are some of the major causes of mortality and morbidity in preterm infants, especially in extremely low birth weight (ELBW) and very low birth weight (VLBW) infants [1-4].

The epidemiology and risk factors for neonatal candidal infections will be reviewed here. The clinical manifestations, prevention, and treatment of neonatal candidal infections are presented separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates" and "Prevention of Candida infection in neonates" and "Treatment of Candida infection in neonates".)

EPIDEMIOLOGY

Incidence — The overall incidence of invasive Candida infections in neonates is approximately 5 to 10 cases per 100,000 live-born infants [5-7]. Candida species are particularly important hospital-acquired pathogens in infants admitted to the neonatal intensive care unit (NICU) [3,4,8]. Reported rates of invasive Candida infections in the NICU setting range from 0.5 to 2 percent [4,9-13]. The incidence varies depending on the average gestational age and birth weight of the cohort studied: The risk is greatest among preterm infants with extremely low birth weight (ELBW; birth weight <1000 g). Reported rates of invasive candidiasis in ELBW infants range from 5 to 15 percent [4,9-12,14].

In a report from a multicenter surveillance system in 30 NICUs in the United Kingdom from 2005 to 2014, Candida species were identified as the causative pathogen in 4 percent of all cases of late-onset neonatal sepsis (defined as ≥48 hours after birth) with positive cultures [8].

Rates of different Candida species — Candida albicans is the most commonly isolated Candida species in neonates, accounting for 60 to 75 percent of cases, followed by Candida parapsilosis, accounting for approximately 20 to 30 percent [4-6,8,15-19]. Other Candida species include Candida tropicalis, Candida lusitaniae, Candida glabrata, and Candida krusei. C. krusei and C. glabrata may be relatively resistant to fluconazole, and C. lusitaniae is completely resistant to amphotericin B. (See "Management of candidemia and invasive candidiasis in adults".)

A change in the distribution of Candida species causing candidemia has been noted in several institutions with increasing isolation of nonalbicans species in neonates [1,20,21]. Neonatal infections caused by nonalbicans species occur at a later age and are more likely to be acquired from the hospital environment compared with C. albicans [22,23]. Although the use of prophylactic fluconazole in preterm neonates does not appear to be responsible for increased nonalbicans Candida infections, it is important to monitor the relative incidences of the different candidal species as fluconazole use increases in NICU patients [22-24]. (See "Prevention of Candida infection in neonates", section on 'Fluconazole'.)

Trend for Candida infections — The overall incidence of candidiasis in NICUs in the United States appears to be decreasing [5,13,25]. 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 results suggest that use of broad-spectrum antibiotics is an important risk factor for invasive candidal infection. (See 'Risk factors for invasive candidiasis' below.)

In a multicenter study from the Pediatrix Medical Group, the overall incidence of neonatal invasive candidiasis decreased from 0.36 to 0.14 percent from 1997 to 2010 [13]. 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 "Prevention of Candida infection in neonates".)

SITE OF INFECTION — Invasive blood stream infections are the most common neonatal presentation of Candida infections. Other candidal infections include meningitis; endocarditis; abscesses in the kidneys, spleen, and liver; endophthalmitis; skin infections; urinary tract infection; and osteomyelitis [27].

Candidemia may be primary or secondary to other sites of primary infection. In the previously mentioned National Nosocomial Infections Surveillance study, 14 percent of the cases (n = 288 cases) were classified as secondary [4]. The primary site of infections included the urinary tract (35 percent), gastrointestinal tract (18 percent), skin or soft tissue (15 percent), lung (13 percent), central nervous system (8 percent), cardiovascular system (5 percent), and other sites (5 percent).

PATHOGENESIS — Candidal infections in the neonate are usually dependent upon transmission of the organism from a carrier, colonization of the infant by the organism, and penetration of the organism through the host epithelial barriers.

Transmission — Neonatal Candida colonization is most commonly the result of vertical transmission from the mother; however, horizontal transmission from health care workers or the hospital environment also plays an important role [28,29].

●Vertical transmission – Using molecular typing techniques, vertical transmission of C. albicans, C. parapsilosis, and C. glabrata has been documented [28,30]. Heavy maternal Candida colonization or vaginitis increases the vertical transmission of the organism and neonatal colonization [31]. 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 [29]. 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 performed on isolates from colonized mother/infant pairs, in which the infants were colonized by C. albicans by one week of age, demonstrated identical banding patterns in 11 of the 13 pairs (85 percent), confirming vertical transmission.

●Horizontal transmission – Several outbreaks of C. albicans [32-37], C. parapsilosis [38,39], C. tropicalis [40], and C. lusitaniae [41] infection have been reported due to horizontal transmission from health care staff. In particular, the primary mode of transmission for C. parapsilosis is horizontal from health care workers [28,42]. In one multicenter study, C. parapsilosis was the most common species cultured from the hands of health care workers [23]. Of the 2989 cultures, C. parapsilosis was recovered in 19 percent of samples and C. albicans in 5 percent. However, the carriage rates did not correlate with the neonatal intensive care unit (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 (3 days), stainless steel (14 days), and fabrics (14 days) for significant time periods [43]. In addition, contamination of medications [44], retrograde medication administration using multiple-use syringes [30], and glycerin suppository [45] have been reported as sources of candidal infectious outbreaks.

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 [30,46].

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 [47]. Approximately 85 percent of the colonization occurred in the first two weeks of life. 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 [30].

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. In a study of 40 VLBW infants, infants with heavy candidal colonization (defined as a colony count of 8 × 10⁶ Candida colony-forming units/g of stool) were more likely to have feeding intolerance, bloody stools, and candidemia compared with those with lower counts [48]. Factors that promote gastrointestinal overgrowth, such as the use of broad-spectrum antimicrobial agents, are associated with an increased risk of Candida infection [1,22,24,47,49-51]. (See 'Risk factors for invasive candidiasis' below.)

Patients who are intubated can have colonization of their upper respiratory tract and are at increased risk of invasive candidal infection [52].

Penetration of host defense — The penetration of the organism through the epithelial barriers from the sites of colonization results in locally invasive or disseminated infection. The balance between benign colonization and invasive infection is primarily dependent on host factors, which are discussed in the next section.

RISK FACTORS FOR INVASIVE CANDIDIASIS — Infants admitted to the neonatal intensive care unit (NICU) are at increased risk for developing invasive candidal infection (defined as a positive culture from blood, urine, or cerebrospinal fluid), especially premature infants [3,18,19,27,53], for the following reasons:

●Immunocompromised host – Neonates, especially premature infants, have immature immune systems. Preterm infants have low levels of circulating maternal immunoglobulin G (IgG) because of the loss of transplacental transfer that occurs during the third trimester of pregnancy. Even in the presence of adequate IgG concentrations, opsonization and complement functions are reduced in infants, especially in preterm infants. Neutropenia is also a common finding in premature infants with candidal infections [54]. The epithelial barriers in preterm infants are immature. In these infants, the skin and mucosal barriers are thin and delicate, readily break down, and provide minimal protection.

●Compromise of epithelial barriers – Neonatal intensive care therapy often requires invasive measures that compromise the host epithelial barrier, such as central venous and arterial catheters, intubation, and surgery [49-52,55]. These invasive procedures are more likely to be performed in infants who are seriously ill (such as those with shock, antenatal asphyxia, or respiratory distress) or who are premature. Clinical conditions, such as necrotizing enterocolitis or skin breakdown, that compromise the host epithelial barriers are also risk factors for candidiasis.

●Increased density of candidal colonization – Factors that promote candidal overgrowth, such as the use of broad-spectrum antimicrobial agents, increase the risk of candidiasis [1,22,24,47,49-51]. These interventions occur more frequently in the preterm infant. (See 'Colonization' above.)

●Multiplicity of colonization sites in infants [54].

These points were illustrated in the National Mycosis Survey study that prospectively followed 2847 infants at six NICUs and identified the following as independent risk factors for candidemia [55]:

●Endotracheal intubation (odds ration [OR] 10.7, 95% CI 1.7-450)

●Length of NICU stay >7 days (OR 5.3, 95% CI 1.2-48)

●Gestational age <32 weeks (OR 4, 95% CI 1.2-14.4)

●Presence of a central venous catheter (OR 3.9, 95% CI 1.5-12.3)

●Exposure to ≥2 parenteral antibiotics (OR 3.8, 95% CI 1.4-11.4)

●Shock (OR 3.6, 95% CI 1.6-7.7)

●Five-minute Apgar score <5 (OR 3.4, 95% CI 1.3-8.1)

●Total parenteral nutrition for >5 days (OR 2.9, 95% CI 1.1-8.4)

●Intralipid infusion alone for >7 days (OR 2.9, 95% CI 1.2-7.2)

●Exposure to H2 blockers (OR 2.4, 95% CI 1.1-5.3)

In another prospective study of 1515 extremely low birth weight (ELBW) infants, identifiable risk factors for invasive candidiasis included previous antibiotic therapy and the presence of a central catheter or endotracheal tube [14]. In addition, increased virulence of the candidal species is associated with a greater risk for invasive disease [56].

Similar risk factors were reported in a retrospective study of larger infants with a birth weight >1500 g. In this report, invasive candidal infections occurred in 330 of 530,162 infants (0.06 percent). In this cohort, the risk factors identified by multivariate logistic regression analysis included the use of broad-spectrum antibiotics and central venous catheter as well as a day of life greater than seven days [57]. Additional risk factors not reported in the National Mycosis study were thrombocytopenia (platelet count <50,000/microL), vaginal birth, and use of prophylactic antifungal agents.

Neonates with multiple or profound 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 [58]. In one study, risk factors for early-onset infection included birth weight <750 g, gestational age <25 weeks, maternal chorioamnionitis, and vaginal delivery [58]. Mortality was considerably high 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.

SUMMARY

●Candida has emerged as a common cause of infections in infants admitted to the neonatal intensive care unit (NICU), particularly preterm infants. The risk is greatest among infants with extremely low birth weight (ELBW; birth weight <1000 g), in whom rates of invasive candidiasis range from 5 to 15 percent. (See 'Incidence' above.)

●Candida albicans is the most commonly isolated Candida species, followed by Candida parapsilosis. Other less common species include Candida tropicalis, Candida lusitaniae, Candida glabrata, and Candida krusei. Neonatal infections caused by nonalbicans species occur at a later age and are more likely to be hospital acquired. (See 'Rates of different Candida species' above.)

●Bloodstream infections are the most common neonatal presentation of invasive Candida infections. Other candidal infections include meningitis; endocarditis; abscesses in the kidneys, spleen, and liver; endophthalmitis; skin infections; urinary tract infection; and osteomyelitis. (See 'Site of infection' above.)

●Candidal infections in the neonate are usually dependent upon transmission of the organism from a carrier, colonization of the infant by the organism, and penetration of the organism through the host epithelial barriers. (See 'Pathogenesis' above.)

●Most candidal infections are due to vertical transmission from the mother. In some cases, infections, particularly those due to C. parapsilosis, are the result of horizontal transmission from health care staff or hospital environment. (See 'Transmission' above.)

●Candida generally colonizes the skin, gastrointestinal tract, lower female genital tract, intertriginous areas, and the foreskin of uncircumcised males. In the neonate, colonization usually precedes invasive fungal infection. The rate of colonization increases with decreasing birth weight. Almost two-thirds of ELBW infants (birth weight <1000 g) are colonized by six weeks of age. (See 'Colonization' above.)

●Infants admitted to the NICU, especially premature infants, are at increased risk for candidal infections because of the immaturity of their immune systems and host epithelial protection, compromise of their epithelial protection with invasive procedures (eg, intubation, central venous catheters, and/or surgery), and factors that promote increased density of candidal colonization (eg, administration of broad-spectrum antimicrobial agents). (See 'Risk factors for invasive candidiasis' above.)

●Systemic candidiasis is a significant cause of neonatal mortality and morbidity, with reported mortality rates of 20 to 40 percent. (See "Treatment of Candida infection in neonates", section on 'Outcome'.)