Prevention of Candida infection in neonates

INTRODUCTION — Candida is a major cause of neonatal infection in preterm infants, especially in extremely low and very low birth weight infants [1-4]. Successful management of neonatal candidiasis requires effective treatment of Candida infection with appropriate antifungal therapy, supportive care, and preventive measures to reduce the risk of systemic Candida infections.

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

BACKGROUND — Prevention of systemic candidal infections in preterm neonates is important because candidemia is associated with poor clinical outcomes in this population. Prevention efforts have focused on the very low birth weight (birth weight <1500 g) and extremely low birth weight (ELBW; birth weight <1000 g) infants who are at the highest risk for invasive candidal infections. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Epidemiology' and "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)

Preventive management includes general measures that can be applied broadly to all infants in the neonatal intensive care unit (NICU) and administration of prophylactic antifungal agents, which is reserved for ELBW infants who are cared for in NICUs with a high baseline rate of systemic fungal infection.

GENERAL MEASURES — General measures are focused upon reducing cross-infection of Candida in the neonatal intensive care unit (NICU) and risk factors that increase the likelihood of candidemia. These include:

●Handwashing, use of gloves, and avoidance of artificial fingernails to reduce the rate of horizontal transmission from health care worker to infant – However, these measures alone may not be sufficient to prevent horizontal transmission, because of the difficulty in eradicating Candida from the hands of health care workers. In one study, commonly used antiseptics or disinfectants for handwashing demonstrated varying degrees of in vitro inhibition of growth of Candida species recovered from hospitalized patients [5].

●Single-room isolation or cohorting infants who are known to be colonized or infected with Candida – With this intervention, health care workers can be segregated to only caring for infants with candidal colonization/infection and caring for noninfected/noncolonized infants. Although patient isolation or cohorting is often a recommended routine infection control measure, there are no clinical trials demonstrating that this practice prevents Candida cross-infection in the NICU [6].

●Reduction of risk factors associated with Candida overgrowth (ie, high density of candidal colonization), which increases the likelihood of disseminated systemic infection – Interventions that promote overgrowth of Candida include H2 receptor antagonists, proton pump inhibitors, broad-spectrum antibiotics (eg, third-generation cephalosporins and imipenems), and glucocorticoids [7-9]. In addition, the use of topical petrolatum is associated with an increase in invasive fungal infection [10]. Minimizing or avoiding these risk factors, if clinically appropriate, may decrease the density of candidal colonization and the likelihood of candidemia [11]. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)

●Medical hardware, such as central venous catheters, that provides a site for bloodstream invasion and/or colonization – Removing central venous catheters once they are no longer needed helps to reduce all types of nosocomial bacteremia, including candidemia. Nutrition policies that promote early initiation and advancement of enteral feeding may reduce central line days. (See "Parenteral nutrition in premature infants" and "Approach to enteral nutrition in the premature infant".).

ANTIFUNGAL PROPHYLAXIS

Targeted prophylaxis — Based upon the available evidence, our approach is to use a targeted approach to antifungal prophylaxis rather than routinely providing prophylaxis for all preterm infants. This approach is consistent with the recommendations of the American Academy of Pediatrics and the Infectious Diseases Society of America [12-14]. Broad use of antifungal prophylaxis for all preterm infants is discouraged because of the concern of promoting resistant Candida species within the NICU. Universal prophylaxis in an NICU with a low incidence of candidiasis would expose a large number of infants to fluconazole to prevent a single case of infection.

Targeted antifungal prophylaxis is reserved for extremely low birth weight (ELBW) infants who are at high risk of Candida infection, including:

●ELBW infants cared for in neonatal intensive care units (NICUs) with a high baseline rate of systemic fungal infection (ie, greater than 5 to 10 percent), or

●ELBW infants who require antibiotic therapy for >48 hours (eg, for a confirmed bacterial infection or necrotizing enterocolitis)

Choice of agent — When antifungal prophylaxis is provided, we suggest fluconazole rather than other agents. (See 'Fluconazole' below.)

We prefer fluconazole over other agents because it is the drug that has been studied most commonly in high-quality clinical trials and it has demonstrated efficacy in this setting [15]. Oral nystatin is a reasonable alternative. Studies directly comparing fluconazole with nystatin are limited to three small trials with very few events. In a meta-analysis of the three trials, the overall rate of invasive fungal infection was lower with fluconazole compared with nystatin; however, the findings was not statistically significant (3 versus 6 percent; risk ratio 0.53, 95% CI 0.19-1.52) [15].

Fluconazole — Clinical trials in preterm infants have demonstrated that prophylactic fluconazole reduces candidal colonization and invasive infection in preterm infants [15-17].

●Dosing – Fluconazole is started within the first 48 to 72 hours after birth at a dose of 6 mg/kg per dose given intravenously (IV) or enterally twice a week for four to six weeks or until the infant no longer requires IV access [12,18,19].

●Efficacy in reducing invasive fungal infection – In a meta-analysis of 10 trials (including 1371 very preterm or VLBW infants), systemic antifungal prophylaxis reduced the incidence of invasive fungal infection compared with placebo or no drug (6.2 versus 15.7 percent; RR 0.43, 95% CI 0.31-0.59); the effect on mortality was not statistically significant (12.7 versus 17.3 percent; RR 0.79, 95% CI 0.61-1.02) [15]. Nine of the 10 trials used systemic fluconazole prophylaxis. Results were similar among ELBW (ie, birth weight <1000 g) infants who are the most vulnerable to invasive candidiasis. In the subgroup analysis (which included two studies with a total of 461 ELBW infants), systemic antifungal prophylaxis reduced the incidence of invasive fungal infection (RR 0.30, 95% CI 0.14-0.63), but the effect on mortality was not statistically significant (RR 0.82, 95% CI 0.55-1.23). The trials in the meta-analysis were generally of good methodologic quality; however, the incidence of baseline invasive candidal infection in these trials (16 percent) was much higher than that reported from large cohort studies (<5 percent).

●Long-term effects – Data on long-term outcomes for neonates treated with prophylactic fluconazole are very limited. In the few patients evaluated, there appears to be no long-term adverse effects of prophylactic fluconazole therapy in ELBW survivors [20]. In the previously discussed meta-analysis, one trial found no difference in neurodevelopmental status and quality of life in the 38 of the 86 survivors who were evaluated in a follow-up study [20-22]. There were also no differences in growth or long-term risk of cholestasis. In a clinical trial of ELBW infants, after adjusting for confounding factors, there was no difference in neurodevelopmental outcomes at 18 to 22 months corrected age between the fluconazole prophylaxis and control groups, based on Bayley-III cognition composite scores, or a diagnosis of blindness, deafness, or cerebral palsy [16].

Nystatin and miconazole — Nystatin and miconazole are local antifungal agents without systemic distribution because they are not well absorbed from the gastrointestinal tract.

Several trials have shown that prophylactic use of oral or topical nonabsorbed agents reduces the risk of candidiasis [23-27]. In a meta-analysis of four trials (including 1800 very preterm or very low birth weight [VLBW] infants), prophylactic therapy reduced the incidence of invasive fungal infection compared with placebo (relative risk [RR] 0.2, 95% CI 0.14-0.27); the effect on mortality was nonsignificant (RR 0.87, 95% CI 0.72-1.05) [21]. However, these results need to be interpreted cautiously because of methodologic limitations of the included trials (including quasi-randomization, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment) and because there was significant heterogeneity between trials.

No role for surveillance cultures — Systematic screening for Candida colonization has been suggested as a possible tool in preventing fungal infections in high-risk patients by initiating antifungal therapy when colonization is detected [28]. However, this approach is not routinely used in most NICUs. Further studies are needed to determine if the benefits outweigh the risks and costs of screening for fungal colonization in high-risk neonates and if antifungal therapy should be initiated when colonization is detected.

EMPIRIC ANTIFUNGAL THERAPY — There are no guidelines for initiating empiric therapy for invasive candidiasis like those that exist for group B Streptococcus infections. While early empiric antifungal therapy (ie, prior to receiving culture results) theoretically might improve outcomes for neonates with candidemia, it is generally not part of routine NICU practice since Candida accounts for a only small proportion of all late-onset bloodstream infections in this population. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Epidemiology'.)

In an observational study of 136 extremely low birth weight (ELBW) infants with invasive candidiasis who were cared for at the National Institute of Child Health and Human Development's Neonatal Research Network sites in the United States, mortality rates were similar for infants who did or did not receive empiric antifungal therapy prior to culture results (33 versus 35 percent, respectively) [29]. However, those who received empiric antifungal therapy were more likely to survive without neurodevelopmental impairment (50 versus 36 percent).

The approach to managing suspected invasive candidiasis in neonates is presented separately. (See "Treatment of Candida infection in neonates", section on 'Invasive infection'.)

LACTOFERRIN AND PROBIOTICS — The use of lactoferrin and/or probiotics to reduce gastrointestinal Candida colonization has been suggested. However, until it has been shown that this intervention is beneficial and safe, and an effective standardized regimen has been developed, the use of lactoferrin and probiotics should be limited to clinical trials.

●Lactoferrin – Based on the available evidence, it remains uncertain if lactoferrin supplementation meaningfully reduces fungal sepsis in preterm infants. If there is an effect, it appears to be small. In a 2020 meta-analysis of six trials (3266 infants), enteral lactoferrin supplementation decreased invasive fungal infection compared with placebo (0.4 versus 1.7 percent; relative risk [RR] 0.23, 95% CI 0.10-0.54) [30]. However, there were few events (33 total episodes in the six trials), the absolute effect size was small (absolute risk difference 1.3 percent [98% CI 0.8-1.5]), and two of the trials had important methodologic limitations that may have biased the findings. In the largest trial, which involved >2200 preterm neonates randomized to enteral bovine lactoferrin or placebo (sucrose), rates of documented fungal sepsis were similar in both groups (0.3 versus 0.2 percent, respectively) [31].

●Probiotics – The use of probiotics to prevent fungal and bacterial infections in neonates has been studied in randomized clinical trials [32]. However, important uncertainties and safety concerns remain, and we suggest not routinely using probiotics for this purpose.

In a meta-analysis of two trials (329 patients), probiotics reduced rates of Candida colonization in preterm infants (12 versus 31 percent; RR 0.43, 95% CI 0.27-0.68) [32]. Despite the apparent large effect in reducing colonization, probiotics did not appear to have a meaningful impact on reducing the incidence of fungal sepsis (1.8 versus 2 percent; RR 0.88, 95% CI 0.44-1.78; six trials, 1259 patients). The studies included in the meta-analysis varied considerably with regard to the probiotic product used and birth weight and gestational age of enrolled infants. In addition, the individual trials were relatively small (80 to 400 patients) and many were deemed to be at high risk of bias.

Other important uncertainties remain, including optimal probiotic strains, doses, and duration of therapy. Appropriate regulatory control of these products is another unresolved issue. In addition, rare but serious cases of probiotic-associated sepsis have been reported [33-36].

Lactoferrin and probiotics for the prevention of sepsis in preterm neonates are discussed in greater detail separately. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Potential prophylactic therapy'.)

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

●Importance – Prevention of systemic candidal infections in preterm neonates is important because candidemia is associated with poor clinical outcomes in this population. Prevention efforts have focused on the very low birth weight (birth weight <1500 g) and extremely low birth weight (ELBW; birth weight <1000 g) infants who are at the highest risk for invasive candidal infections. (See "Clinical manifestations and diagnosis of Candida infection in neonates" and "Epidemiology and risk factors for Candida infection in neonates".)

●Our suggested approach

•General measures – General preventive measures to reduce neonatal candidal infection include efforts aimed at reducing candidal cross-infection (eg, handwashing and use of gloves) and efforts aimed at reducing the risk factors for candidemia (eg, antibiotic stewardship limiting use of broad-spectrum antibiotics, removing central venous catheters once they are no longer needed). (See 'General measures' above.)

•Selective use of antifungal prophylaxis in high-risk neonates – For ELBW infants who are at increased risk of candidal infection (eg, those cared for in centers where the rate of fungal infections is >5 percent or those who require antibiotic therapy for >48 hours), we suggest prophylactic antifungal therapy (Grade 2B). For other preterm neonatal populations, routine use of fungal prophylaxis is generally not necessary. Broad use of antifungal prophylaxis for all preterm infants is discouraged because of the concern of promoting resistant Candida species within the neonatal intensive care unit (NICU). Universal prophylaxis in an NICU with a low incidence of candidiasis would expose a large number of infants to antifungal therapy to prevent a single infection. (See 'Antifungal prophylaxis' above.)

•Preferred prophylactic antifungal agent – When prophylactic antifungal therapy is used, we suggest fluconazole rather than other agents (Grade 2C). Fluconazole is started within the first 48 to 72 hours after birth at dose of 6 mg/kg per dose given intravenously (IV) or enterally twice a week for four to six weeks or until the infant no longer requires IV access. We prefer fluconazole over other agents because it is the drug that has been most commonly studied in high-quality clinical trials and it has demonstrated efficacy in this setting. (See 'Fluconazole' above.)

●Strategies not recommended - We suggest not using lactoferrin supplementation or probiotics for the purpose of reducing fungal infections in preterm neonates (Grade 2C). (See 'Lactoferrin and probiotics' above.)