Can We Prevent Serious Neonatal Candida Infection?
Editor's Note:

Fungi, particularly Candida species, are important hospital-acquired pathogens in infants admitted to the neonatal intensive care unit (NICU) and are currently the third most frequent cause of late-onset sepsis in in very low-birthweight (VLBW) preterm neonates. The incidence is greatest in extremely low-birthweight (ELBW) infants, who have birthweights less than 1000 g and represent an increasing share of preterm infants. The true burden of these infections in this vulnerable group of infants is probably underestimated because early diagnosis is challenging and the clinical presentation can be subtle.

Recognizing these infants early is critical to improving the significant morbidity and mortality associated with these infections. Medscape spoke with Paolo Manzoni, MD, coordinator and chairman of the Collaborative Network on Neonatal Fungal Infection of the Society of Neonatal Infectious Diseases and faculty in the Division of Neonatology at Sant'Anna Hospital in Torino, Italy. Dr. Manzoni recently chaired a session on neonatal infections that was held in conjunction with the annual meeting of the European Society for Paediatric Infectious Diseases.

Medscape: Dr. Manzoni, invasive fungal infections are most common in the smallest infants, although estimates of prevalence vary widely. Is the increase in numbers of ELBW infants who survive likely to result in an increase in overall incidence? Are there other risk factors, modifiable or unmodifiable, that contribute to risk for these infections?

Dr. Manzoni: Indeed, the increase in overall survival of the most immature and premature infants is likely to be associated with a possible increase in incidence of many diseases and conditions related both to prematurity and to the need for care in an ICU. In this view, preterm neonates have to be considered as a population with increased, specific risk for fungal infections, and preventative strategies should be optimized and offered to them.

Among these strategies, the identification of and interventions on all modifiable risk factors are a priority. These include promotion of fresh human milk feeding and use of probiotics. Another important consideration is appropriate medical stewardship of antibiotics, steroids, and H₂-blockers, whose use should be restricted in premature infants. Finally, proper management of central lines and surgical devices is important.

Medscape: Can you briefly summarize the data on the efficacy of intravenous fluconazole in prevention of invasive candidal infections? Is the therapy effective in preventing only bloodstream infections, or is there evidence that sepsis, meningitis, peritonitis, and urinary tract infections (UTIs) are prevented?

Dr. Manzoni: The available evidence on prophylactic fluconazole in preterm infants comes from 4 randomized controlled trials (RCTs) published in 2001-2007. These studied demonstrated that fluconazole 3 mg/kg/dose administered to VLBW neonates every second or third day from birth and up to day 45 of life decreases Candida infections (at any site) by 85%, Candida colonization by 80%, Candida-attributable mortality to nil, and overall (all-cause) mortality by 24%.

Consistent with any other preventative intervention, this strategy obviously has the highest impact in settings with high Candida incidences. However, in neonatal subpopulations with low incidence rates, the number need to treat should be evaluated before widespread implementation of such a strategy.

Medscape: Which infants are candidates for this prophylactic therapy? Is there a subset of infants that can be anticipated to have the most positive result?

Dr. Manzoni: Clearly, the highest-risk infants can be anticipated to have the most benefit from fluconazole prophylaxis. Hence, ELBW neonates, as well as neonates with congenital gastrointestinal disorders or malformations, may receive the highest degree of protection compared with other preterm neonates whose risk is lower (eg, a neonate weighing 1500 g who can be breastfed soon after birth).

Medscape: What are some of the barriers to more widespread use of this therapy?

Dr. Manzoni: A recent European survey conducted by our European Union-funded, collaborative European network TINN (Treat Infections In Neonates) reports that some 55% of European NICUs are currently adopting this strategy. According to this study, most neonatologists who were reluctant to use prophylactic fluconazole in their NICUs described themselves as concerned about the lack of evidence for this practice. Neonatologists not using prophylactic fluconazole also reported that they were concerned about the risks of emerging resistance. Finally, some respondents noted that they were not using prophylaxis owing to an absence of Candida colonization or infection in their own nurseries.

However, currently available class A evidence supports the practice of prophylaxis and does not support a concern about resistance. Evidence also does not support a contention that some nurseries are without risk for Candida.

Medscape: Can you speak a little more about the issue of azole resistance?

Dr. Manzoni: Azole resistance is related to a single patient's exposure and length of therapy; when the NICU is considered, resistance is also related to the overall cumulative dose of fluconazole to which a single nursery has been exposed. In both cases, the neonatal setting (and the neonatal patient) have peculiarities that, in theory, should protect from the occurrence of such phenomena, at least for short periods.

A single neonate is exposed to no more than 45 days of twice-a-week fluconazole administration -- that is, to only 13 doses (a cumulative exposure of 39 mg/kg). As a whole, an NICU usually has only some 20%-30% of patients concomitantly allocated to prophylaxis; thus, its cumulative exposure is much lower than that in other settings where this problem has been reported. Recent data show that after 10 years of routine use of prophylactic fluconazole in 2 different NICUs, no emergence of resistance occurred and no shift toward Candida species inherently resistant to fluconazole was detected.

Medscape: Are there other prophylactic strategies that should be considered?

Dr. Manzoni: Probiotics, such as Lactobacillus rhamnosus GG and Lactobacillus reuteri, may help preventing enteric colonization by Candida species in preterm infants, but no effect to date has be seen on invasive candidiasis. In contrast, bovine lactoferrin proved effective in a multicenter RCT in preventing neonatal sepsis, including Candida infections, and looks like a very promising strategy to be further evaluated.

Medscape: What about the long-term developmental outcome of infants treated with fluconazole compared with that of children who develop invasive candidal infections?

Dr. Manzoni: When evaluating the efficacy of a neonatal preventative strategy, such as fluconazole, the ultimate and most important outcome should be disability-free survival and the long-term neurodevelopmental, behavioral, and cognitive performance of the child. Currently, we have plenty of evidence that invasive fungal infection in premature neonates heavily and negatively affects all of these endpoints, even when the infection is properly managed in the NICU and the infant is discharged free of disease. Even the most effective antifungals may not be that effective in preventing the long-term negative consequences of the infection. Research must address what seems to be a logical question: Does prevention of the infection translate into prevention of the poor outcomes related to the infection?

A recently published first contribution to this evidence gap found that infants who received fluconazole prophylaxis have normal neurodevelopmental and behavioral skills at 8-10 years of age. Further data corroborating these findings are expected to be generated in the next couple of years by the European TINN consortium and a recently completed collaborative study in the United States.