• Infectious Diseases
• Pharmacology
• Neonatology

Progressive changes in clinical practice have improved the survival of even the most vulnerable neonates, such as those born preterm or with a very low birth weight (VLBW). Frequent contacts with healthcare workers, invasive procedures, early exposure to large scale antibiotics and immature immune systems, however, can cause additional, healthcare related, nosocomial infections.

It is estimated that 2.5% of all bloodstream infections occurring in VLBW infants in neonatal intensive care units (NICUs) have a fungal aetiology.1 Candida species (mainly Candida albicans and Candida parapsilosis) are the third most commonly isolated pathogens in the nursery, acquired vertically from the mother or horizontally from the NICU environment, with an estimated incidence of 1.6%–9% in VLBW and 10%–16% in extremely low birthweight (ELBW) infants.2 Candida colonisation is a primary risk factor for the development of invasive candidiasis, estimated to be three times more common in infants born <26 weeks of gestation or with a <750 g birth weight than in infants with 750–1000 g birth weights.3

Antifungal prophylaxis has been proposed to reduce mortality in this vulnerable population, and fluconazole is emerging as the drug of choice because of its ability to treat more than 90% of Candida species isolates, its high oral bioavailability, and its established safety and tolerability profiles. Fluconazole is currently approved by the European Medicines Agency (EMA) and the Food and Drug Administration for use in adults for the treatment of vaginal candidiasis, oropharyngeal and oesophageal candidiasis, and cryptococcal meningitis. Additionally, it is approved by the EMA for the treatment, in term newborns, of mucosal candidiasis, invasive candidiasis, cryptococcal meningitis and for invasive candidiasis prophylaxis in immune-compromised children. Fluconazole has also been included in the EMA's priority list of off-patent products with the greatest need for studies in newborns.

Since 2001, the safety and efficacy of fluconazole prophylaxis in VLBW and ELBW infants have been demonstrated in eight retrospective studies, three prospective randomised controlled trials (RCTs) and two Cochrane meta-analyses. Nevertheless, fluconazole prophylaxis in this population remains controversial and the debate is focused on the efficacy of its routine use to prevent candida infections and on whether this prevention translates into substantial improvements in the outcomes of prematurity. According to the results of the last RCT, involving 361 ELBW infants randomised to receive either fluconazole twice weekly for 42 days or placebo, prophylaxis did not significantly reduce the combined risk of death or invasive candidiasis,4 confirming the results of the more recent meta-analysis.3 In line with the Infectious Disease Society of America and the European Society of Clinical Microbiology and Infectious Diseases guidelines, Benjamin et al4 justify the routine use of antifungal prophylaxis in carefully selected patients and recommend limiting it to units that have moderate-to-high rates of invasive candidiasis despite the implementation of measures targeting known risk factors such as adequate hand hygiene of healthcare workers, careful implementation of vascular systems, rational use of antibiotics, reduction of the enteral nutrition period and avoidance of H₂ blockers use.

Current evidence suggests that treating 11 VLBW infants would prevent one case of invasive fungal infection.3 Thus, when the incidence of such infections in NICUs is lower (<2%), prophylaxis is viewed as unethical given the high number of infants who would be exposed. In deciding whether to use prophylaxis, it is also essential to consider the difficulty in diagnosing invasive candidiasis in neonates with sepsis due to its non-specific clinical presentation and to the low sensitivity of current microbiological diagnostic techniques. At birth, most infants are not colonised or have low colony counts; the risk period starts at 1 week of life and extends well into the third month. The median number of days between the first positive candida culture and death was found to be 13 days, and a delay in administration of systemic antifungals causes central nervous system infections and death. Empirical treatment is an option for high risk patients, that is, those presenting a combination of extreme prematurity, thrombocytopenia and intake of broad spectrum antibiotics, since it has been shown to decrease mortality from candidiasis, although it does not seem to reduce the risk of neurodevelopmental impairment or other morbidities associated with these infections.

Fluconazole prophylaxis was also found to limit the effects of fungal sepsis on the central nervous system. Benjamin et al report that it appears safe, with no association found with adverse neurodevelopmental impairment when comparing language, cognition and motor development scores between the two groups. No significant differences were found in the fraction of infants who developed cerebral palsy, blindness or deafness.4 Nevertheless, neurodevelopmental impairment is a frequent outcome of fungal infection in surviving premature infants, with potentially severe long-term effects.

With increased use of prophylaxis, empirical antifungal therapies and avoidance of broad-spectrum antibiotics, invasive candidiasis in hospitalised infants has decreased over the last 14 years from 3.6 to 1.4 per 1000 infants per year, with the greatest decrease among infants with 750–999 g birth weights.5 Besides reducing the incidence of candidiasis in individual ELBW infants and, more generally, in NICUs implementing it,5 fluconazole prophylaxis significantly decreases the rate and number of days of bacterial infections and co-infections.

Over half of European NICUs reported using antifungal prophylaxis, although with large variations in frequency and dose.2 A NICU's decision to implement prophylaxis is strongly influenced by the risk of increasing resistance, the number of extremely preterm infants resuscitated and cared for in that NICU, and the need for additional efficacy data.2 Several studies have addressed the issue of increasing resistance following increased use of prophylaxis but, to date, there is a paucity of data reporting persistent candida infections due to azole-resistance.3

Regarding the current research situation, a study is being planned by the Pediatric Trials Network aiming to analyse the safety data from the RCTs on fluconazole prophylaxis, and, probably as a consequence of enrolment issues, only three studies on fluconazole are currently ongoing5 (table 1). A formal study evaluating the socioeconomic effects of reducing invasive candidiasis through prophylaxis would also be useful given the importance of cost related factors.

In conclusion, according to Benjamin et al, the use of prophylaxis for preventing mortality is not supported by research. Current recommendations support the use of fungal prophylaxis only for ELBW infants receiving care in NICUs with high rates of invasive candidiasis.3 ,4 Much controversy remains over which infants would benefit from its use and if, and when, antifungal prophylaxis should be started or whether it is better to wait until the infection has been diagnosed. Prophylactic practices are not infallible and have their limits (eg, the use of antibiotics for prevention of early-onset infections or ibuprofen/indomethacin for prevention of patent ductus arteriosus). In contrast, many reports have demonstrated the beneficial effects of early or prophylactic surfactant therapy for preterm infants who often develop respiratory distress syndrome. Benefits arising from preventing invasive candidiasis through fluconazole prophylaxis should take into account the local risk factors for candidemia (based on the annual incidence of confirmed cases) and must be well balanced with the potential risks, if this practice should become routine, such as side effects and drug interactions, considering that this population often has several disorders requiring polypharmacy. The findings of ongoing trials and future research will surely further contribute to this debate.