Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants

Abstract

Invasive fungal infection is an important cause of mortality and morbidity in very preterm (< 32 weeks gestation) or very low birth weight (VLBW) infants. Clinical uncertainly exists about the effect of prophylactic oral/topical non-absorbed antifungals to reduce mucocutaneous colonisation and so limit the risk of invasive fungal infection in this population. To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and morbidity in VLBW infants. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 - May 2009), EMBASE (1980 - May 2009), conference proceedings, and previous reviews. Randomised controlled trials that compared the effect of prophylactic oral/topical non-absorbed antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very preterm or VLBW infants. Data were extracted using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by each review author and synthesis of data using relative risk (RR) and risk difference (RD) and weighted mean difference (WMD). Three trials, in which a total of 1625 infants participated, have compared oral/topical non-absorbed antifungal prophylaxis (nystatin or miconazole) with placebo or no drug. These trials had various methodological weaknesses including quasi-randomisation, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment. The incidence of invasive fungal infection was very high in the control groups of two of the included trials. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection [typical RR 0.19 (95% confidence interval (CI) 0.14, 0.27); typical RD -0.19 (95% CI -0.22,-0.16)] but substantial statistical heterogeneity was detected. A statistically significant effect on mortality was not found [typical RR 0.88 (95% CI 0.72, 1.06); typical RD -0.02 (95% CI -0.06, 0.01)]. Long-term outcomes were not assessed by any of the trials.One small trial (N = 21) that assessed the effect of oral/topical non-absorbed antifungal prophylaxis (nystatin) compared with systemic antifungal (fluconazole) prophylaxis was underpowered to exclude important clinical effects. The finding of a reduction in risk of invasive fungal infection in infants treated with oral/topical non-absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non-absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long-term neurodevelopmental outcomes.