Article Text
Abstract
Systematic review and meta-analysis of four randomised controlled trials suggest that prophylactic fluconazole reduces the incidence of invasive fungal infection in very low birthweight infants. Further trials are needed to provide more precise estimates of effect size, and to assess the effect on mortality, neurodevelopment and the emergence of antifungal resistance.
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Given the difficulty in establishing an early diagnosis, and the high level of associated morbidity and mortality, there is a need to assess the effect of strategies to prevent invasive fungal infection in very low birthweight (VLBW) infants (<1500 g).1 Prophylactic use of topical or oral non-absorbed antifungal agents (nystatin and miconazole) can prevent fungal colonisation. However, currently there are insufficient data to conclude that topical/oral prophylaxis reduces the incidence of invasive fungal infection or mortality in VLBW infants in the modern neonatal intensive care setting.2 Over the past few years, the prophylactic use of systemic antifungal agents, principally fluconazole, has been adopted as routine practice in some centres. Even in the UK, where the overall incidence of invasive fungal infection in VLBW infants is low, clinicians in 1 in 8 neonatal units routinely prescribe fluconazole prophylaxis.3 However, there are concerns that widespread use of fluconazole prophylaxis may contribute to the emergence of antifungal resistance.4
We undertook a systematic review of randomised controlled trials of systemic antifungal prophylaxis for VLBW infants to assess the effect on invasive fungal infection and mortality. The derived risk ratios were applied to the UK population of VLBW infants to provide estimates of effect size (number needed to treat (NNT)) that may be used to guide practice and inform the development of future trials.
METHODS
We searched the Cochrane Library, MEDLINE, EMBASE (until July 2007), and abstracts from the Society for Pediatric Research and the European Society for Pediatric Research (until 2007) for randomised controlled trials comparing prophylactic treatment of VLBW infants consisting of a systemically absorbed antifungal agent with placebo or no drug treatment (see appendix A for search terms).
The prespecified outcomes were:
Confirmed invasive fungal infection defined as:
culture of fungus from a normally sterile site;
findings on autopsy examination consistent with invasive fungal infection;
findings on ophthalmological examination consistent with fungal ophthalmitis or retinitis;
pathognomonic findings on renal ultrasound.
Death prior to hospital discharge.
Neurodevelopmental outcomes assessed using validated assessment tools.
The title and abstract of all of the studies and the full text of any potentially relevant study were screened. Two reviewers evaluated methodological quality and separately extracted data from each included study. A fixed effect model was used for meta-analysis. Heterogeneity between trials was examined using a χ2 statistic. The risk ratios from the meta-analyses were applied to the incidences of invasive fungal infection in VLBW infants and extremely low birthweight (ELBW) infants (<1000 g) estimated by the UK national surveillance study to calculate UK-specific numbers needed to treat.1
RESULTS
We identified four trials in which a total of 536 infants participated.5–8 Three were North American single-centre trials, and the fourth was an eight-centre trial undertaken in Italy. All compared fluconazole with placebo (table 1). The trials were generally of good methodological quality. All achieved satisfactory allocation concealment, blinding of parents or carers and assessors to the intervention, and completeness of assessment in all participants. The primary outcomes were the incidence of fungal colonisation and invasive infection. The three larger trials also reported mortality prior to hospital discharge and assessed changes in the pattern of fluconazole resistance in fungal isolates during the trial period. One trial reported neurodevelopmental outcomes.4
Incidence of invasive fungal infection
Meta-analysis of data from the four trials found a significantly lower incidence of invasive fungal infection in the fluconazole group (typical relative risk (RR) 0.23, 95% CI 0.11 to 0.46; typical risk difference (RD) −0.11, 95% CI −0.16 to −0.06; NNT 9, 95% CI 6 to 17). There was no statistical heterogeneity in this meta-analysis (fig 1). Applying the risk ratio to the estimated incidence of invasive fungal infection in VLBW infants in the UK (1%), the NNT to prevent one extra case of invasive fungal infection is 130 (95% CI 112 to 185). For ELBW infants (UK incidence 2.1%), the NNT is 62 (95% CI 54 to 88).
Death prior to hospital discharge
Three studies reported all-cause mortality.5 6 8 Fifty-seven of 525 infants died. There was no significant difference in any of the individual trials, nor in a meta-analysis of data (typical RR 0.61, 95% CI 0.37 to 1.03; typical RD −0.05, 95% CI −0.11 to 0). There was no statistical heterogeneity in this meta-analysis (fig 1).
Developmental outcomes
Only one trial assessed developmental outcomes.5 There were no significant differences in the incidence of developmental delay (modified Gesell test) or motor or sensory neurological impairment in children assessed at a median age of 16 months.
Antifungal resistance
None of the studies found any significant changes in the minimal inhibitory concentration of fluconazole in fungal isolates during the study period.
DISCUSSION
The available data suggest that prophylactic systemic antifungal treatment reduces the incidence of invasive fungal infection in VLBW infants. The pooled effect size estimates that treating nine infants with prophylactic fluconazole would prevent one extra case of invasive fungal infection. The included trials were generally of good methodological quality and the absence of statistical heterogeneity in the meta-analysis suggests that the estimate is robust. However, this finding should be interpreted and applied with caution for several reasons.
First, in the trials that contributed most weight to the pooled estimate of effect size, the incidence of invasive fungal infection in the placebo group was 13–16%, which is much higher than the 1–2% incidence found in the UK national surveillance study.1 If fluconazole prophylaxis was adopted throughout the UK, 62 ELBW (or 130 VLBW) infants would require treatment to prevent one extra case of invasive fungal infection. Second, the diagnostic sensitivity of microbiological culture for invasive fungal infection is lower in infants receiving systemic antifungal treatment. This may cause selective underdiagnosis in the treatment group and overestimation of the effect size. For that reason, mortality was included as a primary outcome since it is not likely to be affected by ascertainment bias. Furthermore, as it is often difficult to define precisely the cause of death in VLBW infants, and since invasive fungal infection is not always diagnosed, all-cause mortality rather than death attributed to fungal infection was prespecified. The review did not find a significant effect on all-cause mortality but the 95% confidence interval around the estimate of effect is wide (63% risk reduction to 3% risk increase). Data from further trials may provide a more precise estimate of the effect on mortality. There is also a need for long-term follow-up to determine if any beneficial effect on mortality is accompanied by an increase in the incidence of adverse neurodevelopmental outcomes.
Although the available data are reassuring in terms of the emergence of fluconazole resistance, the follow-up periods of the trials (up to 30 months) are insufficient to detect clinically important changes in the resistance profile of fungal isolates. Continuing mycological surveillance is essential in neonatal units where systemic antifungal prophylaxis is used. Limiting prophylaxis to infants at highest risk may help delay the emergence of antifungal resistance. UK clinicians who use fluconazole prophylaxis already target the smallest and least mature ELBW infants with additional risk factors, such as prolonged use of multiple broad-spectrum antibiotics or central venous catheters.3 If further trials of systemic antifungal prophylaxis are undertaken, it may be appropriate to restrict participation to this population of infants, or even smaller or lower gestation infants.
Acknowledgments
We thank the editors of the Cochrane Neonatal Review Group for their input to the Cochrane Library version of this review and Drs Kaufman and Kicklighter for providing unpublished data and clarification of aspects of their studies.
Appendix A: Search terms
Infant, Newborn
Infant, Very Low Birth Weight
Infant, Premature
1 or 2 or 3
Mycoses/drug therapy
Antifungal Agents/
fungi
candida
antifungal
fluconazole
azole
amphotericin
5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12
4 AND 13
The searches were limited to "clinical trial" with the relevant filter. We did not apply any language restriction.
Footnotes
Competing interests: WMcG has received research funds from Pfizer UK Ltd, a manufacturer of fluconazole. This company had no role in the collection, analysis and interpretation of data, or in the writing of the report or decision to submit for publication.