Background
The prevalence of invasive fungal infections accounts for 10 % of all cases of late-onset infection (occurring at least 72 h after birth) in very-low-birth-weight (VLBW) preterm neonates (<1500 g) [
1]. Due to their incomplete immunity and exposure to required invasive procedures and medications (e.g., broad-spectrum antibiotics, parenteral nutrition, H2 blockers and corticosteroids), preterm neonates are at high risk of invasive fungal infections, particularly infections with Candida species [
2,
3]. The consequences of invasive fungal infections are severe. The reported mortality rates are 21–32 % in VLBW infants and 40–50 % in extremely-low-birth-weight (ELBW, i.e., <1000 g) infants [
4,
5]. Significantly higher incidences of short-term morbidity (retinopathy of prematurity, chronic lung disease and periventricular leukomalacia) and long-term complication (neurodevelopmental impairment) have been reported in preterm infants who develop invasive fungal infections compared with infants without invasive candidiasis [
6,
7]. The challenge is to establish adequate prevention strategies for such vulnerable populations and has resulted in the establishment of prevention strategies that aim to reduce the incidence of invasive fungal infection in preterm neonates.
A broad chemo-prophylactic strategy with fluconazole has shown efficacy, safety and long-term neurodevelopmental outcomes in neonatal intensive care units (NICUs) with a high burden (≥15 %) of candidiasis, as demonstrated in both randomized controlled trial (RCT) and non-RCT studies [
8‐
14]. Austin and McGuire’s recent systematic review, which included seven trials involving 880 infants, concluded that prophylaxis with fluconazole or nystatin may be beneficial over no prophylaxis in terms of the incidence of invasive fungal infections but that it is unlikely to produce a better outcome in terms of mortality [
15]. Clinical practice guidelines suggest the administration of prophylactic fluconazole for neonates with a birth weight of less than 1000 g in NICUs [
16]. A recent study found that 42 days of prophylactic fluconazole resulted in a 6 % (95 % CI, 1 % to 11 %,
P = 0.02) decrease in the incidence of invasive candidiasis in premature infants with a birth weight of less than 750 g. However, this treatment did not decrease mortality or neurodevelopmental impairment [
17].
Although these studies indicate that prophylactic fluconazole is both safe and effective for preventing invasive fungal infections, the obvious differences in their comparative efficacy profiles remain. These differences include the duration of prophylaxis and the dosing regimen of fluconazole, which should be assessed. The current meta-analysis aimed to quantitatively pool the results of head-to-head RCTs to examine whether an increased duration of prophylaxis or an increased dosing of fluconazole would improve the outcomes of prophylaxis with fluconazole compared with no prophylaxis in preterm neonates in the NICU.
Discussion
This study extends the prior analyses regarding the choice between prophylaxis with fluconazole and no prophylaxis for the prevention of invasive fungal infections. The current meta-analysis demonstrates that the use of fluconazole for prophylaxis, compared with no prophylaxis, decreases the risk of invasive fungal infections in preterm infants in NICUs. These findings are consistent with the results of Austin’s study, which pooled data from seven trials and showed that the RR of invasive fungal infections between a systemic antifungal agent and no prophylaxis was 0.41 (95 %CI: 0.27 to 0.61) [
15]. This effect was driven by the studies that employed a 42-day course of prophylaxis (RR: 0.30 ([95 % CI: 0.27–0.61]). A reduction of invasive candidiasis was not found in the subgroup of studies that used a shorter 28-day course of prophylaxis (RR: 0.80 [95 % CI: 0.48–1.35]). Because the mean length of stay in NICUs is greater than 40 days and preterm neonates in NICUs are at high risk for systemic fungal infections, the use of prophylactic fluconazole may be most effective within the NICU phase because it would prevent Candida colonization during the first 4 to 6 weeks of the neonates’ life [
13,
24,
25]. This hypothesis may need to be tested through an RCT.
Regarding the dosing of prophylactic fluconazole, clinicians have raised concerns about the safety and cost of fluconazole prophylaxis treatment [
12]. One pharmacokinetic analysis showed that a dose of 3 or 6 mg/kg twice weekly for early prevention during the first 42 days of life is equivalent to an area under the concentration curve (AUC) of 50 or 100 mg × h/L, respectively, and maintains fluconazole concentrations of at least 2 or 4 g/mL, respectively, for half of the dosing interval. For late prevention, a dose of 6 mg/kg every 72 h provides similar exposure as a daily dose of 3 mg/kg. These findings indicate that twice-weekly prophylaxis regimens can provide adequate serum levels for the prevention of invasive candidiasis when the unit-specific minimum inhibitory concentration (MIC) is taken into account [
26,
27]. The current meta-regression suggests that the average dosage of fluconazole (mg/kg/day) and total dose of fluconazole (mg/kg) for the duration of prophylaxis are not significantly associated with the log(RR) of invasive fungal infections. These results are consistent with Manzoni’s findings, which showed no significant differences between the 6-mg and 3-mg arms [
10]. Basically, the findings for these two factors similarly imply that the duration of prophylaxis appears to significantly influence the fluconazole effect. Furthermore, the low dosing of fluconazole indicates that the MICs of fungal strains causing colonization or infection significantly increased over a 10-year period in various NICUs [
13].
Prophylactic fluconazole did not significantly reduce death before discharge. This finding is similar to those obtained in other meta-analyses [
15,
28], but should be carefully explained because the mortality rates in the RCT studies that were included in the meta-analysis were ≤20 % and invasive fungal infections contributed to approximately 20 % of the mortalities [
29]. The previous RCT studies may not have had sufficient power to detect the impact of prophylactic fluconazole on mortality associated with fungal infection due to their relatively small sample sizes (<200 infants in each arm) [
8‐
11,
17]. The low baseline incidence of invasive candidiasis may contribute to the lack of a significant reduction in mortality mediated by a fluconazole-induced reduction in invasive infection. The non-RCT studies found that prophylactic fluconazole eliminated all Candida-related mortality in preterm infants in NICUs [
24,
30].
The limitations of the current analysis should be noted. The first possible limitation is that this study did not compare the efficacy and safety of fluconazole with those of other systemic antifungal agents, such as nystatin, due to the wide usage of prophylactic fluconazole in NICUs. Specifically, more than 20 studies examined fluconazole prophylaxis in more than 5000 neonates [
29]. Furthermore, this study did not include trials that investigated the efficacy and safety of prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in premature infants because of the methodological weaknesses of these trials [
28]. The second limitation is the lack of individual-level data, which prohibited the evaluation of the associations between individual variables and the study outcomes. Instead, we used between-study meta-regressions when possible. Third, the results are limited to Western preterm neonates due to the absence of data on Eastern preterm neonates, and a recent systematic review found a higher incidence of
C. parapsilosis in Australia and North America compared with Europe, as demonstrated by the selected studies from North America (11.4 %) and Europe (13.2 %) in the current meta-analysis [
31]. The different epidemiology may have an impact on the clinical decision of prophylaxis [
32]. Fourth, the safety profile of prophylactic fluconazole was not used as an outcome in the current meta-analysis because serious adverse events or fluconazole-related toxic effects are similar to those observed without prophylaxis. Fifth, the small sample size of the trials that were included in the current analysis may have impacted the trials’ ability to detect events related to fungal infections and mortality. This bias should be taken into account. Finally, this meta-analysis did not include neurodevelopmental impairment as an endpoint because multiple factors can affect neurodevelopmental impairment [
33]. Further larger trials with long-term outcome data are needed.
Conclusion
A six-week course of prophylactic fluconazole decreases late-onset invasive candidiasis. The mortality rate was slightly improved with prophylactic fluconazole compared with no prophylaxis, but the difference was not significant. By weighing the costs and health benefits, a low-intensity dosing and regimen of fluconazole may be employed. However, the clinical decision of administering prophylactic fluconazole routinely to preterm infants should be made based on the local setting, including the epidemiology. Further studies are needed to evaluate the effectiveness and safety of different regimens of fluconazole. Furthermore, the appropriate duration of treatment is an important issue that merits further evaluation through high-quality RCTs.
Abbreviations
ELBW, extremely-low-birth-weight; NICUs, neonatal intensive care units; PRISMA, preferred reporting items for systematic reviews and meta-analyses; RCT, randomized controlled trial; RRs, relative risks; VLBW, very-low-birth-weight
Acknowledgments
We would like to thank the anonymous reviewers for the very useful comments and suggestions which help us improve the quality of our paper.
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