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

 

Abstract

Background

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.

Objectives

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.

Search methods

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.

Selection criteria

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 collection and analysis

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).

Main results

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.

Authors' conclusions

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.

 

Plain language summary

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

Fungi such as candida (the organism that causes thrush) can cause severe infections in very low birth weight (VLBW) infants (birth weight less than 1.5 kilograms). These infections are often difficult to diagnose and frequently cause death or disability. Therefore, it may be appropriate to attempt to prevent such infections by giving VLBW infants antifungal drugs as a routine part of their care. This review assessed the effect of giving VLBW infants antifungal drugs that reduce skin and gut carriage of fungi to minimise the chances of a severe infection developing. The trials that were identified suggested that this treatment might reduce severe infection rates but there was no evidence that death rates were reduced. Larger and higher quality trials are needed to resolve this uncertainty.

 

摘要

背景

以預防性口服或外用不吸收性抗黴菌藥物預防非常低出生體重嬰兒之侵入性黴菌感染

侵入性黴菌感染在小於32周的早產兒或非常低出生體重嬰兒中是死亡與罹病的一個重要原因。以預防性口服或外用不吸收性抗黴菌藥物來減少此嬰兒族群的黏膜表皮黴菌移生進而降低侵入性黴菌感染風險的臨床成效並不確定。

目標

評估使用預防性口服或外用不吸收性抗黴菌藥物對於非常低出生體重嬰兒侵入性黴菌感染發生率、死亡率與罹病率的預防成效。

搜尋策略

使用Cochrane Neonatal Review Group的標準搜尋策略。包括搜尋Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2009), MEDLINE (196 May 2009), EMBASE (1980  May 2009)等資料庫與會議紀錄和之前的回顧。

選擇標準

比較對非常低出生體重或非常早產嬰兒預防性使用一口服或外用不吸收性抗黴菌藥物相對於安慰劑或無治療或另一種抗黴菌藥物或劑量處方之成效的隨機對照試驗(randomised controlled trials)

資料收集與分析

資料以Cochrane Neonatal Review Group的標準方法摘錄，每位作者分別評估試驗品質與資料摘錄。結果以relative risk (RR) and risk difference (RD) and weighted mean difference (WMD)等方式報告。

主要結論

我們找到3個預防性使用口服或外用不吸收性抗黴菌藥物(nystatin or miconazole)與安慰劑或無治療比較的試驗，總共1625嬰兒參與。這些試驗各有不同的方法學上的缺點，包括半隨機、缺乏分配的隱匿性與缺乏介入與結果評估的盲法。其中兩個試驗的控制組侵入性黴菌感染發生率非常高。統合分析發現統計學上顯著地降低侵入性黴菌感染的發生率[RR 0.19(95% CI 0.14, 0.27]，[RD −0.19(95% CI 0.22, −0.16]，但也發現試驗間統計學上的異質性。而死亡率無統計學上的顯著差別[RR 0.88(95% CI 0.72, 1.06]，[RD −0.02(95% CI −0.06, 0.01]。沒有任何一個試驗有分析長期後果。一個收案21個嬰兒的小試驗，比較預防性使用口服或外用不吸收性抗黴菌藥物(nystatin)相對於全身性抗黴菌藥物(fluconazole)的成效，因為檢力不足而排除其重要臨床成效。

作者結論

因為這些臨床試驗中方法學上的缺點，我們需小心解讀以預防性口服或外用不吸收性抗黴菌藥物能降低侵入性黴菌感染風險的研究發現。需要更多基於目前新生兒科之臨床實務環境的大型隨機控制試驗來解決此不確定性。這些試驗可比較口服或外用不吸收性抗黴菌藥物相較於安慰劑或不同藥物間或全身性抗黴菌藥物的效果並評估對長期神經發展的影響。

翻譯人

本摘要由高雄醫學大學附設醫院陳惇杰翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

以預防性口服或外用不吸收性抗黴菌藥物預防非常低出生體重嬰兒之侵入性黴菌感染。黴菌如造成鵝口瘡的念珠菌，可以造成非常低出生體重嬰兒(小於1.5公斤)的嚴重感染。這些感染通常難以診斷，且常造成嬰兒的死亡與殘障。因此給予這些非常低出生體重的嬰兒抗黴菌藥物來預防感染，當做例行照護的一部份也許是適當的。這篇回顧評估給予非常低出生體重的嬰兒抗黴菌藥物來減少皮膚與腸胃帶菌以降低嚴重感染發生機會的成效。這些找到的臨床試驗發現此治療也許會減少嚴重感染的發生率，但沒有降低死亡率的證據。需要更大型且更有品質的試驗來解決這些不確定性。