氟康唑预防极低出生体重儿真菌感染有效性和安全性的Meta分析

Meta-analysis of the efficacy and safety of fluconazole in prophylaxis of fungal infection in very low birth weight infants

目的对NICU高危极低出生体重儿预防性应用氟康唑的有效性及安全性的研究进行Meta分析，为更好地预防性使用氟康唑提供依据。方法制定原始文献的纳入标准及检索策略，检索Cochrane图书馆临床对照试验数据库、PubMed、EMBASE、Ovid全文数据库、近3年有关新生儿感染和抗生素应用的国际儿科会议、中国生物医学文献光盘数据库、中国期刊全文数据库和中国维普数据库中的文献，收集有关对极低出生体重儿预防性应用氟康唑的随机对照临床研究，剔除不符合要求的文献，应用RevMan4．2软件进行Meta分析，采用异质性检验（齐性检验），然后统计合并效应量（加权合并，计算效应尺度及95％CI），得出合并后的RR值及其95％CI。结果共5篇文献符合纳入标准进入Meta分析。数据合并分析结果显示，预防性应用氟康唑可以明显降低极低出生体重儿的真菌定植率，从48％降低到11％，RR值（95％CI）为0．32（0．23to0．44），P〈0．00001；明显降低真菌感染率，从15％降低到6％，RR值（95％CI）为0．44（0．29 to 0．65），P〈0．0001；病死率差异性无统计学意义，RR值（95％CI）为0．68（0．43 to 1．07），P=0．09；预防性使用氟康唑没有增加对极低出生体重儿的肝脏和胆红素等不良反应，对念珠菌的最低抑菌浓度也没有影响，但对是否增加氟康唑耐药菌的发生率结论不同。结论对NICU中高危的极低出生体重儿预防性使用氟康唑可以明显降低真菌的定植率和感染率，但有可能增加氟康唑耐药菌株的发生。不同的NICU是否采用氟康唑预防用药，需要仔细评估，要根据不同NICU的真菌感染率制定不同的预防政策，需要定期随访真菌的感染率，动态观察氟康唑耐药菌株的发生率，随时对预防政策进行调整。

Objective To evaluate the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants. Methods PubMed, EMBASE, Ovid, China National Knowledge Infrastructure, Vip Chinese Periodical Database, Wanfang Chinese Periodical Database and Chinese Bio-medicine Database were searched for the ease-control study on the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants from Jan. 1994 to Jan. 2009. Articles were evaluated according to inclusion eriteria. Poor-quality studies were excluded, and RevMan 4. 22 software was applied for investigating the heterogeneity among individual studies and calculating the pooled risk ratio （RR） and 95% confidence interval （CI）. Results Five eligible randomized clinical trials were included. Four studies were graded as ＂A＂ and one study was graded ＂ B＂. Meta-analysis based on the included studies showed that the prophylactic fluconazole could significantly reduce the fungal colonization （RR： 0. 32 and 95% CI：0. 23 to 0. 44, P 〈0. 000 01 ） ;and infections （RR： 0. 44 and 95% CI：0. 29 to 0. 65, P 〈0. 0001 ） in very low birth weight neonates. However, there was no statistically significant difference between the infants treated and not treated with prophylactic fluconazole in the neonatal mortality （RR：O. 68 and 95% C]： O. 43 to 1.07, P = 0.09 ） and the prophylactic use of flueonazole did not show any side-effects on the liver and bilirubin. None of the studies found any significant changes in the minimal inhibitory concentration of fluconazole in fungal isolates during the study period. There were different results about the emergence of resistance to fluconazole. Conclusions Meta-analysis of five randomized controlled trials suggest that prophylactic fluconazole reduces the incidence of fungal colonization and invasive fungal infection in very low birth weight infants. Further trials arc needed to provide more precise evaluation on efficacy, and to assess the effect on mortality, neurodevelopment and the emergence of resistance to antifungal agents. Different NICU should have different policy on prophylactic flueonazole and also adjust the policy at different time according to the incidence of fungal infection and antifungal drug resistance.