Duke Clinical Research Institute, Durham, North Carolina.
University of Florida College of Medicine-Jacksonville.
JAMA. 2014 May 7;311(17):1742-9. doi: 10.1001/jama.2014.2624.
Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown.
To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants.
DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013.
Fluconazole (6 mg/kg of body weight) or placebo.
The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age.
Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]).
Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants.
clinicaltrials.gov Identifier: NCT00734539.
侵袭性念珠菌病在早产儿中可导致死亡和神经发育损伤。氟康唑预防可减少念珠菌病，但它对死亡率和氟康唑的安全性尚不清楚。
评估氟康唑预防极低出生体重儿死亡或侵袭性念珠菌病的疗效和安全性。
设计、地点和患者：这是一项氟康唑治疗早产儿的随机、双盲、安慰剂对照试验。来自美国 32 个新生儿重症监护病房（NICU）的出生体重<750 g 的婴儿（N = 361）被随机分为两组，分别接受每周两次氟康唑（6 mg/kg 体重）或安慰剂治疗 42 天。存活婴儿在 18 至 22 个月校正年龄时进行神经发育结局评估。该研究于 2008 年 11 月至 2013 年 2 月进行。
氟康唑（6 mg/kg 体重）或安慰剂。
主要终点为研究日 49 天（研究药物完成后 1 周）前死亡或明确或可能侵袭性念珠菌病的复合结局。次要和安全性结局包括侵袭性念珠菌病、肝功能、细菌感染、住院时间、颅内出血、脑室周围白质软化、慢性肺病、需要手术的动脉导管未闭、需要手术的早产儿视网膜病变、坏死性小肠结肠炎、自发性肠穿孔和神经发育结局（定义为校正年龄 18 至 22 个月时贝利-III 认知综合评分<70、失明、失聪或脑瘫）。
接受氟康唑治疗的婴儿中，死亡或侵袭性念珠菌病的复合主要终点为 16%（95%CI，11%-22%），而安慰剂组为 21%（95%CI，15%-28%；比值比，0.73 [95%CI，0.43-1.23]；P=0.24；治疗差异，-5% [95%CI，-13%至 3%]）。氟康唑组侵袭性念珠菌病的发生率较低（3% [95%CI，1%-6%]），而安慰剂组为 9%（95%CI，5%-14%；P=0.02；治疗差异，-6% [95%CI，-11%至-1%]）。两组其他次要结局的累积发生率无统计学差异。两组神经发育障碍的发生率也没有差异（氟康唑组为 31% [95%CI，21%-41%]，安慰剂组为 27% [95%CI，18%-37%]；P=0.60；治疗差异，4% [95%CI，-10%至 17%]）。
在出生体重<750 g 的婴儿中，与安慰剂相比，氟康唑预防 42 天并未降低死亡或侵袭性念珠菌病的复合发生率。这些发现不支持在极低出生体重儿中普遍使用预防性氟康唑。
clinicaltrials.gov 标识符：NCT00734539。
