From the Department of Pediatrics, University of Lübeck, Germany.
Department of Pediatrics, University of Leipzig, Germany.
Pediatr Infect Dis J. 2018 Nov;37(11):1165-1171. doi: 10.1097/INF.0000000000002001.
The diagnostic proof of fungal infection in preterm infants is difficult. Antifungal treatment (AFT) is often initiated empirically when infants with suspected infection do not improve despite broad-spectrum antibiotic therapy. It was the aim of our study to determine the rate of exposure to empirical AFT in a large cohort of very low birth weight infants (VLBWI) of the German Neonatal Network and to address associated risks and outcomes.
The epidemiologic database consisted of n = 13,343 VLBWI born in 54 German Neonatal Network centers between 2009 and 2015. AFT was defined as number of neonates who got any dose of at least one of the following antifungal drugs: fluconazole, amphotericin B, voriconazole and caspofungin (denominator: number of infants enrolled in German Neonatal Network) for treatment (not prophylaxis) of (suspected) fungal infection. Univariate and logistic regression analyses were used to identify risk factors for exposure to AFT and associated short-term morbidities and long-term outcomes at 5-year follow-up.
In our cohort, 724 out of 13,343 (5.4%) VLBWI were exposed to empiric AFT and had a mean gestational age of 25.7 (±2.1) weeks. Forty-four out of 13,343 (0.3%) had proven bloodstream infection with Candida spp. The main risk factors for exposure to AFT were gestational age, postnatal steroid treatment, need for abdominal surgery and use of carbapenems. Notably, AFT was associated with adverse outcomes such as bronchopulmonary dysplasia [adjusted odds ratio (OR): 1.9; 95% confidence interval (CI): 1.6-2.3; P < 0.001) and retinopathy of prematurity requiring intervention (adjusted OR: 1.69; 95% CI: 1.3-2.3; P <0.001) but not mortality. In the subgroup of infants available for 5-year follow-up (n = 895), exposure to AFT was associated with a risk for cerebral palsy (adjusted OR: 2.79; 95% CI: 1.11-7.04; P = 0.04) and intelligence quotient < 85 (adjusted OR: 2.07; 95% CI: 1.01-4.28; P = 0.049).
A significant proportion of VLBWI is exposed to AFT, specifically those born <26 weeks. Exposed infants were found to have a higher risk for adverse outcomes, which may reflect their significant vulnerability in general. Given the observational design of our study, it remains unclear whether potential side effects of empirical or target AFT itself contribute to adverse outcome. Future studies need to include risk-based strategies and stewardship programs to restrict the use of antifungal management in VLBWI.
早产儿真菌感染的诊断证据很难获得。当疑似感染的婴儿在接受广谱抗生素治疗后仍未改善时，常经验性地开始抗真菌治疗（AFT）。我们的研究旨在确定在德国新生儿网络的一个大型极低出生体重儿（VLBWI）队列中经验性 AFT 的暴露率，并探讨相关风险和结局。
该流行病学数据库包括 2009 年至 2015 年期间在德国新生儿网络的 54 个中心出生的 13343 名 VLBWI。AFT 定义为接受任何剂量至少一种以下抗真菌药物的新生儿数量：氟康唑、两性霉素 B、伏立康唑和卡泊芬净（分母：纳入德国新生儿网络的婴儿数量），用于（疑似）真菌感染的治疗（非预防）。采用单变量和逻辑回归分析确定暴露于 AFT 及相关短期并发症和 5 年随访时长期结局的风险因素。
在我们的队列中，13343 名 VLBWI 中有 724 名（5.4%）接受了经验性 AFT，平均胎龄为 25.7（±2.1）周。13343 名中有 44 名（0.3%）患有确诊的血流感染念珠菌属。暴露于 AFT 的主要风险因素是胎龄、产后类固醇治疗、需要腹部手术和使用碳青霉烯类药物。值得注意的是，AFT 与支气管肺发育不良（调整后的优势比（OR）：1.9；95%置信区间（CI）：1.6-2.3；P <0.001）和需要干预的早产儿视网膜病变（调整后的 OR：1.69；95%CI：1.3-2.3；P <0.001）等不良结局相关，但与死亡率无关。在可进行 5 年随访的婴儿亚组（n=895）中，暴露于 AFT 与脑瘫（调整后的 OR：2.79；95%CI：1.11-7.04；P=0.04）和智商<85（调整后的 OR：2.07；95%CI：1.01-4.28；P=0.049）的风险相关。
相当一部分 VLBWI 接受了 AFT，特别是那些胎龄<26 周的婴儿。接受治疗的婴儿被发现发生不良结局的风险更高，这可能反映了他们普遍的脆弱性。考虑到我们研究的观察设计，尚不清楚经验性或靶向 AFT 本身的潜在副作用是否会导致不良结局。未来的研究需要包括基于风险的策略和管理计划，以限制在 VLBWI 中使用抗真菌治疗。
