The impact of early empirical antibiotics treatment on clinical outcome of very preterm infants: a nationwide multicentre study in China
Authors: Zhu Yao , Yang Qing , Wu Fan , Mao Jian , Liu Ling , Zhang Rong , Shen Wei , Tang Lixia , Chang Yanmei , Ye Xiuzhen , Qiu Yinping , Ma Li , Cheng Rui , Wu Hui , Chen Dongmei , Zheng Zhi , Tong Xiaomei , Lin Xinzhu ,   on behalf of the Chinese Multicenter EUGR Collaborative Group, Tian Qianxin , Cui Qiliang , Ren Ling , Yuan Yuan , Shi Bizhen , Wang Yumei , Zhang Jinghui , Zhu Yan , Zou Jingjing , Li Yuhuai , Zhao Baoyin , Liu Shuhua , Xu Ying , Zhou Wenli , Liu Zhiyong , Gao Jinzhi , Liu Jing , Chen Ling , Li Cong , Yang Chunyan , Xu Ping , Zhang Yayu , Hu Sile , Mei Hua , Yang Zuming , Feng Zongtai , Wang Sannan , Meng Eryan , Shang Lihong , Xu Falin , Ou Shaoping , Ju Rong , Li Guinan , Yi Juan , Li Long , Liu Yongqiao , Zhang Zhe , Wu Meigui , Bei Fei , Liu Ye , Deng Chun , Yang Huijie , Su Ping , Chen Shifeng , Luo Lingying , Wang Linlin , Liu Xiaohong , Yan Lihua , Wang Lijun , Wang Xiaokang , Yu Shuqun , Zhu Qiaomian 
Published: January 2023

Abstract
Background
Infants with rule-out infections are responsible for the majority of empirical antibiotics treatment (EAT) in neonatal intensive care units (NICUs), particularly very preterm infants (VPIs). Antibiotic overuse has been linked to adverse outcomes. There is a paucity of data on the association between EAT and clinical outcomes (containing the nutritional outcomes) of VPIs without infection-related morbidities.

Methods
Clinical data of VPIs admitted in 28 hospitals in 20 provinces of China from September 2019 to December 2020 were collected. EAT of VPIs was calculated as the number of days with initial usage in the first week after birth, and then categorized into 3 groups (antibiotic exposure: none, 1-4 days, and > 4 days). Clinical characteristics, nutritional status , and the short-term clinical outcomes among 3 groups were compared and analyzed.

Results
In total, 1834 VPIs without infection-related morbidities in the first postnatal week were enrolled, including 152 cases (8.3%) without antibiotics, 374 cases (20.4%) with EAT ≤4 days and 1308 cases (71.3%) with EAT > 4 days. After adjusting for the confounding variables, longer duration of EAT was associated with decreased weight growth velocity and increased duration of reach of full enteral feeding in EAT > 4 days group (aβ: -4.83, 95% CI: − 6.12 ~ − 3.53; aβ: 2.77, 95% CI: 0.25 ~ 5.87, respectively) than those receiving no antibiotics. In addition, the risk of feeding intolerance (FI) in EAT > 4 days group was 4 times higher than that in non-antibiotic group (aOR: 4.14, 95%CI: 1.49 ~ 13.56) and 1.8 times higher than that in EAT ≤4 days group (aOR: 1.82, 95%CI: 1.08 ~ 3.17). EAT > 4 days was also a risk factor for greater than or equal to stage 2 necrotizing enterocolitis (NEC) than those who did not receive antibiotics (aOR: 7.68, 95%CI: 1.14 ~ 54.75) and those who received EAT ≤4 days antibiotics (aOR: 5.42, 95%CI: 1.94 ~ 14.80).

Conclusions
The EAT rate among uninfected VPIs was high in Chinese NICUs. Prolonged antibiotic exposure was associated with decreased weight growth velocity, longer duration of reach of full enteral feeding, increased risk of feeding intolerance and NEC ≥ stage 2. Future stewardship interventions to reduce EAT use should be designed and implemented.