Association Between Broad-Spectrum Antibiotic Use at Different Stage and Neonatal Enteral Nutrition and Prognosis in Very Low-Birth-Weight Infants with Culture-Negative Sepsis

Review Article

J Pediatr & Child Health Care. 2020; 5(2): 1033.

Association Between Broad-Spectrum Antibiotic Use at Different Stage and Neonatal Enteral Nutrition and Prognosis in Very Low-Birth-Weight Infants with Culture-Negative Sepsis

Zhou W*

Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, China

*Corresponding author: Wei Zhou, Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, No.9 Jinsui Road, Tianhe District, Guangdong, China

Received: May 03, 2020; Accepted: June 02, 2020; Published: June 09, 2020


Objective: Our study is to evaluate the association between broadspectrum antibiotic and enteral nutrition and outcomes among Very Low-Birth- Weight (VLBW) infants without culture-proven sepsis and exploring the timing of antibiotics use which has the minimum effect on enteral nutrition.

Methods: A retrospective cohort study was conducted in a tertiary Neonatal Intensive Care Unit (NICU) in China between November 2011 and November 2017. Infants are divided into four groups, including one no broad-spectrum antibiotic group and three broad-spectrum antibiotic groups. The three broadspectrum antibiotic groups were divided according to the initiating time of broadspectrum antibiotic use: <3d group, 3~13d group, and ≥14d group.

Results: Among the 571 infants, four hundred and ninety-one (85.99%) of the infants were treated with broad-spectrum antibiotics. The distribution in four groups is 14.01%, 64.97%, 12.96% and 8.06%, respectively. The median days reaching the target amount of milk (120mL/kg) in the four groups were 21.66d, 30.52d, 29.52d, and 29.06d, respectively, with statistical significance analyzed by the log-rank test (P=0.023). Bronchopulmonary Dysplasia (BPD) incidence in the <3d group was significantly higher than those in the no broad-spectrum antibiotics groups (P <0.008). Broad-spectrum antibiotics were given after the age of nine days, which had the highest possibility to reach Milk120 within short time (RR=1.41, 95% CI: 0.98-2.04).

Conclusions: Broad-spectrum antibiotic for VLBW infants with culturenegative sepsis, influences enteral nutrition process and increases the incidences of BPD. The broad-spectrum antibiotic use after the age of nine days is more beneficial for enteral nutrition than that at an earlier age.

Keywords: Broad-spectrum antibiotics; Enteral nutrition; Prognosis; VLBW infants; Culture-negative sepsis


Antibiotics are administered shortly after birth to nearly all preterm infants with Very Low Birth Weight (VLBW) (birth weight <1500g) because of the risk of sepsis [1]. Many neonates accepted antibiotic treatment when the sepsis is suspicious. Physicians are often reluctant to discontinue antibsiotics once initiated for many reasons, including the relatively high risk of infection among preterm infants and the relatively high rate of mortality attributable to infection. Early antibiotic use in premature infants negatively influences the colonization of the intestinal tract with normal flora, causing nearterm or long-term health issues.

Until now, most investigations have been focusing on the effects of early empirical antibiotic use on the prognosis of neonates. However, empirical antibiotic use is common in clinic without positive culture results, not only within the first three days after birth. It is known that antibiotic use influences negatively the establishment of intestinal flora in infants. But the effects of antibiotic use, especially broad-spectrum antibiotics, on enteral nutrition and prognosis of premature infants at different stages are not known.

Aminoglycosides, such as gentamicin, are forbidden in neonates in China because of their side effects. The empirical antibiotics use in NICU in China has wider variety. Our aim was to analyze the conditions of broad-spectrum antibiotic use in Very-Low-Birth- Weight (VLBW) infants with culture-negative sepsis in a tertiary NICU in China, in order to promote more rational antibiotics prescription. Analysis was also performed on the influence of broadspectrum antibiotic use at different stages after birth on target enteral nutrition and prognosis. The research on the more beneficial timing for broad-spectrum antibiotic use for suspicious infection could help to discover the key timing when the intestinal microbiota has established in premature infants after birth.


Study design and patients

We conducted a retrospective cohort study in the largest tertiary NICU in Southern China. The hospital’s Research Ethics Committee approved the study protocol. Premature infants with a Very Low Birth Weight (VLBW; Birth Weight [BW] <1500g) and negative culture results were included. Anti-infection agents were antibiotics that were prescribed to actively treat infection according to the Practice of Neonatology of China (4th Edition) [2]. Patients with chromosomal abnormalities, metabolic diseases, gastrointestinal diseases, or positive blood culture before antibiotic use were not eligible. Eventually, 571 VLBW admitted to the NICU between November 2011 and November 2017 were included in the research.

Nutrition supply strategy

Enteral Nutrition (EN) was initiated within 24h after birth. Breast milk, donated milk, or formula milk were started depending on the infants’ enteral feeding intolerance and advanced by 10~20mL/kg•d. Parenteral Nutrition (PN) initiated within 24 h after birth. Both amino acid and lipids started at 1g/kg•d and advanced by 0.5~1g/kg•d to a maximum of 3.0~3.5g/kg•d. PN was discontinued when the infant tolerates 120mL/kg•denterally. PN and EN supports were performed according to the guidelines of the Chinese Society for Parenteral and Enteral Nutrition for neonates and preterm infants [3], which was drafted by referring to the nutrition guidelines in the United States and Europe [4-6].

Measures and management

The data of neonates enrolled was obtained from the Medical Centre’s database. Information was collected on the age of the first antibiotic use, antibiotic type, and total duration of treatment. Then, the neonates were divided into the following four groups: (1) No broad-spectrum antibiotic group: no broad-spectrum antibiotic treatment or only single penicillin treatment was applied. (2) <3d group: antibiotic administration was initiated between day 0 and less than day 3 after birth. (3) 3~13d group: antibiotic administration was initiated between day 3 and less than day 14 after birth. (4) ≥14d group: antibiotic administration was initiated at day 14 or later.


The primary outcome were recorded when infants tolerated 120mL/kg.d (Milk120) before 90 days after birth. Secondary safety outcomes rather than infection-related morbidities were death, Bronchopulmonary Dysplasia (BPD), and Retinopathy of Premature (ROP) before discharged from the hospital. These outcomes were chosen to be included in this study because of their association with systemic inflammatory response and their chronological sequence of usually occurring after the median age of infection in preterm neonates. The time to final weaning from mechanical ventilator support (live) and the time to (live) discharge from the hospital were also assessed.

Statistical analysis

Data are expressed as frequencies (percentages) or means (Standard Deviation, SD). We first compared the timing of antibiotic treatment in VLBW infants using four categories. Univariate comparisons were performed using the Chi-square test (or two-tailed Fisher’s exact test if appropriately), and analysis of variance. Bonferroni’s correction for post-hoc pairwise comparisons was employed to variables with significance in the univariate comparisons. The Kaplan-Meier plot was utilized to determine the time-to-event effect with log-rank testing for Milk 120. The Multivariate cox proportional-hazards analysis was used for the time-to-event outcomes, including Milk 120 and the secondary efficacy outcomes. As we were not certain when they will occur, multivariate logistic regression models were used to ascertain the effect of timing of antibiotic treatments on the secondary safety outcomes. In the broad-spectrum antibiotic treatments of infants, we used restricted cubic splines with knots placed at 1, 3 and 14 days of age for Milk 120. In order to adjust the effect of illness severity and other factors on the stage of the broadspectrum antibiotics treatment, all the outcomes were adjusted for the statuses of premature babies at admission: gestational age; birth weight group; gender; Apgar scores group at 1 and 5 minutes after birth; maternal age; and preterm rupture of membranes. Additionally, the factors related to the management of the premature babies or the conditions of their mothers were also evaluated: age at admission and age at initiation of enteral feeding; type of milk at first intake; mode of respiratory support at admission; and antenatal corticosteroid use. Statistical analyses were performed using SAS software (version 9.4; SAS Institute, Inc., Cary, NC, USA). Two-tailed P-values <0.05 were considered statistically significant, and the P-value for pairwise comparisons had to be below 0.05/6=0.008.



Among the 571 patients included in the study, 491(85.99%) were treated with broad-spectrum antibiotics, including 64.97% accepted antibiotic treatment between day 0 and less than day 3 after birth, 12.96% between day 3 and less than day 14 after birth, and 8.06% at day 14 or later. Broad-spectrum antibiotic treatment was not applied in only 14.01% of the patients. Birth weight, age at admission, and mode of respiratory support differed among the four groups. More specifically, all premature infants with BW <1000 g were prescribed to broad-spectrum antibiotic treatment. The <3d group were younger than the 3~13d group at admission (P=0.005). The infants with mechanical ventilator support or non-invasive auxiliary ventilation at study entry were more likely to be earlier treated with broad-spectrum antibiotics. There were no difference in the other characteristics among the four groups (Table 1).