Effect of prolonged early empirical antibiotic exposures on hospitalization outcomes of premature infants

doi:10.3969/j.issn.1004-583X.2024.08.008

Abstract

Abstract:

Objective To explore the effect of prolonged early empirical antibiotic exposures on the hospitalization outcome of preterm infants by retrospectively analyzing the clinical data of preterm infants born with gestational age <32 weeks or birth weight < 1500 g, and to further guide the rational application of antibiotics in preterm infants. Methods Clinical data of preterm infants born with gestational age <32 weeks or birth weight <1500 g in the Affiliated Hospital of Qingdao University from January 1, 2018 to December 31, 2020 were collected. They were divided into short-term exposure group (≤5 days) and long-term exposure group (>5 days) according to the duration of empirical antibiotic application in the early postnatal period. The complications during hospitalization between the two groups were analyzed and compared. Results A total of 291 cases were retrospectively included, involving 166 males and 125 females. The median duration of antibiotic use in the short-term and long-term exposure groups was 3 days and 9 days, respectively. Compared with those of the short-term exposure group, cases in the long-term exposure group presented significantly higher incidence of feeding intolerance (FI), and longer duration of half-intestinal feeding, full intestinal feeding and the length of stay (P<0.05). The incidence of bronchopulmonary dysplasia (BPD) and late-onset sepsis (LOS) was significantly higher in the long-term exposure group than that of the short-term exposure group (P<0.05). Univariate Logistic regression analysis showed that prolonged antibiotic exposure was associated with increased incidences of FI, BPD, LOS, and composite outcomes during hospitalization. Multivariate Logistic regression analysis showed that prolonged exposure of empirical antibiotics was an independent risk factor for FI and BPD. Multiple linear regression analysis showed that the duration of antibiotic use was positively correlated with the length of stay and the length of whole intestinal feeding. Conclusion Prolonged early empirical antibiotic exposures can increase the risk of BPD in preterm infants, affect intestinal feeding, and lead to a longer length of stay.

Key words: infant, premature, infant, very low birth weight, empirical antibiotics, adverse outcome

CLC Number:

R722

Xu Yuanyuan, Yu Jianmei, Zhang Xiuli, Li Liangliang, Yin Xiangyun, Li Xianghong. Effect of prolonged early empirical antibiotic exposures on hospitalization outcomes of premature infants[J]. Clinical Focus, 2024, 39(8): 728-733.

Add to citation manager EndNote|Ris|BibTeX

URL: https://huicui.hebmu.edu.cn/EN/10.3969/j.issn.1004-583X.2024.08.008

https://huicui.hebmu.edu.cn/EN/Y2024/V39/I8/728

Figures/Tables 5

Tab.1 Basic data of the two groups

组别	例数	产前激素 [例(%)]	产前抗生素 [例(%)]		剖宫产 [例(%)]	妊高症 [例(%)]		妊娠期糖尿病 [例(%)]		胎膜早破 [例(%)]	产前发热或绒毛膜炎 [例(%)]
短期暴露组	104	73(70.2)	43(41.4)		78(75.0)	27(26.0)		33(31.7)		18(17.3)	2(1.9)
长期暴露组	187	143(76.5)	46(24.6)		140(74.9)	55(29.4)		59(31.6)		31(16.6)	6(3.2)
统计值		χ²=1.377	χ²=8.829		χ²=0.001	χ²=0.393		χ²=0.001		χ²=0.025	χ²=0.072
$P$ 值		0.241	0.003		0.980	0.531		0.975		0.873	0.788
组别	胎龄(w)			出生体重(g)			性别男 [例(%)]		多胎 [例(%)]			SGA [例(%)]
短期暴露组	30.00(30.00,31.00)			1450.00(1280.00,1590.00)			57(54, 8)		25(24.0)			5(4.8)
长期暴露组	30.00(29.00,31.00)			1300.00(1110.00,1480.00)			109(58.3)		45(24.1)			32(17.1)
统计值	$Z$ =-1.136			$Z$ =-3.847			χ²=0.331		χ²=0.000			χ²=9.117
$P$ 值	0.256			<0.01			0.565		0.996			0.003
组别	1分钟APGAR评分 (分)			5分钟APGAR评分 (分)			PS应用 [例(%)]		机械通气 [例(%)]			母乳喂养 [例(%)]
短期暴露组	9.00(7.00,10.00)			10.00(9.00,10.00)			30(28.8)		8(7.7)			39(37.5)
长期暴露组	7.00(6.00,9.00)			9.00(8.00,10.00)			65(34.8)		34(18.2)			78(41.7)
统计值	$Z$ =-4.699			$Z$ =-4.371			χ²=1.063		χ²=5.954			χ²=0.493
$P$ 值	<0.01			<0.01			0.303		0.015			0.483

Tab.1 Basic data of the two groups

组别	例数	产前激素 [例(%)]	产前抗生素 [例(%)]		剖宫产 [例(%)]	妊高症 [例(%)]		妊娠期糖尿病 [例(%)]		胎膜早破 [例(%)]	产前发热或绒毛膜炎 [例(%)]
短期暴露组	104	73(70.2)	43(41.4)		78(75.0)	27(26.0)		33(31.7)		18(17.3)	2(1.9)
长期暴露组	187	143(76.5)	46(24.6)		140(74.9)	55(29.4)		59(31.6)		31(16.6)	6(3.2)
统计值		χ²=1.377	χ²=8.829		χ²=0.001	χ²=0.393		χ²=0.001		χ²=0.025	χ²=0.072
$P$ 值		0.241	0.003		0.980	0.531		0.975		0.873	0.788
组别	胎龄(w)			出生体重(g)			性别男 [例(%)]		多胎 [例(%)]			SGA [例(%)]
短期暴露组	30.00(30.00,31.00)			1450.00(1280.00,1590.00)			57(54, 8)		25(24.0)			5(4.8)
长期暴露组	30.00(29.00,31.00)			1300.00(1110.00,1480.00)			109(58.3)		45(24.1)			32(17.1)
统计值	$Z$ =-1.136			$Z$ =-3.847			χ²=0.331		χ²=0.000			χ²=9.117
$P$ 值	0.256			<0.01			0.565		0.996			0.003
组别	1分钟APGAR评分 (分)			5分钟APGAR评分 (分)			PS应用 [例(%)]		机械通气 [例(%)]			母乳喂养 [例(%)]
短期暴露组	9.00(7.00,10.00)			10.00(9.00,10.00)			30(28.8)		8(7.7)			39(37.5)
长期暴露组	7.00(6.00,9.00)			9.00(8.00,10.00)			65(34.8)		34(18.2)			78(41.7)
统计值	$Z$ =-4.699			$Z$ =-4.371			χ²=1.063		χ²=5.954			χ²=0.493
$P$ 值	<0.01			<0.01			0.303		0.015			0.483

Tab.2 Adverse hospitalization outcomes between groups

组别	例数	BPD	ROP	LOS	NEC	死亡	复合不良结局
短期暴露组	104	15(14.4)	6(5.8)	10(9.6)	3(2.9)	1(1.0)	26(24.0)
长期暴露组	187	63(33.7)	13(7.0)	40(21.4)	12(6.4)	6(3.2)	83(44.4)
统计值		χ²=12.645	χ²=0.153	χ²=6.512	χ²=1.706	χ²=1.437	χ²=10.720
$P$ 值		<0.01	0.696	0.011	0.192	0.231	0.001

Tab.2 Adverse hospitalization outcomes between groups

组别	例数	BPD	ROP	LOS	NEC	死亡	复合不良结局
短期暴露组	104	15(14.4)	6(5.8)	10(9.6)	3(2.9)	1(1.0)	26(24.0)
长期暴露组	187	63(33.7)	13(7.0)	40(21.4)	12(6.4)	6(3.2)	83(44.4)
统计值		χ²=12.645	χ²=0.153	χ²=6.512	χ²=1.706	χ²=1.437	χ²=10.720
$P$ 值		<0.01	0.696	0.011	0.192	0.231	0.001

Tab.3 Enteral feeding and hospitalization time between groups

组别	例数	FI[例(%)]	达半量肠道喂养时间(d)	达全肠道喂养时间(d)	住院时间(d)
短期暴露组	104	22(21.2)	10.00(8.00, 14.00)	16.00(13.00, 20.00)	44.00(34.00, 58.00)
长期暴露组	187	85(45.4)	12.00(8.50, 18.00)	23.00(17.00, 33.50)	55.00(43.00, 70.00)
统计值		χ²=16.975	$Z$ =-2.768	$Z$ =-6.032	$Z$ =-3.955
$P$ 值		<0.01	0.006	<0.01	<0.01

Tab.3 Enteral feeding and hospitalization time between groups

组别	例数	FI[例(%)]	达半量肠道喂养时间(d)	达全肠道喂养时间(d)	住院时间(d)
短期暴露组	104	22(21.2)	10.00(8.00, 14.00)	16.00(13.00, 20.00)	44.00(34.00, 58.00)
长期暴露组	187	85(45.4)	12.00(8.50, 18.00)	23.00(17.00, 33.50)	55.00(43.00, 70.00)
统计值		χ²=16.975	$Z$ =-2.768	$Z$ =-6.032	$Z$ =-3.955
$P$ 值		<0.01	0.006	<0.01	<0.01

Tab.4 Regression analysis of early empirical antibiotic exposures with FI and primary outcomes

指标	回归系数	标准误	Wald χ²值	校正前 $P$ 值	校正前 $O R$ 值	校正前 $O R$ 的95% $C I$		校正后 $P$ 值	校正后 $O R$ 值	校正后 $O R$ 的95% $C I$
指标	回归系数	标准误	Wald χ²值	校正前 $P$ 值	校正前 $O R$ 值	下限	上限	校正后 $P$ 值	校正后 $O R$ 值	下限	上限
FI	0.876	0.305	8.267	0.000	3.106	1.789	5.392	0.004	2.401	1.322	4.362
BPD	1.227	0.430	8.151	0.001	3.015	1.613	5.635	0.004	3.412	1.469	7.924
ROP	-0.515	0.713	0.520	0.696	1.220	0.450	3.312	0.471	0.598	0.148	2.419
LOS	0.736	0.407	3.270	0.013	2.558	1.221	5.360	0.071	2.088	0.940	4.636
NEC	0.383	0.705	0.295	0.203	2.309	0.636	8.375	0.587	1.467	0.369	5.837
死亡	0.078	1.329	0.003	0.259	3.414	0.405	28.754	0.953	1.081	0.080	14.622
复合不良结局	0.803	0.335	5.740	0.001	2.394	1.410	4.065	0.017	2.232	1.157	4.306

Tab.4 Regression analysis of early empirical antibiotic exposures with FI and primary outcomes

指标	回归系数	标准误	Wald χ²值	校正前 $P$ 值	校正前 $O R$ 值	校正前 $O R$ 的95% $C I$		校正后 $P$ 值	校正后 $O R$ 值	校正后 $O R$ 的95% $C I$
指标	回归系数	标准误	Wald χ²值	校正前 $P$ 值	校正前 $O R$ 值	下限	上限	校正后 $P$ 值	校正后 $O R$ 值	下限	上限
FI	0.876	0.305	8.267	0.000	3.106	1.789	5.392	0.004	2.401	1.322	4.362
BPD	1.227	0.430	8.151	0.001	3.015	1.613	5.635	0.004	3.412	1.469	7.924
ROP	-0.515	0.713	0.520	0.696	1.220	0.450	3.312	0.471	0.598	0.148	2.419
LOS	0.736	0.407	3.270	0.013	2.558	1.221	5.360	0.071	2.088	0.940	4.636
NEC	0.383	0.705	0.295	0.203	2.309	0.636	8.375	0.587	1.467	0.369	5.837
死亡	0.078	1.329	0.003	0.259	3.414	0.405	28.754	0.953	1.081	0.080	14.622
复合不良结局	0.803	0.335	5.740	0.001	2.394	1.410	4.065	0.017	2.232	1.157	4.306

Tab.5 Regression analysis of early empirical antibiotic exposures and secondary outcomes

指标	未标准化系数	标准化系数	标准误	$t$ 值	校正前 $P$ 值	校正后 $P$ 值	校正前β的95% $C I$		校正后β的95% $C I$
指标	未标准化系数	标准化系数	标准误	$t$ 值	校正前 $P$ 值	校正后 $P$ 值	下限	上限	下限	上限
达半量肠内喂养时间	0.985	0.070	0.803	1.227	0.003	0.221	0.803	4.007	-0.595	2.565
达全肠内喂养时间	5.246	0.221	1.288	4.071	<0.01	<0.01	5.040	10.282	2.709	7.782
住院时间	5.215	0.113	1.552	3.361	<0.01	0.001	5.786	16.188	2.160	8.269

Tab.5 Regression analysis of early empirical antibiotic exposures and secondary outcomes

指标	未标准化系数	标准化系数	标准误	$t$ 值	校正前 $P$ 值	校正后 $P$ 值	校正前β的95% $C I$		校正后β的95% $C I$
指标	未标准化系数	标准化系数	标准误	$t$ 值	校正前 $P$ 值	校正后 $P$ 值	下限	上限	下限	上限
达半量肠内喂养时间	0.985	0.070	0.803	1.227	0.003	0.221	0.803	4.007	-0.595	2.565
达全肠内喂养时间	5.246	0.221	1.288	4.071	<0.01	<0.01	5.040	10.282	2.709	7.782
住院时间	5.215	0.113	1.552	3.361	<0.01	0.001	5.786	16.188	2.160	8.269

References 35

[1]	Dierikx TH, Deianova N, Groen J, et al. Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: A multicenter cohort study[J]. Eur J Pediatr, 2022, 181(10):3715-3724. doi: 10.1007/s00431-022-04579-5 pmid: 35927379
[2]	Rallis D, Giapros V, Serbis A, et al. Fighting antimicrobial resistance in neonatal intensive care units: Rational use of antibiotics in neonatal sepsis[J]. Antibiotics (Basel), 2023, 12(3):508.
[3]	Yu W, Zhang L, Li S, et al. Early antibiotic use and neonatal outcomes among preterm infants without infections[J]. Pediatrics, 2023, 151(5):e2022059427.
[4]	Alsafadi T, Alotaibi B, Banabilah H, et al. Does prolonged initial empirical antibiotics treatment increase morbidity and mortality in preterm infants <34 weeks?[J]. J Clin Neonatol, 2018, 7(3):116.
[5]	王铭杰, 岳少杰, 林锦, 等. 湖南省极低/超低出生体重儿抗生素使用多中心调查报告[J]. 中国当代儿科杂志, 2020, 22(6):561-566.
[6]	Cantey JB, Huffman LW, Subramanian A, et al. Antibiotic exposure and risk for death or bronchopulmonary dysplasia in very low birth weight infants[J]. J Pediatr-US, 2017, 181:289-293.
[7]	Ting JY, Synnes A, Roberts A, et al. Association of antibiotic utilization and neurodevelopmental outcomes among extremely low gestational age neonates without proven sepsis or necrotizing enterocolitis[J]. Am J Perinatol, 2018, 35(10):972-978. doi: 10.1055/s-0038-1632390 pmid: 29475201
[8]	Ting JY, Synnes A, Roberts A, et al. Association between antibiotic use and neonatal mortality and morbidities in very low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis[J]. JAMA Pediatr, 2016, 170(12):1181-1187. doi: 10.1001/jamapediatrics.2016.2132 pmid: 27775765
[9]	Hou S, Yu Y, Wu Y, et al. Association between antibiotic overexposure and adverse outcomes in very-low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis: A multicenter prospective study[J]. Indian J Pediatr, 2022, 89(8):785-792. doi: 10.1007/s12098-021-04023-w pmid: 35286565
[10]	中华医学会儿科学分会新生儿学组, 中国医师协会新生儿科医师分会感染专业委员会. 新生儿败血症诊断及治疗专家共识(2019年版)[J]. 中华儿科杂志, 2019, 57(4):252-257.
[11]	Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary dysplasia: Executive summary of a workshop[J]. J Pediatr, 2018, 197:300-308.
[12]	Kim JH, Sampath V, Canvasser J. Challenges in diagnosing necrotizing nterocolitis[J]. Pediatr Res, 2020, 88(Suppl 1):16-20.
[13]	中国医师协会新生儿科医师分会循证专业委员会. 早产儿喂养不耐受临床诊疗指南(2020)[J]. 中国当代儿科杂志, 2020, 22(10): 1047-1055.
[14]	Puopolo KM, Benitz WE, Zaoutis TE. Management of neonates born at ≤ 34 6/7 weeks'gestation with suspected or proven early-onset bacterial sepsis[J]. Pediatrics, 2018, 142(6):e20182896.
[15]	岳少杰, 王铭杰, 林锦. 早产儿早发型败血症的诊断与抗生素使用建议:湖南省新生儿科专家共识[J]. 中国当代儿科杂志, 2020, 22(1):1-6.
[16]	Fajardo C, Alshaikh B, Harabor A. Prolonged use of antibiotics after birth is associated with increased morbidity in preterm infants with negative cultures[J]. J Matern-Fetal Neo M, 2019, 32(24):4060-4066.
[17]	Briones-Lara E, Trevino-Baez J, Caballero-Trejo A, et al. Prolonged exposure to antibiotics and the risk of late-onset sepsis (LOS) in neonates of 1, 000-1, 500 g: A cohort study[J]. Gac Med Mex, 2015, 151(3):306-312. pmid: 26089265
[18]	Cotten CM, Taylor S, Stoll B, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants[J]. Pediatrics, 2009, 123(1):58-66. doi: 10.1542/peds.2007-3423 pmid: 19117861
[19]	Puopolo KM, Benitz WE, Zaoutis TE. Management of neonates born at ≥35 0/7 weeks' gestation with suspected or proven early-onset bacterial sepsis[J]. Pediatrics, 2018, 142(6):e20182894.
[20]	Neonatal infection: Antibiotics for prevention and treatment[M]. London: National institute for health and care excellence (NICE), 2021.
[21]	Ting JY, Roberts A, Sherlock R, et al. Duration of initial empirical antibiotic therapy and outcomes in very low birth weight infants[J]. Pediatrics, 2019, 143(3):e20182286.
[22]	Jiang S, Zhang L, Yan W, et al. Antibiotic use in neonatal intensive care units in china: A multicenter cohort study[J]. J Pediatr-US, 2021, 239:136-142.
[23]	Wypych TP, Wickramasinghe LC, Marsland BJ. The influence of the microbiome on respiratory health[J]. Nat Immunol, 2019, 20(10):1279-1290. doi: 10.1038/s41590-019-0451-9 pmid: 31501577
[24]	Mukherjee S, Hanidziar D. More of the Gut in the Lung: How two microbiomes meet in ARDS[J]. Yale J Biol Med, 2018, 91(2):143-149. pmid: 29955219
[25]	翁博雯, 蔡成. 肠-肺轴与支气管肺发育不良关系的研究进展[J]. 国际儿科学杂志, 2023, 50(3):150-153.
[26]	王丹虹, 逯军. 肠肺轴对早产儿支气管肺发育不良的影响机制研究进展[J]. 国际儿科学杂志, 2022, 49(9):620-624.
[27]	Flannery DD, Dysart K, Cook A, et al. Association between early antibiotic exposure and bronchopulmonary dysplasia or death[J]. J Perinatol, 2018, 38(9):1227-1234. doi: 10.1038/s41372-018-0146-3 pmid: 29895965
[28]	Vatne A, Hapnes N, Stensvold HJ, et al. Early empirical antibiotics and adverse clinical outcomes in infants born very preterm: A population-based cohort[J]. J Pediatr, 2023, 253:107-114.
[29]	Martinez FE, Ferri W, Leone CR, et al. Early empiric antibiotic use is associated with delayed feeding tolerance in preterm infants: A retrospective analysis[J]. J Pediatr Gastr Nutr, 2017, 65(1):107-110. doi: 10.1097/MPG.0000000000001490 pmid: 28644358
[30]	Zhu Y, Yang Q, Wu F, et al. The impact of early empirical antibiotics treatment on clinical outcome of very preterm infants: A nationwide multicentre study in China[J]. Ital J Pediatr, 2023, 49(1).
[31]	赵琪, 芦起. 新生儿抗生素暴露对肠道菌群及临床结局的影响[J]. 临床儿科杂志, 2019, 37(8):628-631.
[32]	Dollings MC, Brown L. An integrated review of intestinal microbiota in the very premature infant[J]. Neonatal Netw, 2016, 35(4):204-216. doi: 10.1891/0730-0832.35.4.204 pmid: 27461199
[33]	Rooney AM, Timberlake K, Brown KA, et al. Each additional day of antibiotics is associated with lower gut anaerobes in neonatal intensive care unit patients[J]. Clin Infect Dis, 2020, 70(12):2553-2560. doi: 10.1093/cid/ciz698 pmid: 31367771
[34]	Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis[J]. J Pediatr-US, 2011, 159(3):392-397.
[35]	Esmaeilizand R, Shah PS, Seshia M, et al. Antibiotic exposure and development of necrotizing enterocolitis in very preterm neonates[J]. Paed Child Healt-Can, 2018, 23(4):e56-e61.