Effects and changes of intrapartum antimicrobial prophylaxis on antibiotic resistance genes in gut microbiota of infants within 6 months of age

doi:10.11852/zgetbjzz2023-0526

Abstract

Abstract: Objective To explore the impact of intrapartum antibiotic prophylaxis (IAP) on antibiotic resistance genes (ARGs) in the gut microbiota of infants up to 6 months of age and their longitudinal changes, in order to provide theoretical basis for the rational use of antibiotics and antibiotic resistance control. Methods Fecal samples were collected within 3 days, 2 months, and 6 months from a maternal and birth cohort conducted between January 2018 and June 2019. A panel of 6 common ARGs (aac(6')-Ib, qnrS, blaTEM, ermB, mecA, tetM) were tested, the absolute abundance and positive detection rate by qPCR were calculated. Nonparametric and linear mixed model (LMM) analysis were used to assess the influence of IAP on the absolute abundance of antibiotic resistance genes and the longitudinal changes in their abundance at the three time points. Results A total of 157 samples from 65 singleton infants were analyzed, including 15 mothers (23.1%) who received IAP. The detection rate of ARGs was high in infants up to six months of age, and the abundance of ARGs tended to increase over time. IAP significantly increased the abundance of the mecA gene in the gut microbiota of vaginally delivered infants at 6 months of age (6.1±1.1 in the VDIAP group vs. 3.8±4.6 in the VDno-IAP group, P=0.046). Additionally, in cesarean section infants, there was a significant increase in the abundance of aac(6')-Ib genes at 2 months(β=3.81, S_x-=1.45, P<0.05), P<0.05] and 6 months of age (β=4.89, S_x-=1.11, P<0.001), P<0.001) compared to 3 days of age. Conclusions The findings suggest that IAP can increase the abundance of ARGs in 6-month-old infants, and this effect is still significant after stratifying by delivery mode. Therefore, the rational and standardized use of intrapartum antibiotics may help reduce the development of antibiotic resistance.

Key words: intrapartum antimicrobial prophylaxis, gut microbiota, infants, antibiotic resistance

摘要： 目的探究产时抗菌药物预防(IAP)对6月龄内婴儿肠道菌群抗生素耐药基因(ARGs)的影响及纵向变化,为抗生素的规范性使用和耐药性控制提供理论依据。方法基于母婴队列2018年1月—2019年6月数据,采集新生儿3日龄内、2月龄及6月龄粪便,使用qPCR技术检测6种常见ARGs(aac(6')-Ib、qnrS、blaTEM、ermB、mecA、tetM),计算ARGs丰度及阳性检出例数。采用非参数检验及线性混合效应模型(LMM)分析IAP在3个时间点对ARGs绝对丰度的影响,以及ARGs丰度在3个时间点的纵向变化。结果共65名单胎婴儿的157个样本纳入分析,其中15名母亲(23.1%)接受了IAP。婴幼儿在出生后半年内ARGs检出率较高,丰度随时间呈增加趋势。IAP可显著增加经阴道分娩婴儿肠道菌群6月龄时mecA基因丰度(VDIAP组6.1±1.1 vs. VDno-IAP组 3.8±4.6, P=0.046),剖宫产婴儿的aac(6')-Ib 基因丰度则在2月龄(β=3.81,S_x-=1.45,P<0.05)、6月龄(β=4.89,S_x-=1.11,P<0.001)较3日龄有显著升高。结论 IAP可增加6月龄婴儿ARGs丰度,调整分娩方式影响后,该效应依然显著,提示合理规范使用产时抗菌药物可能减少抗生素耐药的形成。

关键词: 产时抗菌药物预防, 肠道菌群, 婴儿, 耐药性

CLC Number:

QI Qi, ZHU Zhonghai, WANG Liang, ZHU Yingze, ZENG Lingxia. Effects and changes of intrapartum antimicrobial prophylaxis on antibiotic resistance genes in gut microbiota of infants within 6 months of age[J]. Chinese Journal of Child Health Care, 2024, 32(2): 142-148.

齐琪, 朱中海, 王良, 祝瑛泽, 曾令霞. 产时抗菌药物预防对6月龄内婴儿肠道菌群抗生素耐药基因的影响及变化研究[J]. 中国儿童保健杂志, 2024, 32(2): 142-148.

References

[1] Nogacka A, Salazar N, Suárez M, et al. Impact of intrapartum antimicrobial prophylaxis upon the intestinal microbiota and the prevalence of antibiotic resistance genes in vaginally delivered full-term neonates[J]. Microbiome, 2017, 5(1):93.
[2] Arboleya S, Sánchez B, Solís G, et al. Impact of prematurity and perinatal antibiotics on the developing intestinal microbiota:A functional inference study[J]. Int J Mol Sci, 2016, 17(5):649.
[3] Aloisio I, Quagliariello A, De Fanti S, et al. Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16s rdna regions[J]. Appl Microbiol Biotechnol, 2016, 100(12):5537-5546.
[4] Li W, Tapiainen T, Brinkac L, et al. Vertical transmission of gut microbiome and antimicrobial resistance genes in infants exposed to antibiotics at birth[J]. J Infect Dis, 2021, 224(7):1236-1246.
[5] Coker MO, Laue HE, Hoen AG, et al. Infant feeding alters the longitudinal impact of birth mode on the development of the gut microbiota in the first year of life[J]. Front Microbiol, 2021, 12:642197.
[6] Bckhed F, Roswall J, Peng Y, et al. Dynamics and stabilization of the human gut microbiome during the first year of life[J]. Cell Host Microbe, 2015, 17(5):690-703.
[7] Nagpal R, Tsuji H, Takahashi T, et al. Sensitive quantitative analysis of the meconium bacterial microbiota in healthy term infants born vaginally or by cesarean section[J]. Frontiers in Microbiology, 2016, 7:1997.
[8] Li X, Stokholm J, Brejnrod A, et al. The infant gut resistome associates with E. coli, environmental exposures, gut microbiome maturity, and asthma-associated bacterial composition[J]. Cell Host Microbe, 2021;29(6):975-987.e4.
[9] Mitchell CM, Mazzoni C, Hogstrom L, et al. Delivery mode affects stability of early infant gut microbiota[J]. Cell Rep Med, 2020, 1(9):100156.
[10] Gosalbes MJ, Vallès Y, Jiménez-Hernández N, et al. High frequencies of antibiotic resistance genes in infants' meconium and early fecal samples[J]. J Dev Orig Health Dis, 2016, 7(1):35-44.
[11] Liu H, Wang HH. Impact of microbiota transplant on resistome of gut microbiota in gnotobiotic piglets and human subjects[J]. Front Microbiol, 2020, 11:932.
[12] Gibson MK, Crofts TS, Dantas G. Antibiotics and the developing infant gut microbiota and resistome[J]. Curr Opin Microbiol, 2015, 27:51-56.
[13] Lebeaux RM, Coker MO, Dade EF, et al. The infant gut resistome is associated with e. coli and early-life exposures[J]. BMC Microbiol, 2021, 21(1):201.
[14] Raveh-Sadka T, Firek B, Sharon I, et al. Evidence for persistent and shared bacterial strains against a background of largely unique gut colonization in hospitalized premature infants[J]. ISME J, 2016, 10(12):2817-2830.
[15] Esaiassen E, Hjerde E, Cavanagh JP, et al. Effects of probiotic supplementation on the gut microbiota and antibiotic resistome development in preterm infants[J]. Front Pediatr, 2018, 6:347.
[16] Coker M, Hoen A, Dade E, et al. Specific class of intrapartum antibiotics relates to maturation of the infant gut microbiota:A prospective cohort study[J]. BJOG, 2020, 127(2):217-227.
[17] Montoya-Williams D, Lemas DJ, Spiryda L, et al. The neonatal microbiome and its partial role in mediating the association between birth by cesarean section and adverse pediatric outcomes[J]. Neonatology, 2018, 114(2):103-111.
[18] 中华医学会围产医学分会,中华医学会妇产科学分会产科学组. 预防围产期B族链球菌病(中国)专家共识[J]. 中华围产医学杂志,2021,24(8):561-566.
Chinese Society of Perinatal Medicine, Chinese Society of Obstetrics and Gynaecology. Chinese experts consensus on prevention of perinatal group b streptococcal disease[J]. Chin J Perinat Med, 2021, 24(08):561-566.(in Chinese)
[19] 汤兰兰, 林洁如, 彭春红, 等. MecA基因及非MecA基因在MRSA耐药机制中的研究进展[J]. 贵州医药, 2019, 43(4):536-539.
Tang LL, Lin JR,Peng CH, et al. Research progress of MecA gene and non-MecA gene in antibiotic resistance mechanism of MRSA[J]. Guizhou Med J, 2019, 43(4):536-539. (in Chinese)
[20] Lubriks D, Zogota R, Sarpe VA, et al. Synthesis and antibacterial activity of propylamycin derivatives functionalized at the 5''- and other positions with a view to overcoming resistance due to aminoglycoside modifying enzymes[J]. ACS Infect Dis. 2021;7(8):2413-2424.
[21] Silva SMD, Ramos BA, Lima AVA, et al. First report of the aac(6')-Ib-cr gene in Providencia stuartii isolates in Brazil[J]. Rev Soc Bras Med Trop,2020,54:e20190524.
[22] Prnnen K, Karkman A, Hultman J, et al. Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements[J]. Nat Commun, 2018, 9(1):3891.
[23] Baron R, Taye M, Besseling-van der Vaart I, et al. The relationship of prenatal and infant antibiotic exposure with childhood overweight and obesity:A systematic review[J]. J Dev Orig Health Dis. 2020;11(4):335-349.
[24] Livanos AE, Greiner TU, Vangay P, et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice[J]. Nat Microbiol, 2016, 1(11):16140.
[25] Tochitani S, Ikeno T, Ito T, et al. Administration of non-absorbable antibiotics to pregnant mice to perturb the maternal gut microbiota is associated with alterations in offspring behavior[J]. PLoS One, 2016, 11(1):e0138293.
[26] Vangay P, Ward T, Gerber JS, et al. Antibiotics, pediatric dysbiosis, and disease[J]. Cell Host Microbe, 2015, 17(5):553-564.
[27] Fouhy F, Ogilvie LA, Jones BV, et al. Identification of aminoglycoside and β-lactam resistance genes from within an infant gut functional metagenomic library[J]. PLoS One, 2014, 9(9):e108016.
[28] Bi Y, Tu Y, Zhang N, et al. Multiomics analysis reveals the presence of a microbiome in the gut of fetal lambs[J]. Gut, 2021.
[29] 关于印发抗菌药物临床应用指导原则(2015年版)的通知[J]. 中华人民共和国国家卫生和计划生育委员会公报, 2015,7:29.
Notice on Issuance of Guidelines for Clinical Application of Antibiotics (2015 edition)[J]. Bulletin of the National Health and Family Planning Commission, 2015,7:29. (in Chinese)