Life Antibiotic Use Research Articles

The developing immune system in preterm born infants: From contributor to potential solution for respiratory tract infections and wheezing.

Moderate-late preterm-born infants experience more frequent and severe respiratory tract infections and wheezing compared to term-born infants. Decreasing the risk on respiratory tract infections and wheezing in this group is vital to improve quality of life and reduce medical consumption during infancy, but also to reduce the risk on asthma and COPD later in life. Until now, moderate-late preterm infants are underrepresented in research and mechanisms underlying their morbidity are largely unknown, although they represent 80% of all preterm-born infants. In order to protect these infants effectively, it is essential to understand the role of the immune system in early life respiratory health and to identify strategies to optimize immune development and respiratory health. This review elaborates on risk factors and preventative measures concerning respiratory tract infections and wheezing in preterm-born infants, exploring their impact on the immune system and microbiome. Factors discussed are early life antibiotic use, birth mode, feeding type and living environment. Further, differences in adaptive and innate immune maturation between term and preterm infants are discussed, as well as differences in local immune reactions in the lungs. Finally, preventative strategies are being explored, including microbiota transplantation, immune modulation (through pre-, pro-, syn- and postbiotics, bacterial lysates, vaccinations, and monoclonal antibodies) and antibiotic prophylaxis.

Neonatal Azithromycin Exposure and Childhood Growth: Long-Term Follow-Up of a Randomized Controlled Trial.

Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.

Investigating the effect of early life antibiotic use on asthma and allergy risk in over 600 000 Canadian children: a protocol for a retrospective cohort study in British Columbia and Manitoba

IntroductionAllergic conditions, such as asthma, hay fever and eczema, are some of the most common conditions impacting children globally. There is a strong incentive to study their determinants to improve...

Asthma occurrence in children and early life systemic antibiotic use: an incidence density study

BackgroundResults of studies evaluating the relationship between asthma occurrence and early life antibiotic use have been conflicting. The aim of this study was to investigate the relationship between occurrence of asthma in children and systemic antibiotic use in the first year of life based on an incidence density study with careful consideration of the temporal aspects of the determinant-outcome relationship.MethodsWe conducted an incidence density study nested in a data collection project with information on 1128 mother–child pairs. Systemic antibiotic use in the first year of life was defined as excessive (≥ 4 courses) vs. non-excessive (< 4 courses) use based on information from weekly diaries. Events (cases) were defined as the first parent-reported occurrence of asthma in a child between 1 and 10 years of age. Population time ‘at risk’ was probed by sampling population moments (controls). Missing data were imputed. Multiple logistic regression was used to assess the association between current first asthma occurrence (incidence density) and systemic antibiotic use in the first year of life, to evaluate effect modification and adjust for confounding.ResultsForty-seven first asthma events and 147 population moments were included. Excessive systemic antibiotic use in the first year of life showed more than twice the incidence density of asthma compared to non-excessive use (adjusted IDR [95% CI]: 2.18 [0.98, 4.87], p = 0.06). The association was more pronounced in children who have had lower respiratory tract infections (LRTIs) in the first year of life compared to children who had no LRTIs in the first year of life (adjusted IDR [95% CI]: 5.17 [1.19, 22.52] versus 1.49 [0.54, 4.14]).ConclusionsExcessive use of systemic antibiotics in the first year of life may play a role in the genesis of asthma in children. This effect is modified by the occurrence of LRTIs in the first year of life, with a stronger association observed in children experiencing LRTIs in the first year of life.

Effect of early life antibiotic use on serologic responses to oral rotavirus vaccine in the MAL-ED birth cohort study

BackgroundOral rotavirus vaccine efficacy is lower in low- and middle-income countries (LMICs) than in high-income countries. The degree to which antibiotic use impacts rotavirus vaccine immunogenicity in LMICs is unknown. Using data from a multisite prospective birth cohort study of malnutrition and enteric disease, MAL-ED, we examined the effect of early life antibiotic use on the immune response to rotavirus vaccine. MethodsWe assessed whether antibiotic use from birth up to 7 days following rotavirus vaccine series completion was associated with rotavirus seropositivity at 7 months of age in Brazil, Peru, and South Africa using a modified Poisson regression. We then used parametric g-computation to estimate the impact of hypothetical interventions that treated all children and alternatively prevented inappropriate antibiotic treatments on seropositivity. ResultsOf 537 children, 178 (33%) received at least one antibiotic course during the exposure window. Probability of seropositivity was 40% higher among children who had at least one course of antibiotics compared with those with no antibiotic exposure (PR: 1.40, 95% CI: 1.04, 1.89). There was no significant difference by the number of antibiotic courses received or total duration of antibiotics. Treating all children with antibiotics would be associated with a 19% (95% CI: 18%, 21%) absolute increase in seropositivity at 7 months. In contrast, removing inappropriate antibiotics would result in a 4% absolute reduction (95% CI: −5%, −2%) in seropositivity. ConclusionsEarly life antibiotic use was associated with increased seropositivity. However, a hypothetical intervention to remove inappropriate antibiotics would have little effect on overall seropositivity. Further investigation into the underlying mechanisms of antibiotic use on the infant gut microbiome and immune response are needed.

Reporting of "Theoretical Design" in Explanatory Research: A Critical Appraisal of Research on Early Life Exposure to Antibiotics and the Occurrence of Asthma.

“Theoretical design” comprises the development of an occurrence relation and the specification of the study domain. In explanatory research, the occurrence relation causally relates one determinant to the occurrence (of an event or a state) taking into account other relevant characteristics (confounders and modifiers). Conflicting results in explanatory research might be (partially) explained by differences in the “theoretical design” or by a mismatch between the “theoretical design” and the “design of data collection”. In this critical review, the reporting of “theoretical design” is assessed in articles on the association between early life antibiotic use and the occurrence of asthma. Articles investigating a relationship between early life antibiotic use and the occurrence of asthma were searched in PubMed and systematically selected for critical review. The full text was read and important elements of study design were extracted (the research question/hypothesis, seven key elements of “theoretical design” (measure of occurrence, case (event or state) definition, conceptualization (and operationalization) of the exposure, temporal relation between outcome and exposure, confounders and effect modifiers taken into account and the domain of the study), the method of data collection and the method of data processing). A comparison was made between articles published before and after the publication of the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) statement (2007). Sixty-three articles were included for review. Thirteen articles reported the seven key elements of “theoretical design” that were questioned. No marked differences in reporting were observed pre- and post-STROBE. All articles reported some key elements of “theoretical design”; however, the reporting is not structured and not linked to the concept of “theoretical design”. Conceptualizing, delineating and explicit reporting of “theoretical design” is quintessential for the quality and transparency of explanatory research.

4444 The effect of early life antibiotics on gut microbiome and fecal bile acid concentrations in children

OBJECTIVES/GOALS: The current proposal seeks to investigate the effect of early life antibiotic use in the development of functional gastrointestinal (GI) disorders. We propose that infants exposed to antibiotics will present with gut microbial dysbiosis, changes in fecal bile acid concentrations and develop more GI symptoms compared to unexposed children. METHODS/STUDY POPULATION: We analyzed fecal samples from 174 subjects at 12 months of age, of whom 52 were exposed to antibiotics in their first year of life. Of these, 33 subjects were sampled again at 24 months of age. DNA from 200mg of frozen stool (−80C) was isolated with the Qiagen DNeasy PowerSoil kit. Shotgun libraries were generated using the NexteraXT kit and sequenced on the Illumina HiSeq 2500 using 2x125 bp chemistry. Sequence data were analyzed using the Sunbeam metagenomics pipeline. The abundance of bacteria was estimated using Kraken version 2.0.8. Fecal bile acids will be quantified by liquid chromatography–mass spectrometry (LC-MS). RESULTS/ANTICIPATED RESULTS: Overall bacterial community composition at 12 or 24 months was not associated with antibiotic exposure (PERMANOVA test, Bray-Curtis distance). An increase in Enterobacteriaceae, in particular Escherichia coli, is a signature of antibiotic-induced dysbiosis, but also of early infant gut. Children with antibiotic exposure had slightly higher abundance of Escherichia coli compared to those with no exposure (p = 0.03). At 24 months, the abundance of Bacteroides caccae, a commensal gut species, was decreased for children exposed to antibiotics in the first year of life (fdr = 0.02). We will perform further analysis of bile acid modifying bacteria, fecal bile acid concentrations and correlate to GI symptoms. DISCUSSION/SIGNIFICANCE OF IMPACT: Our findings suggest a significant but nuanced impact of early life antibiotic use on the composition of the gut microbiota. The association of antibiotic exposure with B. caccae and E. coli warrant further attention in the context of the rapidly developing early-life microbiome. CONFLICT OF INTEREST DESCRIPTION: The authors declare no conflicts of interest relevant to this work.

The impact of early life antibiotic use on atopic and metabolic disorders: Meta-analyses of recent insights.

Background and objectivesThe impact of antibiotics use early in life on later-in-life morbidities has received substantial attention as explanations for atopic and metabolic disorders with a surge as modern lifestyle diseases. The objective of this study was to perform meta-analyses to determine if antibiotics administration during the first 2 years of infant life is associated with increased risks of atopic or metabolic disorders later in life.MethodologyWe screened more than 100 English-language prospective and retrospective studies published between January 2002 and March 2020 and assessed study quality using the Newcastle–Ottawa scale. We performed overall and subgroup meta-analyses on 31 high-quality comparable studies on atopic and 23 on metabolic disorders, involving more than 3.5 million children.ResultsAntibiotic exposure prenatally and during the first 2 years of life significantly impacts the risk of developing atopic and metabolic disorders. Exposure during the first 6 months of life appears most critical, consistent with this being the time when the microbiome is most susceptible to irreversible perturbations. The presence of dose−response associations and stronger impacts of broad- than narrow-spectrum antibiotics further point to effects being mediated by microbiota-induced changes.Conclusions and implicationsOur findings support that antibiotics use is a mismatch to modernity that can negatively affect the symbiotic associations we rely on for proper immune function and metabolism. Improving our understanding of these associations, the underlying proximate mechanisms and the impact of antibiotics use on future human−symbiont evolution will be important to improve human health.Lay SummaryThe use of antibiotics in infancy has been suggested to increase the risks of atopic and metabolic disorders later in life. Through meta-analyses of more than 100 studies of >3.5 million children, we confirm these risks, and show that patterns are consistent with effects being due to microbiota-driven changes.

Are environmental risk factors for current wheeze in the International Study of Asthma and Allergies in Childhood (ISAAC) phase three due to reverse causation?

BackgroundPhase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication.ObjectiveTo explore the role of reverse causation in risk factors of asthma symptoms.MethodsWe compared two sets of multilevel logistic regression analyses, using (a) individual level exposure data and (b) school level average exposure (ie prevalence), in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels.ResultsThere were 131 924 children aged 6‐7 years (2428 schools, 25 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (odds ratio = 2.06; 95% confidence interval 1.97‐2.16), early life antibiotic use (1.65; 1.58‐1.73) and open fire cooking (1.44; 1.26‐1.65). In school level analyses, these risk factors again showed increased risks.There were 238 586 adolescents aged 13‐14 years (2072 schools, 42 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (1.80; 1.75‐1.86), cooking on an open fire (1.32; 1.22‐1.43) and maternal tobacco use (1.23; 1.18‐1.27). In school level analyses, these risk factors again showed increased risks.Conclusions & clinical relevanceThese analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation.

Perinatal antibiotic exposure alters composition of murine gut microbiota and may influence later responses to peanut antigen

BackgroundAccumulating evidence suggests that the gut microbiota shapes developmental processes within the immune system. Early life antibiotic use is one factor which may contribute to immune dysfunction and the recent surge in allergies by virtue of its effects on gut microbiota.Objective and methodsAs a first step towards determining whether a relationship exists between perinatal antibiotic induced changes in the gut microbiota and the later development of a peanut allergy, we exposed newborn mice to either the broad-spectrum antibiotic vancomycin or to a vehicle for 6 weeks and then used a novel murine model of peanut allergy.ResultsEarly-life treatment with vancomycin resulted in a significant shift in the gut microbiota community characterized by a reduction in the abundance of firmicutes and preponderance of inflammatory proteobacteria. Mice with an antibiotic-altered microbiota, showed a localized allergic-like response characterized by ear swelling and scratching following intra-dermal peanut antigen challenge. Likewise, circulating IgE levels were increased in antibiotic-treated mice, but no evidence of a systemic allergic or anaphylactic-like response was observed. Importantly, we utilized the naturally occurring pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), rather than the more commonly used cholera toxin, as an adjuvant together with the peanut antigen.ConclusionOur data suggest that early antibiotic exposure promotes a shift in the gut microbiota community that may in turn, influence how mice later respond to a TNF-α + antigen challenge. However, further studies verifying the capacity of microbiota restoration to protect against allergic responses will be needed to confirm a causal role of antibiotic-induced microbiota variations in promoting allergic disease phenotypes.

Influences of Chemical and Non-Chemical Stressors on Childhood Obesity

Background/Aim: Children are exposed to diverse chemical and non-chemical stressors in their built, natural, and social environments; and these are thought to contribute to their health and well-being during each developmental stage throughout life. Here we focus on growing evidence that interacting stressors in children’s environments contribute to recent and marked increases in childhood overweight/obesity/obesity-related metabolic dysfunction. Additionally, inherent characteristics (age, sex, genetics) and lifestage-specific activities and behaviors need to be considered along with the stressors. Our objective is to show evidence of the interrelationships between chemical and non-chemical stressors, inherent characteristics, and activities/behaviors in addressing childhood overweight/obesity/obesity-related metabolic dysfunction. Methods: Literature reviews, data mining, meta-analyses, and laboratory work collected information on chemical and non-chemical stressors and their links to childhood overweight/obesity/obesity-related metabolic dysfunction. In vitro evaluations of the obesogenic potentials of chemicals were conducted with the 3T3-L1 pre-adipocyte culture system. Results: A literature survey identified many stressors associated with childhood obesity. In our individual stressor meta-analyses, smoking in the home/during pregnancy, early life antibiotic use, bisphenol A, family income, access to supermarkets, diet, and stress had significant (p&lt;0.05) results and increased odds of the child being overweight/obese. Hours of television and sedentary behavior also increased the odds of the child being overweight/obese. Breastfeeding was associated with reduced odds (p&lt;0.05). Cross-sectional analyses suggested childhood metabolic dysfunction may be associated with interactions between endocrine-disrupting chemicals and selected non-chemical stressors such as family income. Cell culture analyses illustrated the influence of perfluorinated chemicals on adipocyte differentiation and function. Conclusions: Our analyses suggest that childhood overweight/obesity/obesity-related metabolic dysfunction result from interactions of many chemical and non-chemical stressors in combination with inherent characteristics and children’s activities and behaviors. Further research is required to infer causal associations.

Association between early life antibiotic use and childhood overweight and obesity: a narrative review.

Recent research implicates antibiotic use as a potential contributor to child obesity risk. In this narrative review, we examine current observational evidence on the relation between antibiotic use in early childhood and subsequent measures of child body mass. We searched PubMed, Web of Science and the Cochrane Library to identify studies that assessed antibiotic exposure before 3 years of age and subsequent measures of body mass or risk of overweight or obesity in childhood. We identified 13 studies published before October 2017, based on a total of 6 81 332 individuals, which examined the relation between early life antibiotic exposure and measures of child body mass. Most studies did not appropriately account for confounding by indication for antibiotic use. Overall, we found no consistent and conclusive evidence of associations between early life antibiotic use and later child body mass [minimum overall adjusted odds ratio (aOR) reported: 1.01, 95% confidence interval (95% CI) 0.98-1.04, N = 2 60 556; maximum overall aOR reported: 2.56, 95% CI 1.36-4.79, N = 616], with no clinically meaningful increases in weight reported (maximum increase: 1.50 kg at 15 years of age). Notable methodological differences between studies, including variable measures of association and inclusion of confounders, limited more comprehensive interpretations. Evidence to date is insufficient to indicate that antibiotic use is an important risk factor for child obesity, or leads to clinically important differences in weight. Further comparable studies using routine clinical data may help clarify this association.

Early life antibiotic use and the risk of asthma and asthma exacerbations in children.

The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first 3years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7393, The Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, The Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I2 : 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I2 : 0.0%). Children treated with antibiotic in the first 3years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations.

Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an emergent disease with unclear environmental causes. In the few studies of the epidemiology of EoE, male sex and white race have been identified as risk factors.1 A recent report suggested that cesarean section and early life antibiotic use may increase the risk of EoE, but other studies have not specifically looked at these factors,2 nor have they examined associations between early life gastrointestinal symptoms and EoE. The aim of this study was to investigate associations between EoE and dietary, environmental, and medical exposures during infancy.

Early Life Antibiotic Use and Allergic Rhinitis

Early Life Antibiotic Use and Allergic Rhinitis