Impact Of Antimicrobial Resistance On Obesity Development In Children – Critical Appraisal

Research Question

According to Australian Government (2018), Antimicrobial resistance (AMR) is one of the biggest concern for global public health due to threat that it can cause in human and animal health today. AMR occurs when microorganisms like bacteria, parasites and viruses become resistance to antibiotics and stop them from working against antimicrobial medicines (World Health Organisation, 2018). Although antibiotics are lifesaving drugs and are used in human medicines, 50 % of the time due to antibiotics not optimally prescribed, incorrect duration and dosage can lead to emergence of AMR (Centers for Disease Control and Prevention, 2018). The use of antimicrobial resistance in Australia is high (Australian Commission on Safety & Quality in Health Care, 2015). The author also states that in 2014, Australians were prescribed more than 30 million antibacterial through Pharmaceutical Benefits Scheme (PBS). Moreover, in 2015, 45% of the Australian population were given at least 1 antibiotic (Australian Government, 2018). Regulation on the over the counter antibiotics availability, using the antibiotics rationally and improving hand hygiene are some important approaches to reduce and combat the rising number of AMR (Uchil, Kohli, Katekhaye, & Swami, 2014). The purpose of this paper is to critically appraise research articles with an aim of understanding the effect/impact of antibiotics/antimicrobial resistance including the development of obesity in children. The focus is to

Research Question

What is the effect/impact  of antimicrobial resistance in the development of obesity in Children

The keywords used to run the search were Antimicrobial resistance; antibiotics; and administration of antibiotics which was merged with more specific words which were Children; Obesity; Childhood Obesity. The databases used to search the relevant articles was Google Scholar, PudMed, Laureate Australia Library and Research Gate. The articles which were used are peer-reviewed journal articles and were critically appraised using the Critical Appraisal Skills Programme (CASP) checklist (2017). There were total number of 5 articles used for critical appraisal using CASP checklist. Additionally the studies were rank according to the FORM (Hillier et al., 2011) or GRADE levels of evidence (The GRADE working Group, 2008) and the level of evidence were accessed using National Health and Medical Research Council (NHMRC, 2009) body for evidence matrix.

5 Research articles (peer-reviewed journal articles) which are used for antimicrobial resistance were all of cohort study design.  Critical Appraisal Skills Program (CASP) checklist were used to answer 12 questions in order to critical appraise the 5 articles which were Infant antibiotic exposures and early-life body mass; Association of antibiotics in infancy with early childhood obesity; Administration of antibiotics to children before age 2 years increases risk for childhood obesity; Infant antibiotic exposure and the development of childhood overweight and central adiposity; and Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Moreover, NHMRC Body of evidence matrix has been used for the group level of evidence including various components such as Evidence base, Consistency, Clinical Impact, Generalizability and Applicability of 5 articles. 

Table 1. Critical appraisal using CASP checklist for Cohort Studies Questions

Questions	Trasande et al., 2013	Bailey et al., 2014	Scott et al., 2016	Azad et al., 2014	Ajslev et al., 2011
1. Did the study address a clearly focused issue?	Yes	Yes	Yes	Yes	Yes
2. Was the cohort recruited in an acceptable way?	Yes	Yes	Yes	Yes	Yes
3. Was the exposure accurately measured to minimise bias?	Yes	Yes	Yes	No	No
4. Was the outcome accurately measured to minimise bias?	No	Yes	Yes	No	No
5. (a) Have the authors identified all important confounding factors?	Yes	Yes	Yes	Yes	Yes
5. (b) Have they taken account of the confounding factors in the design and/or analysis?	Yes	Yes	Yes	Yes	Yes
6. (a) Was the follow up of subjects complete enough?	Yes	Yes	Yes	Yes	Yes
6. (b) Was the follow up of subjects long enough?	Yes	Yes	Yes	Yes	Yes
7. What are the results of this study?	Exposure to antibiotic in early life is related to increase body mass and exposure to non-antibiotic medication is not associated with increase body mass.	69% children were used antibiotics in early life and among them 95% have been found to be associated with obesity in later life.	1306 children were obese at the age of 4 years due to exposure to antibiotics and antifungal agents are not associated with obesity.	32.4% children found to be associated with childhood obesity at the age 12 due to exposure to antibiotics during infancy.	Administering antibiotics during infancy leads to the high risk of obesity in childhood and association of delivery mode with childhood obesity is not significant.
8. How precise are the results?	Precise	Precise	Precise	Precise	Precise
9. Do you believe the results?	Yes	Yes	Yes	Yes	Yes
10. Can the results be applied to the local population?	Yes	Yes	Yes	Yes	Yes
11. Do the results of this study fit with other available evidence?	Yes	Yes	Yes	Yes	Yes
12. What are the implications of this study for practice?	Exposure to some antibiotics in early life may leads to the increase body mass in the later life.	Using broad spectrum antibiotics in early life such as before 24 months is one of the potential risk factor of obesity.	3 or more antibiotics administration in early age is associated with obesity in childhood.	Risk of obesity in childhood is related to the antibiotic exposure in the first three years of life.	Combination of using antibiotics in infancy and pre-pregnancy or maternal BMI leads to the high tendency of overweight in childhood.

Keywords and Databases Used

Table 2. NHMRC Body of evidence matrix

Component	A	B	C	D
	Excellent	Good	Satisfactory	Poor
Evidence Base	One or more level I studies with a low risk of bias or several level II studies with a low risk of bias	One or two level II studies with a low risk of bias or an SR/several level III studies with a low risk of bias	One or two level III studies with a low risk of bias, or level I or II studies with a moderate risk of bias	Level IV studies, or level 1 to II studies/SRs with a high risk of bias
Consistency	All studies consistent	Most studies consistent and inconsistency may be explained	Some inconsistency reflecting genuine uncertainty around clinical question	Evidence is inconsistent
Clinical Impact	Very large	Substantial	Moderate	Slight or restricted
Generalizability	Population/s studied in body of evidence are the same as the target population in the guideline	Population/s studied in the body of evidence are similar to the target population for the guideline	Population/s studied in the body of evidence differ to the target population guideline but it is clinically sensible to apply this evidence to the target population	Population/s studied in the body of evidence differ to the target population and hard to judge whether it is sensible to generalize to target population
Applicability	Directly applicable to Australian healthcare context	Applicable to Australian health care context with few caveats	Probably applicable Australian healthcare context with some caveats	Not applicable to Australian healthcare context

FORM ranking for the body of evidence: Grade A (Body of evidence can be trusted to guide practice) (nhmrc.gov.au, 2018)  Body of the evidence has provided adequate support for the findings related to the association of exposure to antibiotics in early life such as before 24 months of life with high risk of childhood obesity.

Cohort study is one of the most effective study design that helps to answer the research questions related to the fundamental development of epidemiology used in the medical field. The analysis of epidemiology helps to identify the risk factors associated with a particular disease or use of medicine and treatment and provide effective pre-clinical identification of protective factors as well. In this regards cohort study design is most effective as it does not use any intervention or treatment for the participants, rather it focuses on the history of individual and population and identify the potential factors associated with a particular disease, use of medicine and treatment (Tigchelaar et al., 2015). Thus, it can be said that for this study cohort study design is appropriate as the aim of the study is to identify the impact of the antibiotics with the incident of obesity in children.

The interpretation of CASP check list has indicated that, there is some similarities in the studies that have selected for the assignment (casp-uk.net, 2018). The studies have provided a clear aim for their research. All of them have focused to identify the association of exposure to antibiotics during first 24 months of life with increase in the risk of childhood obesity. All the study have implemented the cohort design in an acceptable manner. The authors have identified all the contributing factors in an effective manner. Most of the studies have identify that, exposure to the antibiotics in the first 24 months of life may leads to the consequence of childhood obesity. While one study has indicated the relation of delivery mode and BMI of pregnant mother with childhood obesity (Ajslev et al., 2011). The studies have recruited different cohorts but concluded the same thing. The studies have followed up the subject of the research completely. The confounding factors such as sensitivity analysis, restrictions in design and others have been considered by the studies (casp-uk.net, 2018). 

Complete description of the cohort has been provided by each study. Trasande et al., (2013) has interpreted the characteristics of the sample, potentiality of childhood obesity and has used quantitative analysis of the result. One study has used cohort such as electronic health records from the year 2001 to 2013, thus the result has included findings from the large span (Bailey et al., 2014). In order to derive the result the study provided by Scott et al., (2016) has recruited 21714 children from the health improvement network, thus it can be said that large sample size has been used for the study that has helped to generalize the findings. Proper representation of graphs, table and data interpretation have been used by the studies.

Critical Appraisal and Levels of Evidence

Study has indicated that exposure to antibiotics in the first 6 months is similar in case of the normal delivery and CS. The possibility for exposure to antibiotics is higher in case of children with high birth weight. Children of the mother with high BMI in pre-pregnancy period also has high possibility for exposure to antibiotics (Ajslev et al., 2011). Such high possibility leads to the rise in the risk of overweight in later life. One study has indicated that use of antibiotics is determined by the provincial prescription. It has been found that 71.1% children have received antibiotics during early life and minimum 1 prescription has been associated with them before first birthday. Such exposure to antibiotics during first year of their life has increased their central adiposity in an effective manner (Azad et al., 2014). In a study the participants were classified according to the diagnosis criteria of International Classification of Disease, clinical modification codes and Ninth revision as well. After such classification the outcomes have compared with the National health survey and Nutrition examination survey, then it has been concluded that broad spectrum antibiotics using in the first 24 months of life leads to the consequence of childhood obesity (Bailey et al., 2014). Research conducted by Scott et al., (2016) has used the growth reference table provided by the World Health Organization and measured the height and weight of 1306 children then interpreted that administering antibiotics during early life resulted in high body weight in later life. In addition, other evidences have supported the findings of the studies used in the assignment of critical appraisal. Thus, it can be said that, all the studies have provided precise result in an effective manner and the thorough discussion of the findings has helped to understand that the results are applicable to the general population as well.

However, in some studies exposure and outcomes were not measured accurately in order to diminish the risk of bias. In most cases the risk of parents’ recall bias was associated. Bias regarding the use of over-the -counter medications has been found, however, one study has eliminated the over-the-counter medicines from the analysis as they lack specific dosage (Bailey et al., 2014). In some studies, primary analysis has been repeated and the association of prescriptions for antibiotics and the weight and height of the children has been examined in order to diminish the risk of selection bias. Thus, it can be said that most of the studies have limited the risk of bias in an effective manner.

Level of evidence: The level of evidence for the systemic review of cohort study has been described as level III-2 by the NHMRC Evidence Hierarchy (nhmrc.gov.au, 2018). As mentioned in the body of evidence matrix, most of the study has successfully eliminated the risk of bias and the all of the studies represented the adequate findings with the support of other evidence. Thus, the evidence of the studies has been put into excellent category.

Consistency: Consistency has been rated grade A as well (nhmrc.gov.au, 2018). Because all of the studies have indicated the same fact that is exposure to antibiotics in the early life leads to the consequence of obesity in the later life. All the studies have provided significant result for their research question. All of them have analyzed the impact of exposure to antibiotics in an effective manner and have provided adequate findings that has helped them to answer the research questions in a complete manner.

Results and Implications

Clinical impact: The clinical impact of the findings of the study is very high. All of the studies that have been used in the assignment have represented the findings regarding the association of antibiotics with childhood obesity without any doubt. The relevance of the findings presented by the studies highly impact the clinical questions and the impact is conclusive as well. Using the findings of the studies the medical field could introduce effective interventions for addressing the effect of antibiotics on obesity. Thus, the clinical impact of the findings has been graded A (nhmrc.gov.au, 2018).

Generalizability and applicability: The studies that have been used in the assignment have recruited the cohort and performed the research in different settings and populations. Some of the cohort have been recruited from hospital settings, some from clinical survey data, health care network, National birth cohort and hospital records. Studies have been performed in different countries and different age groups as well. Thus, the applicability of the evidence depends on the regulations source and limitations of each country. Generalizability of the evidence depends on the culture and health perceptions of each population ((nhmrc.gov.au, 2018). Most of the studies have been performed in developed countries, thus it can be said that the evidence could be applied in the target population that is Australia.

The implications of the studies have indicated that, administering a course of antibiotics before 24 months or in early life leads to the incident of obesity in the later life. Most of the children have been found to suffer from childhood obesity due to the exposure to antibiotics during infancy or early life. All of the study has implicated the same fact, provided a precise result and represented the findings in an effective manner, thus the evidence has been graded A. The Grade A implications to the policy and practice is very large. It has been mentioned in the NHMRC that Grade A level of evidence are trustworthy to apply in the clinical practice (nhmrc.gov.au, 2018). However, some studies have not considered the bias in exposure and outcomes, thus it is recommended that, more empirical analysis need to be done in order to eliminate the risk of bias (Bray, Lanza & Tan, 2015). It is also recommended that further studies need to be conduct in order to understand the impact of early exposure to antibiotics on childhood obesity in order to make the result more generalized within the population.

Beside effective findings and evidence, the critical appraisal also contains some limitations as well. One of such limitation is the use of limited secondary sources. Only 5 sources have been used in order to conduct the research, thus the study has represented limited evidence. Another limitation is that the literature sources have been collected from one database, thus risk of selection bias is present in the study. In addition, language is another limitation of the study because articles in English language has been selected for the study.

Conclusion

From the above discussion it can be said that, Antimicrobial resistance has become one of the biggest concern for public health across the world. It can cause potential threat for the health of human and animal as well. AMR occurs when microorganisms like bacteria, parasites and viruses become resistance to antibiotics and stop them from working against antimicrobial medicines. Regulation on the availability of the over the counter antibiotics, using the antibiotics rationally and improving hand hygiene have been considered as some effective strategies in order to reduce increasing number of events of AMR. Adequate research is needed to identify the factors of AMR. In this regards the study have focused to identify the impact of exposure to antibiotics during infancy or before 24 months on childhood obesity. The study has used 5 most relevant literatures from the current years. It has been found that most of the children associated with exposure to antibiotics in early life are obese. The findings and evidence of the articles have been graded A using the NHMRC grade. As some studies have failed to consider the bias in research, it has been recommended that further studies need to be conduct with minimum risk of bias.

References:

Ajslev, T. A., Andersen, C. S., Gamborg, M., Sørensen, T. I. A., & Jess, T. (2011). Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. International journal of obesity, 35(4), 522.

Australian Commission on Safety & Quality in Health Care. (2015). AURA 2016: First Australian Report on Antimicrobial Use and Resistance in Human Health. Australian Commission on Safety & Quality in Health Care.

Australian Government. (2018). Antimicrobial Resistance. Retrieved from https://www.amr.gov.au/

Azad, M. B., Bridgman, S. L., Becker, A. B., & Kozyrskyj, A. L. (2014). Infant antibiotic exposure and the development of childhood overweight and central adiposity. International journal of obesity, 38(10), 1290.

Bailey, L. C., Forrest, C. B., Zhang, P., Richards, T. M., Livshits, A., & DeRusso, P. A. (2014). Association of antibiotics in infancy with early childhood obesity. JAMA pediatrics, 168(11), 1063-1069.

Bray, B. C., Lanza, S. T., & Tan, X. (2015). Eliminating bias in classify-analyze approaches for latent class analysis. Structural equation modeling: a multidisciplinary journal, 22(1), 1-11.

casp-uk.net (2018).  CASP Checklists – CASP – Critical Appraisal Skills Programme. Retrieved from https://casp-uk.net/casp-tools-checklists/

Centers for Disease Control and Prevention, 2018). Antibiotic/ Antimicrobial Resitance. Retrieved from https://www.cdc.gov/drugresistance/about.html

nhmrc.gov.au (2018). Retrieved from https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf

Scott, F. I., Horton, D. B., Mamtani, R., Haynes, K., Goldberg, D. S., Lee, D. Y., & Lewis, J. D. (2016). Administration of antibiotics to children before age 2 years increases risk for childhood obesity. Gastroenterology, 151(1), 120-129.

Tigchelaar, E. F., Zhernakova, A., Dekens, J. A., Hermes, G., Baranska, A., Mujagic, Z., … & Franke, L. (2015). Cohort profile: LifeLines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics. BMJ open, 5(8), e006772.

Trasande, L., Blustein, J., Liu, M., Corwin, E., Cox, L. M., & Blaser, M. J. (2013). Infant antibiotic exposures and early-life body mass. International journal of obesity, 37(1), 16.

Uchil, R. R., Kohli, G. S., Katekhaye, V. M., & Swami, O. C. (2014). Strategies to Combat Antimicrobial Resistance. Journal of Clinical and Diagnostic Research?: JCDR, 8(7), ME01–ME04. https://doi.org/10.7860/JCDR/2014/8925.4529

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