Inappropriate antibiotic use in low and middle-income countries disrupts infant gut health, fuels antimicrobial resistance

Children in low- and middle-income countries (LMICs) often receive inappropriate antibiotics, a key driver of antimicrobial resistance (AMR).

Infections with AMR-bearing pathogens disproportionately burden young children and are more difficult and expensive to treat. Moreover, the impact of AMR genes on the microbiome and their selection, persistence, and horizontal spread remains poorly understood.

In a recent study published in PLOS Medicine, researchers review available evidence discussing the impact of antibiotics on the infant gut microbiome.

Study: Impact of antibiotics on gut microbiome composition and resistome in the first years of life in low- to middle-income countries: A systematic review. Image Credit: Lifebrary / Shutterstock.com

About the study

In the present study, researchers reviewed randomized control trials (RCTs), clinical trials, and cohort studies examining the use of antibiotics in infants below the age of two from LMICs. These studies also included data on the gut microbiome and resistome composition of these infants following antibiotic treatment. 

Five electronic databases including MEDLINE EMBASE, SCOPUS, WHO Global Index Medicus, and SciELO were used for the analysis. Two independent assessors screened the studies, first by title and abstract, then by full text. A third assessor resolved differences in the selected studies. 

The studies primarily used ribosomal ribonucleic acid (rRNA) or metagenomics to assess differences in median microbiome composition and diversity after antibiotic use in the study test groups as compared tthe o control. Data on alpha and beta diversity, resistome composition, and relative abundance of antibiotic-specific genes from the studies were also reviewed. 

Alpha diversity measures species richness at different taxonomic scales, such as operational taxonomic units (OTUs), regardless of the frequencies. Likewise, the Shannon and Simpson indices measure species’ evenness and richness, with species richness more sensitive to species’ evenness.

The Bray-Curtis method calculated dissimilarity matrices between control and treatment groups in resistome composition assessment after comparing total resistance gene abundance at baseline and following antibiotic treatment.

Antibiotic use in infants alters microbiome diversity and resistant gene expression

A total of 4,369 articles were extracted from the databases. After removing duplicates, 2,748 unique articles met the screening criteria.

After screening, 10 RCTs met the eligibility criteria. These studies were subsequently assessed for risk of bias using the Cochrane risk-of-bias tool. 

None of the studies from LMICs evaluated antibiotics frequently used to treat children, such as clindamycin and metronidazole. Rather, most studies involved azithromycin (AZI), as this antibiotic reduces childhood mortality through prophylactic mass administration. Other antibiotics that were evaluated in the reviewed studies included cotrimoxazole (CTX) and amoxicillin (AMX).

Both antibiotic class and their duration of administration impacted microbiome diversity and composition, as well as AMR-resistant genes, in infants. Short courses of AZI immediately reduced microbiota diversity, with persistent reductions in microbiota richness for up to six months after antibiotic use.

Similarly, the short-term use of CTX diminished alpha diversity indexes, whereas its chronic use increased alpha diversity over time. These findings related to AZI and CTX use agree with previously reported experimental data obtained from adults. 

AZI treatment consistently increased persistent macrolide-resistant levels up to six months following usage. Comparatively, the long-term biannual use of AZI increased key resistance determinants to non-macrolide antibiotics. CTX increased aggregate resistance gene diversity and key determinants of resistance to sulfonamide and trimethoprim. 

Conclusions

The gut microbiome plays a crucial role in various aspects of health, including immune system maturation, regulation, and metabolism of the host, particularly during infancy. All studies included in the current analysis found that antibiotic use significantly contributed to antibiotic class-specific increases in AMR gene determinants.

The loss of species diversity in infants treated with antibiotics correlates with altered immunity against exogenous pathogens. Antibiotic treatment during infancy also reduced the nutritional and growth outcomes in these infants.

It is not uncommon that children residing in LMICs are prescribed both appropriate and inappropriate antibiotics multiple times throughout their life. Thus, the studies evaluated in this review are likely a gross underestimate of the impact of antibiotic use throughout childhood.

These findings indicate the immediate need for more research to understand how antibiotics affect microbiome diversity on a functional level, phenotypic resistance in enteropathogens, and the risk of disease in infants in LMICs. These future studies could inform antibiotic prescribing practices and health policies around AMR pathogens by clinicians, as well as antibiotic administration for the general public.