The word "bystander" is defined in the Merriam-Webster Dictionary as "one who is present but not taking part in a situation or event: a chance spectator." It's a word you often see in relation to a crime or a car accident.
It's also a term that can also be applied to bacterial pathogens that are not the cause of a person's infection but are nonetheless exposed to antibiotics for another infection. And a new study published this week in the Proceedings of the National Academy of Sciences suggests that in low-resource settings where young children often carry subclinical levels of pathogenic bacteria in their gut, there's a high level of bystander exposure to antibiotics that could provide selection pressure for the development of resistance.
It's a finding that the study authors say could "shift the focus" on antibiotic stewardship efforts in low-resource settings.
Quantifying the frequency of bystander exposure
For the study, which was funded by the UK charitable foundation Wellcome, an international team of researchers conducted a secondary analysis of data originally collected for the MAL-ED study, a previously published study that explored enteric infections and diarrheal illness in children in eight countries in South Asia, Africa, and South America. In the MAL-ED study, children were enrolled at birth and closely followed until the age of 2, with researchers collecting monthly stool samples and detailed information on illnesses, treatment, feeding practices, and child growth.
Elizabeth Rogawski McQuade, PhD, MSPH, lead author of the new study and assistant professor of epidemiology at Emory University's Rollins School of Public Health, said that the MAL-ED cohort provided a really rich and unique data set that allowed her and her colleagues to examine bystander exposures in these children.
"We actually have information on every day of the child's life from birth to 2 years of age, if they were sick, or if they got an antibiotic, or what other medications they received," she told CIDRAP News.
What the researchers were looking to evaluate was how frequently enteric bacteria in these children—pathogens like Escherichia coli, Campylobacter and Shigella, which are common causes of diarrhea—were being exposed to antibiotics that the children received for other illnesses, like respiratory tract infections. Because children in low-resource settings often lack access to clean water and sanitation facilities and live in crowded conditions, they are constantly exposed to these pathogens, but don't always get diarrhea because of built up immunity.
"The bacteria that we focused on this study are still pathogenic, in that they can cause illness," Rogawski McQuade explained. "But the bystander exposure happens when those pathogenic bacteria that can cause illness are not currently causing illness. They're just present as an asymptomatic infection…and the child is getting antibiotics for another reason."
To determine the frequency of bystander exposure, the researchers looked at every antibiotic course prescribed for each child and then analyzed the bacteria from a stool sample that had been collected within the previous 30 days. Among the 1,715 children included in the analysis, caregivers reported 15,697 total antibiotic courses, and 13,629 of those antibiotic courses were matched to a stool sample collected within the previous 30 days.
The analysis found that there were 22,161 distinct exposures of subclinical enteric bacteria to antibiotics. For any subclinical bacterial pathogen analyzed, there were 744.1 antibiotic exposures per 100 child-years—or more than seven antibiotic exposures per year, Rogawski McQuade explained. Enteroaggregative E coli was the most frequently exposed enteric pathogen, with 229.6 antibiotic exposures per 100 child-years. The sites in Bangladesh and Pakistan (1,670 and 1,243.3 exposures, respectively) had the highest incidence rates of subclinical pathogen exposure to antibiotics, while sites in Brazil and South Africa (57.3 and 89.4 exposures, respectively) had the lowest.
Nearly all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E coli (95.6%), and Shigella (77.6%) occurred when those pathogens were not the target of treatment. Upper respiratory infections (37.6%) and acute lower respiratory infections (12.3%) accounted for nearly half (49.9%) of the antibiotic courses in which bystander pathogens were exposed, while diarrheal illness accounted for 24.6%.
Rogawski McQuade notes that the concern about this bystander exposure and selection pressure is not necessarily at the individual level, but rather at the community level. For example, a child carrying Shigella bacteria in their gut may not be affected even if repeated antibiotic exposure causes the Shigella to become resistant. But the pathogen can be spread to others.
"That child will probably be fine, but then the Shigella is transmitted to someone else in the community, causes disease, and because it is resistant, when that individual goes for treatment, they might have treatment failure or some other poor outcome from the resistant illness," she said.
That concern about community-level resistance is underscored by the study's analysis of 2,630 E coli isolates from 505 children in the study, which found that a total of 87% of those isolates exhibited resistance to at least one antibiotic. Further analysis showed that bystander exposure to macrolide antibiotics within the previous 30 days was associated with a 29% increase in the prevalence of macrolide resistance.
"These exposures matter," Rogawski McQuade said. "The more bystander exposures you have, the more resistance there is at the community level."
How vaccines might help
Rogawski McQuade and her colleagues say the findings are important because antibiotic stewardship efforts for diarrheal illness in low-resource settings have focused on how overuse of antibiotics for diarrhea can promote resistance in pathogens like Shigella and Campylobacter, which have been deemed priority pathogens by the World Health Organization. Quantifying the frequency of bystander exposure, they suggest, could help broaden those efforts.
"This work expands the value proposition for antibiotic stewardship programs and informs which types should be prioritized," they write. "Specifically, for example, our results suggest that reducing antibiotic use for respiratory infections may have a larger impact on the development of resistance in enteric pathogens than reducing antibiotic use for the treatment of enteric bacteria directly."
Furthermore, Rogawski McQuade says the findings bolster the underlying rationale for the study, which was to explore a growing area of interest among antibiotic resistance and global health researchers—what role vaccines for diarrheal and respiratory illness could play in reducing unnecessary antibiotic use in children in low-income countries.
Respiratory infections and diarrheal illness are the primary drivers of antibiotic use in young children low- and middle-income countries (LMICs). Although these illnesses are frequently caused by viruses, low-resource settings often lack the diagnostic tools to quickly make that determination, and antibiotics are among the few tools that healthcare providers have at their disposal.
But recent research suggests vaccines could play a big role in reducing childhood antibiotic use in these settings. A study published in Nature in 2020 found that pneumococcal conjugate and rotavirus vaccines prevents more than 23 million episodes of antibiotic-treated acute respiratory infections annually in children in LMICs, and more than 13 million episodes of antibiotic-treated diarrhea.
Rogawski McQuade says the next step of this work will be to identify which vaccines might be most effective at reducing bystander exposure.
"We want to prevent resistance from happening in pathogens that we might want to treat in the future," she said. "Vaccines that prevent these infections might actually end up being more effective [than antibiotic stewardship] because they prevent the illness from occurring."
