Low antibiotic levels in the environment may spur drug resistance

bacteria are exposed to low concentrations of antibiotics, the impact on complex microbial communities, where different species of bacteria are competing against one another, is less clear.

Metagenome analysis of the samples, and comparison with a control sample that wasn’t exposed to the antibiotics, revealed that the beta-lactam resistance gene blaCTX-M was the most abundant antibiotic-resistance mechanism. Even at the lowest concentration of cefotaxime, the abundance of blaCTX-M increased by eightfold over the control sample.

In addition, while cefotaxime exposure killed off many species of bacteria in the wastewater samples, it also increased the presence of dangerous gram-negative pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii. Co-selection for other resistance to other antibiotics was also observed.

“This increases the relevance of our research to real-world environments, as bacteria do not exist as single species but in complex communities where competition within and between different species may affect bacterial fitness and selection for antibiotic resistance,” Murray said. 

Murray and her colleagues theorize that the selection for blaCTX-M at environmentally relevant concentrations of cefotaxime is likely due to clonal expansion of bacteria carrying the gene, along with the horizontal transfer of plasmids carrying the gene. And the fact that blaCTX-M appeared to outcompete other resistance genes at all concentrations could explain the worldwide spread of CTX-M-type genes, which have become increasingly prevalent in urinary tract infections.

But while the prevalence of the blaCTX-M gene increased over time and with higher amounts of cefotaxime, it ultimately reached a plateau and remained relatively constant until it was exposed to concentrations that were 30 and 50 times the amount used in clinical settings. The researchers believe this could be the result of the antibiotic-resistant bacteria degrading the cefotaxime and providing protection for susceptible bacteria.

That discovery could have clinical relevance, the researchers suggest, because during antibiotic treatment, antibiotic concentrations can be different in different parts of the body. As a result, even sub-inhibitory levels of antibiotics in some parts of the body, like the gut, could be selecting for resistant bacteria.

“This finding shows we need to understand how bacteria evolve in communities rather than isolation, and further work is needed to understand how we can use these findings to improve antibiotic stewardship and treatment,” Murray said.

Environmental resistance
The study adds to a growing concern about the environmental dimension of antibiotic resistance. Several studies in recent years have documented the presence of antibiotics, and antibiotic resistance genes, in agricultural soil, river and lake sediment, tidal estuaries, and wastewater facilities. Understanding how antibiotics and antibiotic resistance impact the environment, and how to mitigate the effects, is part of the One Health approach to antimicrobial stewardship

Antibiotic residues can follow several paths into the environment. According to a recent United Nations report, up to 80 percent of antibiotics are excreted unmetabolized through human urine and feces into sewage systems. Likewise, antibiotics used in food-producing animals are excreted through manure, which is spread onto fields as fertilizer and can be carried into nearby lakes and streams. Pharmaceutical production facilities also release antibiotic residues into waterways.

The question is how much this environmental contamination is contributing to the evolution of antibiotic resistant bacteria, and how much of an impact, if any, it’s having on human health.

“There is currently very little known about the effects antibiotics and other selective chemicals in the environment may have on evolution of antibiotic resistance,” Murray said. “This research is contributing to filling that knowledge gap.”