Since ionophores—a class of antibiotics used widely in animal production—are not used in human medicine, it has largely been assumed that they do not contribute to medically important AMR. However, a new study suggests that ionophores may contribute to the development of medically important antimicrobial resistance (AMR).

Ionophores are commonly used as anti-coccidials in poultry, and for growth promotion in swine and cattle. As of 2022, ionophores represent 37 percent of antibiotics used in food-producing animals in the U.S., with nearly 4.2 kilograms sold. Classified as having low or no importance for human medicine in the U.S. and Canada, their use is regulated less strictly than other classes of antibiotics.

Despite assumptions about the relative human medical insignificance of ionophore use in animal agriculture, recent evidence suggests that ionophore use in animal populations has the potential to contribute indirectly to human-relevant AMR. This may potentially occur through cross-resistance (i.e., a gene that causes ionophore resistance also causes resistance to a medically important antibiotic) or co-selection (i.e., a gene that causes ionophore resistance is genetically linked to genes causing resistance to medically important antibiotics). At present, however, actual human risks posed by ionophore use in animals are still unclear.

To investigate growing concerns that ionophore usage could co-select for clinically relevant AMR, using publicly available data, researchers investigated the global distribution and linkage of ionophore resistance genes narA and narB with other AMR genes. The researchers identified more than 2,400 narAB-bearing isolates reported from 51 countries, derived from a variety of species including poultry, cattle, and humans. narAB sequences were found in ten bacterial species, with Enterococcus faecalis and E. faecium most highly represented.

The more than 2,400 narAB-containing isolates harbored an average of 8.26 resistance genes, with the most commonly detected resistance genes predicted to confer resistance to medically important antibiotics erythromycin, tetracycline, and aminoglycosides. The narAB-containing isolates also harbored an average 2.13 point mutations predicted to confer daptomycin resistance, ampicillin resistance, or a multidrug resistant (MDR) phenotype.

Additionally, statistically positive associations were detected between resistance determinants in E. faecalis and 13 medically important resistance genes, including all members of a vancomycin resistance gene cluster. In E. faecium, the researchers found positive associations between narAB and 11 resistance genes, as well as four point mutations.

Overall, the researchers caution that, based on their findings showing clear potential for co-selection for clinically relevant AMR, ionophore use cannot be assumed to be risk-free. While the direction of narAB transfer has not been established, transfer from farm animals to humans seems most likely, say the researchers.

Published in Antimicrobial Chemotherapy, the study was conducted by researchers in the Carleton University Department of Biology. funded through a research service agreement with Perdue Farms, as well as through a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant.