Ionophores: An Overlooked Risk for the Spread of Medically Relevant Antibiotic Resistance

Author: Dr. Inge Heinzl, Editor EW Nutrition

Antibiotic resistance is one of the biggest threats to global health today. When bacteria become resistant to antibiotics, infections that were once easily treatable can become deadly. For decades, the discussion surrounding the causes of antimicrobial resistance (AMR) has primarily focused on the misuse of antibiotics in human medicine and agriculture. But some antibiotics have escaped critical scrutiny—until now.

Ionophores, a special group of antibiotics

Ionophores are a group of antibiotics used as feed additives in ruminants and pigs as growth promoters and in poultry as anticoccidials since the early 1970s (Chapman et al., 2010). They are among the most widely used classes of antibiotics in animal production. In the US, e.g., more than 4 million kilograms were sold in 2016 (Wong, 2019).

Unlike many other antibiotics, ionophores are not used in human medicine because of their toxicity. For this reason, regulators have often assumed that ionophores pose little to no threat to human health. In North America, for example, ionophores are officially classified as having low or no importance for human medicine, which means their use is less strictly regulated than antibiotics that are directly relevant for human health.

However, new scientific findings challenge this assumption. A research team led by Asalia Ibrahim (2025) has provided compelling evidence that the use of ionophores in agriculture may indirectly contribute to the spread of resistance to antibiotics crucial for treating human infections.

What did the researchers discover?

The researchers focused on two specific genes, narA and narB, transporters which enable Enterococcus faecium to resist ionophores like narasin, salinomycin, and maduramicin. Initially, these genes were found in bacteria isolated from Swedish broiler chickens AND on the same plasmid as vancomycin resistance genes (Nilsson et al., 2012). More recent studies have identified the NarA and NarB genes in other countries as well, raising questions about their global distribution and their connection to resistance to medically important antibiotics.

To investigate, Asalia Ibrahim (2025) analyzed publicly available genome data from the NCBI Pathogens database, a massive resource that collects bacterial genome sequences from around the world. They identified more than 2,400 bacterial isolates from 51 countries that carry both narA and narB. The bacteria were found in various host animals, including poultry, swine, and cattle, but also in humans. Alarmingly, over 500 of the samples containing these resistance genes came from human sources!

Why is this a problem?

The core concern is that these ionophore resistance genes do not exist in isolation. Instead, they are often genetically linked with other resistance genes that protect bacteria from antibiotics that are critical for human medicine.

This can happen in two ways:

• Cross-resistance, where a single gene provides resistance to multiple drugs at once. In this case, it appears unlikely because ionophores belong to a class (polyether antibiotics) that is not used for humans.
• Co-selection occurs when different resistance genes sit close together on the same piece of genetic material (like a plasmid) or in the same bacterial genome. If one gene is selected because the antibiotic it resists is used, then the other genes hitch a ride and spread too.

The researchers found clear evidence for co-selection. Many narAB-carrying bacteria also contained resistance genes for vancomycin, a last-resort antibiotic (Nilsson et al., 2012), erythromycin, tetracycline (Pikkemaat et al., 2022), and other antibiotics. On average, each narAB isolate carried more than 10 additional resistance determinants, including both resistance genes and mutations.

The link is not just theoretical. When the Norwegian poultry industry stopped using narasin in 2016, the levels of vancomycin-resistant Enterococcus dropped significantly (Simm et al., 2019). This real-world example suggests that the use of ionophores can indeed help maintain resistance to medically relevant antibiotics in animal populations, potentially allowing these bacteria to enter the food chain and reach humans.

What does this mean for food safety and public health?

The study’s findings highlight how actions taken in agriculture can have far-reaching effects on human health. Suppose bacteria carrying narAB genes also carry resistance to life-saving human antibiotics. In that case, the routine use of ionophores in animal feed can indirectly contribute to maintaining a reservoir of resistant genes. These bacteria can spread from animals to humans through direct contact, contaminated meat, or environmental exposure.

This raises questions about the long-held belief that ionophores are risk-free. In reality, they might be acting as a hidden driver for the maintenance and spread of resistance genes that severely limit our treatment options in human medicine.

What should be done?

The researchers argue that ionophores need to be reevaluated within the broader framework of the “One Health” approach, which recognizes that the health of people, animals, and ecosystems are deeply interconnected. Simply because ionophores are not used in hospitals does not mean they are harmless to human health.

Possible steps could include:

• Stricter monitoring of ionophore use in livestock.
• Better surveillance of resistance genes like narA and narB in both animal and human bacterial isolates.
• Considering limits or alternatives to routine ionophore use in industrial farming.
• More research to understand how these resistance genes move between bacteria, species, and environments.

The bottom line

Ionophores play a crucial role in intensive animal production worldwide, helping to maintain the health and productivity of animals. But this convenience comes at a potential cost. The research of Ibrahim et al. (2025) serves as a clear reminder that the use of antibiotics—whether for humans or animals—can have unintended consequences for global health.

Prudent, science-based management of all antibiotics is crucial to slowing the spread of antimicrobial resistance and preserving the effectiveness of life-saving drugs for future generations.

References

Chapman, H.D., T.K. Jeffers, and R.B. Williams. “Forty Years of Monensin for the Control of Coccidiosis in Poultry.” Poultry Science 89, no. 9 (September 2010): 1788–1801. https://doi.org/10.3382/ps.2010-00931.

Ibrahim, Asalia, Jason Au, and Alex Wong. “The Ionophore Resistance Genes narA and narB Are Geographically Widespread and Linked to Resistance to Medically Important Antibiotics.” mSphere, June 17, 2025. https://doi.org/10.1128/msphere.00243-25.

Nilsson, O., C. Greko, B. Bengtsson, and S. Englund. “Genetic Diversity among VRE Isolates from Swedish Broilers with the Coincidental Finding of Transferrable Decreased Susceptibility to Narasin.” Journal of Applied Microbiology 112, no. 4 (March 5, 2012): 716–22. https://doi.org/10.1111/j.1365-2672.2012.05254.x.

Pikkemaat, M.G., M. Rapallini, J.H.M. Stassen, M. Alewijn, and B.A. Wullings. “Ionophore Resistance and Potential Risk of Ionophore Driven Co-Selection of Clinically Relevant Antimicrobial Resistance in Poultry.” Food Safety Report, Wageningen, 2022. https://doi.org/10.18174/565488.

Simm, Roger, Jannice Schau Slettemeås, Madelaine Norström, Katharine R. Dean, Magne Kaldhusdal, and Anne Margrete Urdahl. “Significant Reduction of Vancomycin Resistant E. Faecium in the Norwegian Broiler Population Coincided with Measures Taken by the Broiler Industry to Reduce Antimicrobial Resistant Bacteria.” PLOS ONE 14, no. 12 (December 12, 2019). https://doi.org/10.1371/journal.pone.0226101.

Wong, Alex. “Unknown Risk on the Farm: Does Agricultural Use of Ionophores Contribute to the Burden of Antimicrobial Resistance?” mSphere 4, no. 5 (October 30, 2019). https://doi.org/10.1128/msphere.00433-19.