In the global effort to combat antimicrobial resistance, the primary driver has long been identified as the overuse of antibiotics. However, emerging evidence suggests that the use of non-antibiotic medications may also be an overlooked factor. A recent study finds that common, non-antibiotic painkillers, including ibuprofen and acetaminophen, can significantly promote the development of antibiotic resistance in bacteria when co-administered with an antibiotic.
Antimicrobial resistance is a growing public health threat, rendering once-treatable infections difficult to manage. The process involves microorganisms, like bacteria, viruses, or fungi, developing mechanisms to resist the drugs designed to kill them. The issue is particularly pronounced in settings like nursing homes, where antibiotic use is frequent. Residents in these facilities often receive multiple medications at a time for chronic conditions, a practice known as polypharmacy, which can interact with and alter the microorganisms living in the body.
The human gut is a crucial environment for studying these interactions. When a person takes medications orally, the drugs become concentrated in the digestive tract, where they mix directly with the trillions of bacteria that make up the gut microbiota. This makes the gut a primary site where bacteria are exposed to the combined pressure of different drugs, potentially creating opportunities for the development of resistance.
While these drug-bacteria interactions begin at a microscopic level, their consequences are global in scale. The World Health Organization identifies antimicrobial resistance as a top global public health threat, responsible for an estimated 1.27 million direct deaths in 2019 and contributing to nearly 5 million others. This resistance crisis jeopardizes the foundations of modern medicine, making essential procedures like surgery, organ transplants, and cancer chemotherapy far more dangerous without the protection of effective antibiotics.
To investigate the possible link between non-antibiotic medications and increased antibiotic resistance, researchers from the University of South Australia selected nine non-antibiotic medications commonly used in elderly care and assessed their impact on Escherichia coli. In the lab, the researchers exposed E. coli bacteria to gut-level amounts of these drugs, along with a low dose of the antibiotic ciprofloxacin. They then measured the frequency of mutations that led to ciprofloxacin resistance.
The results showed that while most of the non-antibiotic medications had little effect, ibuprofen and acetaminophen significantly increased the mutation frequency in both strains of E. coli used. These mutations conferred high-level resistance to ciprofloxacin, allowing the bacteria to survive in what should have been a lethal environment.
To determine the underlying cause of this resistance, the team sequenced the genomes of the mutated bacteria. The analysis revealed two primary mechanisms. The first involved mutations in the gene gyrA. Ciprofloxacin functions by targeting the protein this gene produces, which is essential for bacterial DNA replication. The mutations altered this protein, preventing the antibiotic from binding and carrying out its function effectively. The second mechanism was the overexpression of the AcrAB-TolC efflux pump, a pump that actively expels harmful substances, including antibiotics, from the bacterial cell. Mutations in the regulatory genes marR and acrR caused the pump to be overexpressed, removing ciprofloxacin from the cell before it could reach its target. To confirm the role of this pump, the researchers applied an efflux pump inhibitor, which successfully reversed the antibiotic resistance in many of the mutants.
The researchers also explored the effects of polypharmacy by exposing E. coli to combinations of two non-antibiotic medications along with ciprofloxacin. This scenario did not increase the frequency of mutations for all drug combinations, but it did consistently result in mutants with substantially higher levels of resistance. For instance, bacteria exposed to ibuprofen combined with other drugs evolved to withstand ciprofloxacin concentrations up to 64 times higher than the wild-type strain.
These findings suggest that certain non-antibiotic drugs, while having no antibacterial properties on their own, can act as catalysts for the evolution of antibiotic resistance when an antibiotic is also present. This does not mean that standard use of common painkillers is dangerous on its own, but it highlights a hidden risk for individuals on complex medication regimens, particularly in elderly care facilities. The study underscores the need for greater awareness among clinicians and patients about the unseen interactions in our medicine cabinets and calls for a re-evaluation of how drug combinations may contribute to antimicrobial resistance.