Antimicrobial resistance (AMR) poses a global threat to public health. While antibiotic overuse is a primary driver, emerging evidence suggests that non-antibiotic medications (NAMs) may also contribute. This concern is particularly relevant in residential aged care facilities (RACFs), where both NAMs and antibiotics are frequently used. We investigated whether nine commonly used NAMs in RACFs, including ibuprofen, diclofenac, acetaminophen, furosemide, metformin, atorvastatin, tramadol, temazepam, and pseudoephedrine at gut-relevant concentrations, enhance ciprofloxacin-induced mutagenesis in Escherichia coli. Our findings showed that ibuprofen and acetaminophen significantly increased mutation frequency and conferred high-level ciprofloxacin resistance. Whole-genome sequencing identified mutations in GyrA, MarR, and AcrR, with the latter two correlated with overexpression of AcrAB-TolC drug efflux pump. Co-exposure to two NAMs further elevated mutation rates and ciprofloxacin resistance levels. This study underscored the overlooked role of NAMs in driving AMR and highlighted the need to reassess polypharmacy risks in aged care settings.
Antimicrobial resistance (AMR) has emerged as one of the main threats to public health on a global scale due to the excessive overuse and misuse of antibiotics. Projections to evaluate the future global economic cost of AMR estimate about 10 million deaths caused by infections with multi-resistant pathogens in 2050, exceeding by almost 2 million cases the death numbers attributed to cancer (1). However, recent analysis revealed a more dramatic development, as 4.95 million deaths associated with AMR were reported in 2019 (2).
The current EAU Guideline on urinary tract infections responded to this alarming trend and included non-antibiotic measures to the management of localised urinary tract infections like cystitis. Among others, non-steroidal anti-inflammatory drugs like ibuprofen or diclofenac were shown to reduce the use of antibiotics in 67% and 37%, respectively.
A recent study by Chen et al found an intriguing interaction between commonly used non-antibiotic medications (NAMs) on AMR development in Escherichia coli (E. coli), representing the most common uropathogen (3). Their findings demonstrated that pain medications like ibuprofen and acetaminophen in combination with ciprofloxacin increased mutation frequency resulting in high-level ciprofloxacin resistance. Genomic sequencing identified two known resistance mechanisms, i.e. gene mutations for targets like topoisomerase 2 (GyrA) and the overexpression of efflux pumps (AcrAB-TolC). The NAMs under investigation included ibuprofen, diclofenac, acetaminophen, furosemide, metformin, atorvastatin, tramadol, temazepam, and pseudoephedrine. Diclofenac, ibuprofen and acetaminophen were even shown to have a positive impact on fitness features like growth in the presence of ciprofloxacin. However, not all substances under investigation demonstrated comparable effects. For example, temazepam, tramadol and pseudoephedrine had minimal impact on the mutation frequency. Authors stressed that with the world’s population both growing and aging, polypharmacy needs to be acknowledged, especially when bacterial infections demand antimicrobial management.
The question arises whether we should question the guideline recommendations on non-antibiotic management based on these new findings. Firstly, the evidence-based recommendations on the management of cystitis comprise several options like d-mannose, phytotherapeutics, probiotics, topical oestrogen therapy, immunomodulation agents, methenamine hippurate and endovesical instillation. They are effective and contribute to the reduction of antibiotics. Therefore, these options are valuable tools for clinical practice and support the concept of antibiotic stewardship.
Secondly, the study by Chen et al shows several limitations that need to be acknowledged. This in vitro study investigated a common laboratory E. coli K12 isolate and a resident intestinal E. coli isolate. Uropathogenic E. coli (UPEC) belongs to a pathotype termed extraintestinal pathogenic E. coli (ExPEC), which represent a different phylogenetic group, mainly groups B2 and E. This means that they are equipped with a plethora of virulence and fitness factors, which are absent in the strains used in the current study. Furthermore, the authors used common cultivation conditions, which are not comparable to urine. The harsh and nutrition limited environment of the urinary tract requires the coordinated action of several virulence and fitness factors in order to survive and cause infection. The observed reactions of the apathogenic strains used in the study do not represent uropathogenic bacteria. Whether UPEC or other uropathogenic species may react in a similar fashion still needs to be investigated. Moreover, it needs to be stressed that the resistance mechanisms described in the study were the result of the combination of NAMs and antibiotics, not NAMs alone.
Nevertheless, the interactions of various substances in polypharmacy and their impact on the human microbiome are complex and still remain elusive. Future studies are warranted to understand beneficial and harmful combinations. The role of NAMs like diclofenac, ibuprofen and acetaminophen as non-antibiotic options for the development of AMR still has to be elucidated in clinical studies. In order to tackle the crisis of AMR, it is of utmost importance to apply antibiotics only after careful evaluation, adhere to hygiene and preventive measures, and consider non-antibiotic alternatives.
1) Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations; The Review on Antimicrobial Resistance chaired by Jim O’Neill; December 2014
2) Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629-655
3) Chen H, Sapula SA, Turnidge J, Venter H. The effect of commonly used non-antibiotic medications on antimicrobial resistance development in Escherichia coli. NPJ Antimicrob Resist. 2025 Aug 25;3(1):73. doi: 10.1038/s44259-025-00144-w. PMID: 40855113; PMCID: PMC12379211.