Antimicrobial resistance (AMR) poses a global public health threat. Recent reports estimated that 4.95 million deaths in 2019 were associated with AMR. Beyond antibiotics, it has also been shown that the use of nonantibiotic medications (NAMs), such as diuretics, statins, and proton pump inhibitors, contributes to the emergence of AMR.

Australian researchers led by Henrietta Venter at the University of South Australia, Adelaide, conducted laboratory experiments to determine whether commonly used NAMs, at concentrations similar to those found in the intestinal environment of nursing home residents, could enhance ciprofloxacin-induced mutagenesis in Escherichia coli.

The drugs tested included ibuprofen, diclofenac, acetaminophen (paracetamol), furosemide, metformin, atorvastatin, tramadol, temazepam, and pseudoephedrine. The findings were published in npj Antimicrobials and Resistance, part of the Nature portfolio.

The researchers chose nursing homes as a model environment because older adults often take multiple medications, not only antibiotics but also analgesics, sleep aids, and antihypertensive drugs. Some individuals may take up to nine different medications per day. This population also represents one of the highest consumers of antibiotics, which are frequently overused in long-term care facilities for treating urinary and respiratory infections.

Because NAMs are often prescribed alongside antibiotics, the team measured mutation frequencies in the presence of ciprofloxacin, a fluoroquinolone antibiotic known to induce genetic mutations and widely used to treat urinary tract infections, among the most common bacterial infections in older adults. The frequent use of ciprofloxacin has already led to the emergence of ciprofloxacin-resistant E coli, posing a growing threat in nursing home settings.

To test the effect of the nine NAMs, as well as combinations of two NAMs, researchers evaluated mutation frequency in two E coli strains: E coli BW25113 (a derivative of the standard laboratory strain E coli K-12) and E coli 6146, which was isolated from the feces of a nursing home resident. The antimicrobial susceptibility of mutants induced by NAM exposure was then assessed, and the genetic mechanisms of resistance were analyzed through whole-genome sequencing.

Overall, the results showed that two commonly used painkillers, ibuprofen and acetaminophen, can significantly exacerbate antibiotic resistance through mutation at concentrations relevant to the gut. This was reflected in an increased number of bacterial mutants and higher maximum cell density.

Other NAMs, such as diclofenac and furosemide, also increased mutation frequency compared with the control group (ciprofloxacin with dimethyl sulfoxide). In contrast, temazepam, tramadol, and pseudoephedrine had minimal impact on mutation frequency in both E coli strains tested.

The study found that diclofenac increased the bioavailability of ciprofloxacin, ruling out the possibility that its effect on mutation frequency was simply due to reduced antibiotic availability. When bacteria were exposed to both ibuprofen and acetaminophen, the resulting mutation frequency was similar to that of ibuprofen alone, suggesting no cumulative effect from combining the two drugs.

However, mutants derived from exposure to two NAMs showed higher levels of resistance to ciprofloxacin. In addition, mutants from both E coli strains, BW25113 and 6146, exhibited reduced sensitivity (atleast fourfold) to multiple antibiotics. The increase in resistance was particularly marked for ciprofloxacin, reaching up to 32-fold in some cases.

Resistance was not limited to fluoroquinolones. It also extended to beta-lactam antibiotics such as amoxicillin, ceftazidime, and meropenem, as well as to levofloxacin and minocycline.

This story was translated from MediQuality.