The emergence and spread of antimicrobial-resistant organisms and resistance genes are a significant public health threat. In 2019, 4.95 million deaths worldwide were linked to antimicrobial resistance (AMR). It occurs when microbial organisms, such as bacteria, viruses, fung and parasites, no longer respond to antimicrobial medicines. Antimicrobials, such as antibiotics, antiparasitics, antivirals, and antifungals are medicines used to prevent and treat infectious diseases in humans, animals, and plants. A combination of various factors contributes to the development of AMR. Overuse of antibiotics in clinical and agricultural settings commonly leads to AMR development. In addition to antibiotics, non-antibiotic medications or NAMs (e.g., statins, diuretics and proton-pump inhibitors) also contribute to the rise of AMR.
Currently, 95% of medicines in the global pharmaceutical market are non-antibiotic drugs and recent data revealed that over 200 commonly used NAMs have antibiotic-like effects on gut bacteria. Statins, for example, have antibacterial activity, while certain nonsteroidal anti-inflammatory drugs (NSAIDs) promote cross-resistance development. Many older people are highly dependent on medicines to manage chronic disease, and some even take nine or more prescribed drugs per day. This phenomenon is referred to as polypharmacy. The elder population has been associated with higher antibiotic intake. Previous studies have indicated antibiotic overuse among elderly facilities, particularly in managing urinary tract and respiratory infections, since ciprofloxacin is among the most used antibiotic for urinary infections.
A last investigation published in NPJ Antimicrobials and Resistance investigated whether commonly used non-antibiotic medications (NAMs), particularly ibuprofen and acetaminophen, in residential aged care facilities, enhance ciprofloxacin-induced mutagenesis in Escherichia coli. The study also assessed other widely used NAMS, including diclofenac and furosemide, which influenced resistance development even when they did not increase mutation frequency. The current study investigated nine NAMs commonly used by older people: ibuprofen, diclofenac, acetaminophen, furosemide, pseudoephedrine, atorvastatin calcium, metformin, temazepam, and tramadol. Since these medicines are frequently co-administered with antibiotics, mutation frequencies were determined in the presence of ciprofloxacin, a known mutation inducer.
Compared to non-exposed bacterial mutant cells, those exposed to NAMs alone did not impact the growth of E. coli cells. However, for both E. coli isolates, the growth rate was significantly affected at about three-quarters of ciprofloxacin’s minimum inhibition concentration (MIC). In the presence of three-quarters, the MICs of ciprofloxacin, ibuprofen, diclofenac and acetaminophen enhanced the growth rates of E. coli BW25113. These three NAMs also reduced the length of the lag phase. In E. coli 6146, ciprofloxacin exposure delayed exponential growth, although certain NAM combinations modestly improved adaptability. Higher mutation frequencies were observed in E. coli BW25113 and E. coli 6146 exposed to ibuprofen and acetaminophen than those exposed to ciprofloxacin alone.
The current study observed that NAM exposure elevated ciprofloxacin resistance in select isolates. A higher mutation frequency was observed in cells following exposure to ibuprofen and ciprofloxacin. Furosemide + ciprofloxacin increased 32-fold for ciprofloxacin MIC and 16-fold for levofloxacin MIC. Atorvastatin + ciprofloxacin exposed and diclofenac + ciprofloxacin exposed mutants revealed a 16-fold increase in ciprofloxacin MIC. In some two-NAM exposures, resistance rose even higher, with ibuprofen plus diclofenac producing a 64-fold increase in ciprofloxacin MIC. Notably, while two NAMs did not synergistically increase mutation frequency, mutants derived from two NAMs plus ciprofloxacin showed higher levels of ciprofloxacin resistance than those exposed to a single NAM.
In summary, there are enough data indicating that common drugs, such as acetaminophen and ibuprofen, when combined with ciprofloxacin, significantly increase mutation frequency and lead to multiple antibiotic resistance. Other NAMs, including diclofenac and furosemide, also contributed to higher resistance levels, even if they did not always elevate mutation frequency. The authors emphasize that polypharmacy in aged care settings (elder facilities) may amplify these risks and highlight the need to reassess medicine combinations, rather than issuing direct prescribing guidance.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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