Antimicrobial and Antibiofilm Activities of Paracetamol in Combination with Various Antimicrobials

Abstract

Background and Aims: In recent years, very few new antimicrobial agents have been approved and used for the treatment of infectious diseases. Paracetamol (acetaminophen) is one of the nonsteroidal anti inflammatory drugs with analgesic and antipyretic effects, which is frequently preferred and used safely in our country and in many other countries. In addition, because it is the most frequently prescribed drug after antibiotics and is often administered with antimicrobial therapy, understanding the interactions between these two drug classes is extremely important for drug repurposing. Methods: For this purpose, the effects of paracetamol alone or in combination with various antimicrobial agents and their activities on adhesion and biofilm formation were investigated against various standard bacteria and yeasts. Results: The minimum inhibitory concentration of paracetamol against standard strains was found 10,000 μg/mL, and the minimum bactericidal and fungicidal concentrations were found 10,000 - > 20,000 μg/mL. Cefepime and paracetamol combinations against Escherichia coli and Achromobacter xylosoxidans, and gentamicin and paracetamol combinations against Klebsiella pneumoniae and Acinetobacter baumannii showed synergistic effect. No antagonism was observed. According to the biofilm adhesion and formation inhibition assays, it was found that paracetamol was more effective against gram-negative bacteria than gram-positive bacteria and yeasts. Conclusions: In conclusion, this study proved that paracetamol, which is one of the most common analgesic and antipyretic agents in clinical use for many years, has antimicrobial and antibiofilm activity and can show synergistic effect in combination with various antibiotics.

Keywords

• Paracetamol
• Antimicrobial activity
• Combination
• Biofilm
• Checkerboard

References

1. Abidi, S. H., Ahmed, K., & Kazmi, S. U. (2019). The antibiofilm activity of acetylsalicylic acid, mefenamic acid, acetaminophen against biofilms formed by P. aeruginosa and S. epidermidis. JPMA. The Journal of the Pakistan Medical Association, 69(10), 1493–1495. google scholar
2. Altaf, M., Ijaz, M., Ghaffar, A., Rehman, A., & Avais, M. (2019). Antibiotic susceptibility profile and synergistic effect of non-steroidal anti-inflammatory drugs on antibacterial activity of resistant antibiotics (Oxytetracycline and Gentamicin) against methicillin resistant Staphylococcus aureus (MRSA). Microbial Patho- genesis, 137, 103755. https://doi.org/10.1016/j.micpath.2019.103755 google scholar
3. Aydın, S. (2019). Antibacterial and Anti-Urease Activities of chloropheniramine maleat, paracetamol and clarithromycine. Düzce Üniversitesi Bilim ve Teknoloji Dergisi, 7(1), 194–200. https://doi.org/10.29130/dubited.432506 google scholar
4. Botting, R. M. (2000). Mechanism of action of acetaminophen: Is there a cyclooxygenase 3? Clinical Infectious Diseases, 31(5), 202–210. https://doi.org/10.1086/ 317520 google scholar
5. Bozkurt Guzel, C., Hacioglu, M., Inci, G., & Savage, P. B. (2019). Antibacterial and antibiofilm activities of ceragenins against Pseudomonas aeruginosa Clinical Isolates. Turkish Journal of Pharmaceutical Sciences, 16(4), 444–449. https:// doi.org/10.4274/tjps.galenos.2018.59023 google scholar
6. Brune, K., Renner, B., & Tiegs, G. (2015). Acetaminophen/paracetamol: A history of errors, failures and false decisions. European Journal of Pain (United Kingdom), 19(7), 953–965. https://doi.org/10.1002/ejp.621 google scholar
7. Chan, E. W. L., Yee, Z. Y., Raja, I., & Yap, J. K. Y. (2017). Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. Journal of Global Antimicrobial Resistance, 10, 70–74. https://doi.org/10.1016/j.jgar. 2017.03.012 google scholar
8. Christaki, E., Marcou, M., & Tofarides, A. (2020). Antimicrobial resistance in bacteria: mechanisms, evolution, and persistence. Journal of Molecular Evolution, 88(1), 26–40. https://doi.org/10.1007/S00239-019-09914-3 google scholar

9. Ciofu, O., Tolker-Nielsen, T., Jensen, P. Ø., Wang, H., & Høiby, N. (2015). Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients. Advanced Drug Delivery Reviews, 85, 7–23. https:// doi.org/10.1016/J.ADDR.2014.11.017 google scholar
10. Clinical and Laboratory Standards Institute (CLSI). (2008). Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard-third edition. google scholar
11. Clinical and Laboratory Standards Institute. (2023). Performance standards for antimicrobial susceptibility testing, informational supplement M100-S33. CLSI. google scholar
12. Freo, U., Ruocco, C., Valerio, A., Scagnol, I., & Nisoli, E. (2021). Paracetamol: A review of guideline recommendations. Journal of Clinical Medicine, 10(15), 3420. https:// doi.org/10.3390/jcm10153420 google scholar
13. Gil, D., Daffinee, K., Friedman, R., Bhushan, B., Muratoglu, O. K., LaPlante, K., & Oral, E. (2020). Synergistic antibacterial effects of analgesics and antibiotics against Staphylococcus aureus. Diagnostic Microbiology and Infectious Disease, 96(4), 114967. https://doi.org/10.1016/j.diagmicrobio.2019.114967 google scholar
14. Grecka, K., & Szweda, P. (2021). Synergistic effects of propolis combined with 2-phenoxyethanol and antipyretics on the growth of Staphylococcus aureus. Pharmaceutics, 13(2), 1–17. https://doi.org/10.3390/pharmaceutics13020215 google scholar
15. Hacioglu, M., Oyardi, O., & Kirinti, A. (2021). Oregano essential oil inhibits Candida spp. biofilms. Zeitschrift Für Naturforschung C, 76(11–12), 443–450. https://doi. org/10.1515/znc-2021-0002 google scholar
16. Król, J., Nawrot, U., & Bartoszewicz, M. (2018). Anti-candidal activity of selected analgesic drugs used alone and in combination with fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole. Journal de Mycologie Medicale, 28(2), 327–331. https://doi.org/10.1016/j.mycmed.2018.03.002 google scholar
17. Lagadinou, M., Onisor, M. O., Rigas, A., Musetescu, D. V., Gkentzi, D., Assimakopoulos, S. F., Panos, G., & Marangos, M. (2020). Antimicrobial properties on non-antibiotic drugs in the era of increased bacterial resistance. Antibiotics, 9(3), 107. https:// doi.org/10.3390/antibiotics9030107 google scholar
18. Li, X. H., & Lee, J. H. (2017). Antibiofilm agents: A new perspective for antimicrobial strategy. Journal of Microbiology (Seoul, Korea), 55(10), 753–766. https://doi. org/10.1007/S12275-017-7274-X google scholar
19. Miró-Canturri, A., Ayerbe-Algaba, R., & Smani, Y. (2019). Drug repurposing for the treatment of bacterial and fungal infections. Frontiers in Microbiology, 10, 41. https://doi.org/10.3389/fmicb.2019.00041 google scholar
20. Munita, J. M., & Arias, C. A. (2016). Mechanisms of antibiotic resistance. Microbiology Spectrum, 4(2), VMBF-0016-2015. https://doi.org/10.1128/microbiolspec.VMBF-0016-2015 google scholar
21. National Committee for Clinical Laboratory Standards, & Barry, A. L. (1999). Methods for determining bactericidal activity of antimicrobial agents: approved guideline. google scholar
22. Odds, F. C. (2003). Synergy, antagonism, and what the chequerboard puts between them. Journal of Antimicrobial Chemotherapy, 52(1), 1–1. https://doi.org/10. 1093/jac/dkg301 google scholar
23. Öztürk, İ., Eraç, Y., Ballar Kirmizibayrak, P., & Ermertcan, Ş. (2021). Nonsteroidal antiinflammatory drugs alter antibiotic susceptibility and expression of virulence-related genes and protein A of Staphylococcus aureus. Turkish Journal of Medical Sciences, 51(2), 835–847. https://doi.org/10.3906/sag-2003-60 google scholar
24. Pillai, S., Moellering, R.C. & Eliopoulos, G. (2005). Antimicrobial combinations. In V. Lorian (Ed.), Antibiotics in laboratory medicine (pp. 365–440). Lippincott Williams & Wilkins. google scholar
25. Reygaert, W. (2018). An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiology, 4(3), 482–501. https://doi.org/10.3934/microbiol. 2018.3.482 google scholar
26. Seleem, N. M., Atallah, H., Abd El Latif, H. K., Shaldam, M. A., & El-Ganiny, A. M. (2021). Could the analgesic drugs, paracetamol and indomethacin, function as quorum sensing inhibitors? Microbial Pathogenesis, 158, 105097. https://doi. org/10.1016/j.micpath.2021.105097 google scholar
27. Sihotang, T. S. U., Widodo, A. D. W., & Arfijanto, M. V. (2022). Comparison of doses of paracetamol or ibuprofen to inhibit the formation of biofilms Pseudomonas aeruginosa bacteria. International Journal of Health Sciences, 6, 361-367. https://doi.org/10.53730/ijhs.v6ns9.12265 google scholar
28. Spellberg, B., Blaser, M., Guidos, R. J., Boucher, H. W., Bradley, J. S., Eisenstein, B. I., Gerding, D., Lynfield, R., Reller, L. B., Rex, J., Schwartz, D., Septimus, E., Tenover, F. C., & Gilbert, D. N. (2011). Combating antimicrobial resistance: policy recommendations to save lives. Clinical Infectious Diseases, 52, S397–S428. https:// doi.org/10.1093/CID/CIR153 google scholar
29. Sultan, A. R., Lattwein, K. R., Lemmens-den Toom, N. A., Snijders, S. V., Kooiman, K., Verbon, A., & van Wamel, W. J. B. (2021). Paracetamol modulates biofilm formation in Staphylococcus aureus clonal complex 8 strains. Scientific Reports, 11(1), 5114. https://doi.org/10.1038/s41598-021-84505-1 google scholar
30. Ugurel, E., & Turgut-Balik, D. (2023). Synergistic combination of carvedilol, amlodipine, amitriptyline, and antibiotics as an alternative treatment approach for the susceptible and multidrug-resistant A. baumannii infections via drug repurposing. European Journal of Clinical Microbiology and Infectious Diseases, 42(9), 1063–1072. https://doi.org/10.1007/s10096-023-04634-5 google scholar
31. World Health Organization. (2021). WHO model list of essential medicines - 22nd list. google scholar
32. Yadav, A., Ravichandran, K., Singh, B. R., Pruthvishree, B. S., Karthikeyan, R., Vinodhku-mar, O. R., & Sinha, D. K. (2021). Comparative antimicrobial activity of aspirin, google scholar
33. paracetamol, flunixin meglumine, tolfenamic acid, diclofenac sodium and pheniramine maleate. Acta Scientific Veterinary Sciences, 3. https://www. researchgate.net/publication/354005864 google scholar