title: The Influence of Efflux Pump Inhibitors on the Activity of Non-Antibiotic NSAIDS against Gram-Negative Rods.
abstract: BACKGROUND
  Most patients with bacterial infections suffer from fever and various pains that require complex treatments with antibiotics, antipyretics, and analgaesics. The most common drugs used to relieve these symptoms are non-steroidal anti-inflammatory drugs (NSAIDs), which are not typically considered antibiotics. Here, we investigate the effects of NSAIDs on bacterial susceptibility to antibiotics and the modulation of bacterial efflux pumps.
  
  
  METHODS
  The activity of 12 NSAID active substances, paracetamol (acetaminophen), and eight relevant medicinal products was analyzed with or without pump inhibitors against 89 strains of Gram-negative rods by determining the MICs. Furthermore, the effects of NSAIDs on the susceptibility of clinical strains to antimicrobial agents with or without PAβN (Phe-Arg-β-naphtylamide) were measured.
  
  
  RESULTS
  The MICs of diclofenac, mefenamic acid, ibuprofen, and naproxen, in the presence of PAβN, were significantly (≥4-fold) reduced, decreasing to 25-1600 mg/L, against the majority of the studied strains. In the case of acetylsalicylic acid only for 5 and 7 out of 12 strains of P. mirabilis and E. coli, respectively, a 4-fold increase in susceptibility in the presence of PAβN was observed. The presence of Aspirin resulted in a 4-fold increase in the MIC of ofloxacin against only two strains of E. coli among 48 tested clinical strains, which included species such as E. coli, K. pneumoniae, P. aeruginosa, and S. maltophilia. Besides, the medicinal products containing the following NSAIDs, diclofenac, mefenamic acid, ibuprofen, and naproxen, did not cause the decrease of clinical strains' susceptibility to antibiotics.
  
  
  CONCLUSIONS
  The effects of PAβN on the susceptibility of bacteria to NSAIDs indicate that some NSAIDs are substrates for efflux pumps in Gram-negative rods. Morever, Aspirin probably induced efflux-mediated resistance to fluoroquinolones in a few E. coli strains.
authors.affiliation: Department of Pharmaceutical Microbiology, Medical University of Warsaw, Oczki 3 Str., 02-007, Warsaw, Poland.
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Laudy
authors.affiliation: Department of Antibiotics and Microbiology, National Medicines Institute, Chełmska 30/34 Str., 00-725, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Mrowka
authors.affiliation: Department of Pharmaceutical Microbiology, Medical University of Warsaw, Oczki 3 Str., 02-007, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Krajewska
authors.affiliation: Department of Pharmaceutical Microbiology, Medical University of Warsaw, Oczki 3 Str., 02-007, Warsaw, Poland.|Department of Antibiotics and Microbiology, National Medicines Institute, Chełmska 30/34 Str., 00-725, Warsaw, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tyski
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D007052:Ibuprofen / Q000494:pharmacology; D008528:Mefenamic Acid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009288:Naproxen / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D000082:Acetaminophen; D008528:Mefenamic Acid; D009288:Naproxen; D001241:Aspirin; D007052:Ibuprofen