Antimicrobial Activity of Ibuprofen against Cystic Fibrosis-Associated Gram-Negative Pathogens.

Parth N Shah,Christopher A Rodesney,Henry H Le,Jasur A Tagaev,Kimberly R Marshall-Batty,Justin A Smolen,Qingquan Chen,Vernita D Gordon,David E Greenberg,Carolyn L Cannon

doi:10.1128/aac.01574-17

Abstract

ABSTRACTClinical trials have demonstrated the benefits of ibuprofen therapy in cystic fibrosis (CF) patients, an effect that is currently attributed to ibuprofen's anti-inflammatory properties. Yet, a few previous reports demonstrated an antimicrobial activity of ibuprofen as well, although none investigated its direct effects on the pathogens found in the CF lung, which is the focus of this work. Determination of ibuprofen's in vitro antimicrobial activity against Pseudomonas aeruginosa and Burkholderia species strains through measurements of the endpoint number of CFU and growth kinetics showed that ibuprofen reduced the growth rate and bacterial burden of the tested strains in a dose-dependent fashion. In an in vitro Pseudomonas biofilm model, a reduction in the rate of biomass accumulation over 8 h of growth with ibuprofen treatment was observed. Next, an acute Pseudomonas pneumonia model was used to test this antimicrobial activity after the oral delivery of ibuprofen. Following intranasal inoculation, ibuprofen-treated mice exhibited lower CFU counts and improved survival compared with the control animals. Preliminary biodistribution studies performed after the delivery of ibuprofen to mice by aerosol demonstrated a rapid accumulation of ibuprofen in serum and minimum retention in lung tissue and bronchoalveolar lavage fluid. Therefore, ibuprofen-encapsulated polymeric nanoparticles (Ibu-NPs) were formulated to improve the pharmacokinetic profile. Ibu-NPs formulated for aerosol delivery inhibited the growth of P. aeruginosa in vitro and may provide a convenient dosing method. These results provide an additional explanation for the previously observed therapeutic effects of ibuprofen in CF patients and further strengthen the argument for its use by these patients.

Highlights

Clinical trials have demonstrated the benefits of ibuprofen therapy in cystic fibrosis (CF) patients, an effect that is currently attributed to ibuprofen’s antiinflammatory properties
In the case of Burkholderia cenocepacia K56-2, exposure to 50 ␮g/ml of ibuprofen over 12 h led to an approximately 1/3-log10 reduction in the bacterial count, which further decreased by approximately 1 and 2 logs following exposure to 75 ␮g/ml and 100 ␮g/ml ibuprofen, respectively. These trends were conserved for other strains of Burkholderia spp. as well; the greatest dose-dependent reduction was observed for B. cenocepacia HI4277
A few reports in the literature document the antimicrobial properties of ibuprofen ranging from bacteriostatic to bactericidal against several different pathogens, as well as its synergy with other antimicrobials [23,24,25,26,27,28,29]

Summary

Introduction

Clinical trials have demonstrated the benefits of ibuprofen therapy in cystic fibrosis (CF) patients, an effect that is currently attributed to ibuprofen’s antiinflammatory properties. Oral ibuprofen treatment in a rat model of chronic Pseudomonas endobronchial infection, resulting in a drug plasma concentration of 55 Ϯ 24 ␮g/ml, led to a significant reduction in the inflammatory response and improved weight gain compared with placebo treatment [16]. At this concentration, ibuprofen significantly reduced the level of leukotriene B4 production by stimulated rat neutrophil-rich leukocyte preparations; no effect on the pulmonary bacterial burden was observed [16]. The beneficial effects of ibuprofen were attributed to inhibition of the lipoxygenase pathway and its downstream effects on neutrophils

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Results

Conclusion