Chen, Qingquan (2019-08). Identification of Synergistic Drug Combinations Against Cystic Fibrosis Pathogens. Doctoral Dissertation.
Cystic fibrosis (CF) is a common, fatal, genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF has many clinical manifestations. The most important site of disease is the lung, where often colonized or infected in infancy or early childhood with microorganisms. The chronic bacterial infections, often with Pseudomonas aeruginosa, and concomitant airway inflammation damage the lung and lead to respiratory failure. The chronic use of multiple antibiotics increases the possibility of multidrug resistant (MDR) bacteria, and limits the treatment options. Therefore, there is a need to identify alternative antimicrobial strategies to optimize treatment of infections. Studies have demonstrated that synergy results in superior antimicrobial activity, while avoiding potential side-effects of both therapeutics. Hence, we hypothesize that by using drug combinations with an efficient delivery system, we could achieve improved antimicrobial efficacy against MDR bacteria. Studies have demonstrated that high-dose ibuprofen (peak serum concentrations of 50-100 ?g/mL) can improve the outcomes in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Our group demonstrated that high-dose ibuprofen has antimicrobial activity both in vitro and in vivo. Despite silver has been used as a antimicrobial agent with a low incidence of resistance, poor availability mandates a high dosage to effectively eradicate infections. A silver carbene complex, SCC1, was conjugated with ibuprofen, SCC1-IBU. Compared with SCC1, SCC1-IBU demonstrated improved antimicrobial activity against CF pathogens while preserving the anti-inflammatory activity of ibuprofen. Then, checkerboard assays and end-point colony forming unit (CFU) assays demonstrated synergistic combination of silver/minocycline against P. aeruginosa isolates. Furthermore, the synergistic combination can be co-loaded into nanoparticles as a next-generation antibiotic to combat MDR bacteria. Lastly, disc diffusion assay demonstrated that FDA approved antibiotics have a significant increased zone of inhibition in the presence of ibuprofen. In a 24-hour endpoint CFU assay, amikacin, aztreonam and ceftazidime demonstrated synergy in combination with either ibuprofen or naproxen. Finally, mice treated with ceftazidime/ibuprofen demonstrated a significant survival advantage compared to the individually treated groups. Thus, therapy with high-dose ibuprofen in combination with antibiotics may improve outcomes in patients infected with MDR bacteria.