A rationally designed phage cocktail to treat MDR P. aeruginosa infections - SUMMARY Infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa pose an urgent public health threat. MDR P. aeruginosa is a critical priority global pathogen for which new therapeutic approaches are desperately needed. At UPMC, over 100 patients each year develop serious infections with MDR P. aeruginosa; these infections are difficult to manage, frequently evolve resistance to last-line antibiotics, and are often deadly. There is an urgent need to develop new antimicrobial approaches for the treatment of MDR P. aeruginosa infections. Bacteriophage (phage) therapy is one such approach that has gained significant attention in recent years. We currently treat dozens of patients each year at both UPMC and across the country with phage therapy under compassionate use, which uses personalized phage cocktails to treat resistant bacterial infections in individual patients who have no other viable treatment options. Most of the patients we treat are suffering from MDR P. aeruginosa infections, and in the majority of patients treated thus far, phage therapy improved their clinical status. Despite this success, single patient anecdotes are not sufficient to rigorously test and develop phage therapy for widespread use. Here we propose to systematically assemble and evaluate a multi-phage cocktail targeting diverse MDR P. aeruginosa clinical isolates which can be paired with new β-lactam/β-lactamase inhibitor (BL/BLI) combinations currently used to treat MDR P. aeruginosa infections to improve antibacterial efficacy. Our central hypothesis is that a rationally selected cocktail of P. aeruginosa phages targeting contemporary MDR P. aeruginosa isolates will improve the activity of antibiotics commonly used to treat MDR P. aeruginosa infections. To test this hypothesis, we will leverage a large collection of contemporary MDR P. aeruginosa clinical isolates collected from 28 medical centers across the country as well as a panel of 10 lytic phages that have been previously approved for use in phage therapy to treat patients, and which were safe and well tolerated. In Aim 1, we will assemble a P. aeruginosa-targeting multi-phage cocktail that exhibits broad lytic activity against a national panel of 100 diverse MDR P. aeruginosa clinical isolates. In Aim 2, we will determine whether the combination of this P. aeruginosa-targeting phage cocktail and P. aeruginosa-targeting antibiotics results in superior and more sustained in vitro killing than either agent alone. Successful completion of these aims will establish a phage-antibiotic combination therapy that can advance in preclinical development and be used in an eventual clinical trial. The project will also directly inform the treatment of critically ill patients who cannot wait for a trial but could still benefit from receiving phage therapy under compassionate use.
