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UC San Diego Electronic Theses and Dissertations (2024)

Bacteriophages are viruses of bacteria that are among the leading alternative antimicrobials for treatment of the multidrug resistant (MDR) and opportunistic pathogen Pseudomonas aeruginosa. Although phage therapy is now generally considered safe, access to the treatment remains limited and its efficacy remains unproven. The goal of this dissertation is to develop innovative phage processes and intravenous treatment regimens to combat MDR P. aeruginosa. In the third chapter, I evaluate how to select phages to combat P. aeruginosa and study the interactions between different phage strains during combination treatment. In two-phage cocktail treatment, I found that mixing phages with inequal activities diminishes initial treatment potency. Sequential treatment with the same phages improved potency but generated unique patterns of resistance. This study provides new insight on how to formulate and administer phage combinations based on the infectivity of each phage to its bacterial host. In the fourth chapter, I develop and optimize the standardized production of phages by introducing cross-flow filtration to improve the removal of endotoxin from phage preparations. The simultaneous washing and concentration of phage particles was found to improve endotoxin removal across multiple Gram-negative species. Leveraging the kinetics of each phage, the accumulation of phage-resistant bioburden could then be reduced in an improved purification process. In the fifth chapter, I validate the targeting and replication of clinical phages during the treatment of patients infected by multidrug resistant P. aeruginosa. Phages suitable for therapy were determined by screening across a multi-infection isolate library. The efficacy of clinical phage treatments were then validated using a combination of microbiological and metagenomic markers of failure or success. In conclusion, this thesis provides insights into current barriers for phage therapy. Identifying and characterizing individual phage properties will have important implications on how to treat and reduce the mortality of MDR P. aeruginosa infections.

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UC San Diego Previously Published Works (2019)
Increasingly, clinical infections are becoming recalcitrant or completely resistant to antibiotics treatment and multidrug resistance is rising alarmingly. Patients suffering from infections that used to be treated successfully by antibiotic regimens are running out of the treatment options. Bacteriophage (phage) therapy, long practiced in parts of Eastern Europe and the states of the former Soviet Union, is now being reevaluated as a treatment option complementary to and synergistic with antibiotic treatments. We discuss some current studies that have addressed synergistic killing activity between phages and antibiotics, the issues of treatment order and antibiotic class, and point to considerations that will have to be addressed by future studies. Overall, co-treatments with phages and antibiotics promise to extend the utility of antibiotics in current use. Nevertheless, a lot of work, both basic and clinical, remains to be done before such co-treatments become routine options in the hospital setting.
    Creative Commons 'BY-NC-ND' version 4.0 license
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    • Peer Reviewed
    UC San Diego Previously Published Works (2024)
    Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.
      Cover page: Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.Creative Commons 'BY' version 4.0 license
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