Phage Therapy Related Microbial Succession Associated with Successful Clinical Outcome for a Recurrent Urinary Tract Infection

Abstract

We rationally designed a bacteriophage cocktail to treat a 56-year-old male liver transplant patient with complex, recurrent prostate and urinary tract infections caused by an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) (UCS1). We screened our library for phages that killed UCS1, with four promising candidates chosen for their virulence, mucolytic properties, and ability to reduce bacterial resistance. The patient received 2 weeks of intravenous phage cocktail with concomitant ertapenem for 6 weeks. Weekly serum and urine samples were collected to track the patient’s response. The patient tolerated the phage therapy without any adverse events with symptom resolution. The neutralization of the phage activity occurred with sera collected 1 to 4 weeks after the first phage treatment. This was consistent with immunoassays that detected the upregulation of immune stimulatory analytes. The patient developed asymptomatic recurrent bacteriuria 6 and 11 weeks following the end of phage therapy—a condition that did not require antibiotic treatment. The bacteriuria was caused by a sister strain of E. coli (UCS1.1) that remained susceptible to the original phage cocktail and possessed putative mutations in the proteins involved in adhesion and invasion compared to UCS1. This study highlights the utility of rationally designed phage cocktails with antibiotics at controlling E. coli infection and suggests that microbial succession, without complete eradication, may produce desirable clinical outcomes.

Development of Phage Cocktails to Treat E. coli Catheter-Associated Urinary Tract Infection and Associated Biofilms

“…Creating a phage cocktail active against contemporary E. coli isolates from patients with SCI at our institution circumvents many of the barriers to initiating clinical evaluation of phage as a therapeutic option to recalcitrant CAUTI. Since the phage included in our phage mixtures have been extensively characterized, and some have also been successfully used for phage therapy in animal models of infection and in a human case of compassionate use ( Green et al, 2017 ; Aslam et al, 2020 ; Terwilliger et al, 2021 ), we believe that these anti-biofilm phage cocktails have high therapeutic potential to treat CAUTI. Future studies will evaluate the efficacy, pharmacokinetics and pharmacodynamics of the cocktails described here in animal models of CAUTI and will allow further refinement of our phage cocktails before clinical evaluation.…”

“…Our group previously characterized a library of phage that lyse multidrug-resistant extra-intestinal pathogenic E. coli strains ( Gibson et al, 2019 ). Some of these phage have been shown efficacious in several murine models of infection and in a case of compassionate use of phage to treat a recurrent UTI ( Green et al, 2017 ; Terwilliger et al, 2021 ). Here, we screened and characterized this phage library and additional novel phage for their ability to reduce the viability of bacterial cells in biofilms of E. coli clinical strains.…”

Pharmacokinetic Assessment of Staphylococcal Phage K Following Parenteral and Intra-articular Administration in Rabbits

“…Bacteriophage. High-titer (2 × 10 12 pfu/mL ± 1 × 10 1 pfu/mL), purified phage K (ATCC 19695-B1) in phage buffer (100 mM NaCl, 10 mM MgCl Tris, pH 8.0) was prepared by TAILΦR Labs of Baylor College of Medicine (Houston, TX), as previously described ( Green et al, 2017 ; Gibson et al, 2019 ; Terwilliger et al, 2021 ). Working stocks passed in-house sterility and endotoxin testing (8 EU/mL endotoxin C).…”

Two Newly Isolated Enterobacter-Specific Bacteriophages: Biological Properties and Stability Studies

“…Promising clinical trials in this area are slowly emerging [ 117 , 118 ], but many issues still need to be refined [ 119 ]. There are reports of clinical successes in the treatment of UTIs as a result of intravenous phage cocktail administration, which, although it did not completely eradicate the pathogen, its succession resulted in a significant improvement in the patient’s condition [ 120 ]. As a preliminary study determining the possibility of using our phages in the treatment of UTI, we decided to evaluate their stability in a urine sample.…”