Phage Therapy for Urinary Tract Infections in Spinal Cord Injury (Phage Trial)
Recruiting in Palo Alto (17 mi)
Overseen ByBarbara W Trautner, MD, PhD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Barbara Wells Trautner
Trial Summary
What is the purpose of this trial?This is a Phase 1b study to assess the safety, tolerability, PK, and PD of investigational phage therapy (IP) in adults with SCI and bladder colonization (ASB). It is a single-center, randomized, double-blind, placebo-controlled study in adults with SCI with neurogenic bladders and bacteriuria who use indwelling catheters, or who require intermittent catheterization for bladder drainage.
Will I have to stop taking my current medications?
The trial protocol does not clearly specify if you need to stop taking your current medications. However, it mentions that prescription drugs, over-the-counter medications, and supplements that acidify the urine are excluded unless deemed acceptable by the sponsor-investigator.
What data supports the effectiveness of the treatment Phage Therapy for Urinary Tract Infections in Spinal Cord Injury?
Research shows that phage therapy has been effective in treating urinary tract infections caused by drug-resistant bacteria in both animal studies and human cases. In one study, phage therapy cured urinary tract infections in rats, and another study found it to be 84% effective in treating urinary infections in humans.
12345Is phage therapy generally safe for humans?
Phage therapy has been used successfully in some cases as an alternative treatment for infections, and studies in animals suggest it can be safe, but more research is needed to confirm its safety in humans.
12678How is phage therapy different from other treatments for urinary tract infections?
Phage therapy is unique because it uses viruses called bacteriophages to specifically target and kill bacteria causing the infection, unlike antibiotics which can affect a broad range of bacteria and lead to resistance. This treatment is particularly promising for infections that are resistant to multiple drugs and can be administered locally or orally, offering a targeted approach with potentially fewer side effects.
12349Eligibility Criteria
This trial is for adults over 18 with spinal cord injury (SCI) who have neurogenic bladders and E. coli bacteriuria, using catheters for bladder drainage. Participants must consent to study procedures, use two forms of contraception if applicable, and be available for the study duration. Those hospitalized or able to visit the clinic for treatment initiation can join.Inclusion Criteria
I use a catheter regularly for urination.
Participant Groups
The trial tests a new phage therapy against a placebo in SCI patients with bladder colonization by E. coli. It's designed to check safety and how the body processes the therapy (pharmacokinetics) and responds to it (pharmacodynamics), in a controlled environment where participants are randomly assigned.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Phage ArmExperimental Treatment1 Intervention
A sterile solution of one to three individual phages (cocktail) (3 x 10\^8 plaque forming units \[PFU\]) phage(s) will be administered intravesicularly (instilled into the participant's bladder via catheter) twice a day for 7 days. The name of the active treatment IP is TAILФR Phage Cocktail (TPC).
Group II: Placebo ArmPlacebo Group1 Intervention
Sterile 0.9% saline solution will be instilled into the bladder via catheter twice a day for 7 days
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Michael E. DeBakey VA Medical CenterHouston, TX
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Who is running the clinical trial?
Barbara Wells TrautnerLead Sponsor
References
Phage therapy for urinary tract infections: does it really work? [2022]Although phage therapy is still in the research and development stage, there are already a small number of cases where phages have been successfully used as an alternative treatment for multidrug-resistant infections. Given this, this Commentary discusses the potential contribution of phage therapy to combat urinary tract infections.
Bacteriophage therapy for Escherichia coli-induced urinary tract infection in rats. [2023]Background: The present study evaluates the efficacy of bacteriophage therapy for urinary tract infection (UTI) in rats. Methods: UTI was established by inoculating Escherichia coli (100 μl) at a concentration of 1.5 × 108 CFU/ml per urethra via a cannula in different groups of rats. For treatment, phage cocktails (200 μl) were administered at varying concentrations of 1 × 108 PFU/ml, 1 × 107 PFU/ml and 1 × 106 PFU/ml. Results: The two doses of phage cocktail at the first two concentrations resulted in the cure of UTI. However, the lowest concentration of the phage cocktail warranted more doses to eradicate the causative bacteria. Conclusion: The quantity, frequency and safety of doses could be optimized in a rodent model using the urethral route.
[The efficacy of bacteriophage preparations in treating inflammatory urologic diseases]. [2020]Urinary infection is the most commonly encountered hospital infection. Antibacterial therapy promotes selection and dissemination of polyresistant microorganism strains, development of intestinal dysbacteriosis, reduction of intestinal contamination resistance. Clinical and bacteriological efficacy of urinary infection treatment with bacteriophage preparations (pyocyanic, proteus, staphylococcal, coliphage, combined pyobacteriophage) was studied. Sensitivity of the infective agent phage isolated from urological patients was tested before treatment. The preparations were adapted to recently isolated agents from urological patients to raise phage sensitivity of the strains. A total of 293 strains were studied. Phage sensitivity made up 68.9%. Bacteriophage preparations were used both locally and orally in 46 patients with acute and chronic urogenital inflammation. Bacteriological efficacy amounted to 84%, clinical one to 92%. It is inferred that phagotherapy is effective and safe therapeutic modality in the treatment of urinary infection in monotherapy and in combination with antibiotics.
Characterization of Anti-Bacterial Effect of the Two New Phages against Uropathogenic Escherichia coli. [2021]Urinary tract infections (UTIs) are among the events that most frequently need medical intervention. Uropathogenic Escherichia coli are frequently their causative agents and the infections are sometimes complicated by the presence of polyresistant nosocomial strains. Phage therapy is a tool that has good prospects for the treatment of these infections. In the present study, we isolated and characterized two bacteriophages with broad host specificity against a panel of local uropathogenic E. coli strains and combined them into a phage cocktail. According to genome sequencing, these phages were closely related and belonged to the Tequatrovirus genus. The newly isolated phages showed very good activity on a panel of local clinical E. coli strains from urinary tract infections. In the form of a two-phage cocktail, they were active on E. coli strains belonging to phylogroups B2 and D, with relatively lower activity in B1 and no response in phylogroup A. Our study is a preliminary step toward the establishment of a national phage bank containing local, well-characterized phages with therapeutic potential for patients in Slovakia.
Phage Resistance Accompanies Reduced Fitness of Uropathogenic Escherichia coli in the Urinary Environment. [2022]Urinary tract infection (UTI) is among the most common infections treated worldwide each year and is caused primarily by uropathogenic Escherichia coli (UPEC). Rising rates of antibiotic resistance among uropathogens have spurred a consideration of alternative treatment strategies, such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, namely, HP3 and ES17, against clinical UPEC isolates using in vitro and in vivo models of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6 to 8 h of coincubation. Whole-genome sequencing revealed that UPEC strains resistant to HP3 and ES17 harbored mutations in genes involved in lipopolysaccharide (LPS) biosynthesis. Phage-resistant strains displayed several in vitro phenotypes, including alterations to adherence to and invasion of human bladder epithelial HTB-9 cells and increased biofilm formation in some isolates. Interestingly, these phage-resistant UPEC isolates demonstrated reduced growth in pooled human urine, which could be partially rescued by nutrient supplementation and were more sensitive to several outer membrane-targeting antibiotics than parental strains. Additionally, phage-resistant UPEC isolates were attenuated in bladder colonization in a murine UTI model. In total, our findings suggest that while resistance to phages, such as HP3 and ES17, may arise readily in the urinary environment, phage resistance is accompanied by fitness costs which may render UPEC more susceptible to host immunity or antibiotics. IMPORTANCE UTI is one of the most common causes of outpatient antibiotic use, and rising antibiotic resistance threatens the ability to control UTI unless alternative treatments are developed. Bacteriophage (phage) therapy is gaining renewed interest; however, much like with antibiotics, bacteria can readily become resistant to phages. For successful UTI treatment, we must predict how bacteria will evade killing by phage and identify the downstream consequences of phage resistance during bacterial infection. In our current study, we found that while phage-resistant bacteria quickly emerged in vitro, these bacteria were less capable of growing in human urine and colonizing the murine bladder. These results suggest that phage therapy poses a viable UTI treatment if phage resistance confers fitness costs for the uropathogen. These results have implications for developing cocktails of phage with multiple different bacterial targets, of which each is evaded only at the cost of bacterial fitness.
Effects of oral immunomodulation therapy on urinary tract infections in individuals with chronic spinal cord injury-A retrospective cohort study. [2020]To investigate the effect of an oral immunomodulation therapy with E. coli fractions on the frequency of urinary tract infections (UTIs) in patients with spinal cord injury (SCI) in a retrospective cohort study with a follow-up of 12 months.
Urinary tract infection prophylaxis using Escherichia coli 83972 in spinal cord injured patients. [2007]Escherichia coli 83972 was previously shown to establish bladder colonization in select patient groups. We evaluate the safety and feasibility of using bacterial interference with E. coli 83972 to prevent urinary tract infection in spinal cord injured patients.
A Novel Phage Cocktail Therapy of the Urinary Tract Infection in a Mouse Model. [2023]Escherichia coli (E. coli) is a major bacterial pathogen associated with many cases of serious infections, such as urinary tract infections (UTI) and meningitis intestinal. The rapid emergence of antimicrobial multidrug-resistant bacteria occurring worldwide has been attributed to the overuse of antibiotics. Alternative strategies must be developed to overcome antibiotic resistance. A promising alternative for the treatment of infections is the use of phages as antibacterial agents. A total of 90 female albino mice were randomly divided into three groups (n=30) and used for the induction of UTI. The animals were acclimatized in their cages for 24 h before inoculation and allowed to access chow and water freely. For UTI induction, the peri-urethral area was sterilized with 70% ethanol, and bacterial inoculation was then injected into the bladder through the urethra using a 24-gauge sterile Teflon catheter with an outer diameter of 0.7 mm and length of 19 mm. A single phage and a phage cocktail preparation have been evaluated for their therapeutic activity in the mouse model of chronic UTI induced by transurethral injection of two isolates of the uropathogenic E. coli 8 and E. coli 302. The results of the transurethral and intra-peritoneal injection of phage(s) that prepared on day 10 after the establishment of the mouse chronic model showed no effect of a single phage PEC80 in the treatment of UTI, whereas both administration routes of the phage cocktail preparation resulted in the clearance of bacteria from mice urine and homogenates of the urinary bladders and kidneys of the sacrificed mice after 24 h following the administration of phage cocktail dose. The high activity of the phage cocktail in the treatment of mouse chronic model of UTI is attributed to the broader host range of the phage cocktail, compared to the very narrow host range of the phage PEC80. It is concluded that the phage therapy by using phage preparations as the 25 phages cocktail evaluated in this study is a highly promising and potential alternative therapy for human UTIs.
Development of Phage Cocktails to Treat E. coli Catheter-Associated Urinary Tract Infection and Associated Biofilms. [2023]High rates of antimicrobial resistance and formation of biofilms makes treatment of Escherichia coli catheter-associated urinary tract infections (CAUTI) particularly challenging. CAUTI affect 1 million patients per year in the United States and are associated with morbidity and mortality, particularly as an etiology for sepsis. Phage have been proposed as a potential therapeutic option. Here, we report the development of phage cocktails that lyse contemporary E. coli strains isolated from the urine of patients with spinal cord injury (SCI) and display strong biofilm-forming properties. We characterized E. coli phage against biofilms in two in vitro CAUTI models. Biofilm viability was measured by an MTT assay that determines cell metabolic activity and by quantification of colony forming units. Nine phage decreased cell viability by >80% when added individually to biofilms of two E. coli strains in human urine. A phage cocktail comprising six phage lyses 82% of the strains in our E. coli library and is highly effective against young and old biofilms and against biofilms on silicon catheter materials. Using antibiotics together with our phage cocktail prevented or decreased emergence of E. coli resistant to phage in human urine. We created an anti-biofilm phage cocktail with broad host range against E. coli strains isolated from urine. These phage cocktails may have therapeutic potential against CAUTI.