Phage Therapy for Recurrent UTIs in Kidney Transplant Recipients

PROJECT SUMMARY/ ABSTRACT
Recurrent urinary tract infections (rUTI) are a common problem in kidney transplant recipients (KTR), especially
women, and lead to serious consequences – pyelonephritis, bacteremia, kidney dysfunction, and death.
Escherichia coli and Klebsiella pneumoniae are usually implicated. Antibiotics are associated with adverse
events, increased multi-drug resistance; and they do not prevent a future recurrent UTI (rUTI) due to microbiome
persistence of the uropathogen. New strategies to combat rUTI are critically needed. Bacteriophage (phage)
therapy consists of administration of viruses that specifically bind to target bacteria leading to an intracellular
replicative lytic cell cycle causing bacterial cell death; phage therapy is currently in clinical trials for a variety of
indications. Phages are highly specific to their target bacteria; this relatively narrow host range is a significant
advantage that has the potential to precisely target the causative pathogen in the gut and urinary microbiome
and thus remove the reservoir of rUTI.
We hypothesize that phage therapy directed against E. coli and K. pneumoniae in female KTR will be safe and
lead to a reduction in UTI event rate via a targeted impact on the gut and urinary microbiome. We plan to conduct
a randomized phase I/II pilot clinical trial to compare the safety, tolerability, and feasibility in addition to efficacy
and microbiome effects of phage therapy vs. placebo administration in asymptomatic female KTR with a history
of rUTI due to E. coli or K. pnuemoniae. Participants will be randomized to receive a 7-day course of twice daily
intravenous phage therapy (16 participants) or normal saline placebo (16 participants) and will be followed for
180 days for assessment of study outcomes. Primary outcome of safety and tolerability will be measured by the
incidence of adverse events, abnormal vital signs and clinical laboratory tests; feasibility will be assessed with
specific goals for enrollment, phage match, study drug administration, and follow-up. The main efficacy endpoint
is number of UTI events due to the original infecting pathogen (E. coli, K. pneumoniae) over the 180-day study
observation period (event rate), calculated for the intent to treat population. Participants will also undergo
sampling (urine, stool) at baseline and during various timepoints to determine microbiome characteristics before,
during, and after phage, and to establish a biospecimen repository for further hypothesis-driven research.
We will use our significant expertise in kidney transplantation and UTI, unique experience with the microbiome
and virome, and visionary phage therapy infrastructure to evaluate the feasibility of moving rUTI therapy in KTR
towards a successful individualized approach. This research has major potential to reduce allograft injury and
improve bladder health in KTR, while reducing morbidity and mortality. The results of this pilot clinical study will
directly inform the design of a larger, phase III randomized trial.

Grant Number: 5R01DK134726-02
NIH Institute/Center: NIH
Principal Investigator: Saima Aslam