New Avenues of Collaborative Research: Recurrent and Refractory Urinary Tract Infections

There are few centers in the United States invested or interested in the study of recurrent and refractory urinary tract infections (rUTI). One of the newest faculty members in the Department of Obstetrics, Gynecology, and Reproductive Sciences, Megan Bradley, MD, has her sights set on uncovering new information on the causes and contributing factors, patient phenotypes, and better treatment options for this common and problematic condition that disproportionately affects older women.

Dr. Bradley joined the Department in August 2017 as an assistant professor after completing her medical school and residency training at the University of Pittsburgh School of Medicine, followed by a fellowship in urogynecology at Duke University. She also practices clinically in the Women’s Center for Bladder and Pelvic Health at UPMC Magee-Womens Hospital and the surrounding community, where she treats patients for the entire spectrum of bladder and pelvic floor disorders.

“As I progressed through fellowship, I became interested in how lower urinary tract symptoms burden our patients. These are issues such as overactive bladder and also refractory urinary tract infections, which tend to occur more frequently as women age, for a variety of reasons,” says Dr. Bradley. Dr. Bradley’s research during fellowship looked at how to optimize urinary processing for translational studies with respect to infections, bladder pain, and other various lower urinary tract symptoms, all of which ultimately led to her desire to focus on the study of rUTIs. 

rUTIs: Risk Factors and Limited Treatment Options

Female gender is one of the biggest risk factors for recurring and refractory UTIs because of the anatomic make-up of the female genitourinary tract. Aging is also another risk factor. “Aging predisposes women to a number of changes in the vaginal environment, such as vaginal atrophy due to a decrease in estrogen production that leads to an increased susceptibility not only for acute UTIs but also the more problematic recurrent and refractory ones.” 

At present, the treatment arsenal for rUTI is somewhat limited to estrogen replacement therapy and antibiotic therapy. There have been attempts to find or create different vaccines, but as yet none have proven effective or better than the current standards of care. 

“With an aging population, the issue of UTI becomes complicated with respect to asymptomatic bacteriuria. This can make it difficult to disentangle symptoms of actual infection from asymptomatic colonization. As women age, there is a general worsening of urinary symptoms, such as frequency and incontinence, that may or may not be related to the presence of a refractory or recurrent UTI. Also, in this current era of antibiotic resistance, determining the phenotypes in patients of rUTI is vitally important. Knowing who will respond to a specific antibiotic regimen in advance is of great interest. Antibiotic use needs to be judicious in this and many other populations because of the growing problems of resistance patterns,” says Dr. Bradley.

The Importance of the Microbiome of the Urinary Tract

The importance and composition of the female urinary microbiome (FUM) is another focus of Dr. Bradley’s research. “Interestingly, the urinary microbiome is newer in the spectrum of research in the field. The urine was previously thought to be a sterile environment, so no one paid much attention to it. Even the Human Microbiome Project, when it first started, had planned to exclude urinary studies. However, the initial work of Linda Brubaker and Alan Wolfe in Chicago pioneered the research on the female urinary microbiome with respect to incontinence. Now, we’re trying to extrapolate that research in terms of recurring UTIs. We hope to understand the different ways we may be able improve the microbial environment of the urinary tract as opposed to wiping it out with antibiotic therapies. This is all very new research and an area that my own investigations are beginning to move into,” says Dr. Bradley.

Dr. Bradley is currently working on research meant to better understand the differences of UTI between younger and older populations of women. This research extends to symptomatology, the types of bacteria involved, and antibiotic resistance patterns in each age cohort. “Empiric therapy is difficult in postmenopausal women because we don’t understand the specific resistance patterns or types of bacteria in this cohort,” says Dr. Bradley. One theory under investigation posits that the microbiome environment in some patients with UTI lends some form of protection from future infection, while other microbiome compositions may hinder infection clearance or predispose individuals to recurrent infection.

Antibiotic Therapy Studies and UTI

One of Dr. Bradley’s interests in the study of UTI deals with antibiotic therapy. There is currently limited evidence in the literature from randomized trials comparing the use of antibiotics to placebo. “About 50 percent of patients with a UTI will improve without receiving antibiotic therapy. On the other hand, nearly 50 percent of patients who are given the correct course of antibiotics clinically do not improve. Both of these scenarios are of interest in my research,” says Dr. Bradley. Current research by Dr. Bradley is actively working to develop phenotypes of these two broad patient populations in an effort to better understand who may improve with antibiotic therapies and also to characterize patients who have refractory UTIs despite seemingly appropriate therapy.

“All providers who see patients with UTIs have a vested interest in this kind of research. Some of these patients are being prescribed extensive amounts of antibiotics. This has consequences for the patient and the health care system at large. The only way we can understand the problem is through prospective cohort studies where patients are longitudinally enrolled and followed closely in a study environment.”

Collaborative Investigations on Recurrent UTI

For Dr. Bradley, her research is a collaborative endeavor. “When I came back to Pittsburgh after completing my fellowship, I immediately began to seek out other investigators from across the University of Pittsburgh who also were conducting research into UTI who I could potentially collaborate with on new projects. Yohei Doi, MD, PhD, director of the Center for Innovative Antimicrobial Therapy in the Division of Infectious Diseases at the University of Pittsburgh School of Medicine, has been very helpful with his assistance in my formulation of some research ideas. Recently, I have started to investigate collaborations with the Center for Medicine and the Microbiome, specifically with Barbara Methé, PhD, who has done some tremendous work on aspects of the microbiome. I am currently planning to submit a grant application that would allow for us to continue our collaborative efforts.”

Another research interest of Dr. Bradley’s is the examination of the efficacy of various antibiotics on UTI. “Dr. Doi has an extensive research background examining the antibiotic fosfomycin. It’s a first-line therapy for UTI, but it is incredibly expensive and insurances do not cover it well, which limits our ability to use it. I also have started to work on cost-minimization analyses to make fosfomycin cost-effective by better understanding which patients will benefit the most from taking it.”