Nutraceutical Efficacy for rUTI

The objective of this study is to determine the efficacy of a nutraceutical as a
non-antibiotic prophylaxis for postmenopausal women on vaginal estrogen therapy (VET) with a
history of symptomatic, culture-proven recurrent urinary tract infection (rUTI) by means of a
randomized, controlled trial. Recurrent urinary tract infections have a significant impact on
patient health, quality of life, and finances (personal and societal).

The most common uropathogen for both acute and recurrent UTIs is Escherichia coli.

Historically, patients with rUTI have been placed on long-term prophylactic antibiotics to
prevent recurrence. Long term antibiotic use can lead to antibiotic resistance, collateral
damage to normal flora, and organ damage, such as pulmonary and hepatic toxicity with
long-term nitrofurantoin use. There is an increasing prevalence of antibiotic resistance of
uropathogenic E. coli and other uropathogens. Antibiotic resistance and its consequences have
resulted in a need for non-antibiotic prophylaxis regimens.

A growing body of literature supports the use of vaginal estrogen therapy as a first-line
non-antibiotic UTI prevention strategy in postmenopausal women. While VET has been shown to
significantly reduce the risk of rUTIs, some women continue to have rUTIs. Other
non-antibiotic strategies have been utilized including D-mannose, a nutraceutical. Three
prior studies examined D-mannose as an isolated therapy with promising results, but in our
experience, a multimodal approach has often been needed. Therefore, additional studies, such
as this proposed research, are needed to determine the potential additive effect of a
nutraceutical as a non-antibiotic prophylaxis for postmenopausal women using vaginal estrogen
therapy.

Inclusion Criteria:

For the RCT arms of the study, the following inclusion criteria will apply:

a. Postmenopausal women with recurrent UTI

i. Recurrent UTI defined as:

1. ≥ 2 symptomatic, culture-proven UTI in 6 months OR

2. ≥ 3 symptomatic, culture-proven UTI in 12 months

ii. Postmenopausal defined as no menses for at least 12 months or surgical menopause

b. At least one documented prior uropathogen susceptible to D-mannose

c. Using VET for a minimum of four weeks prior to study day 1

Inclusion criteria for the Observational arm of the study are the same with the
exception of item 'c.' above (using VET for a minimum of four weeks) as participants
will not be on vaginal estrogen therapy.

Exclusion Criteria:

For the RCT arms of the study, the exclusion criteria are as follows:

1. Not postmenopausal

2. Currently on daily antibiotic UTI prophylaxis (If this is the only exclusion
criteria met, a woman could be cleared for inclusion in study/enrollment after a
2 week washout period occurs prior to inclusion in the study (RCT or
Observational arm))

3. Complicated UTIs (known renal tract anomaly, inability to empty bladder due to
neurologic causes, performs self-catheterization or has an indwelling catheter)

4. Patients with incomplete bladder emptying (defined as post void residual > 150 cc
when minimal voided volume is >150 cc)

5. Known contraindication to VET unless approved by patient's oncologist, oncologic
surgeon, or primary care physician (History of or current endometrial cancer;
History of estrogen sensitive breast cancer without approval of patient,
patient's oncologist, oncologic surgeon, or primary care physician to use vaginal
estrogen after counseling)

6. History of interstitial cystitis/painful bladder syndrome

7. Urothelial cancer

8. Non-English speaking

9. Enrolled in other clinical trials for UTIs

10. Currently using D-mannose or Methenamine for UTI prevention

Exclusion criteria for the Observational arm of the study are the same with the
exception of item 'e.' above (known contraindication to VET) as participants will not
be on vaginal estrogen therapy.