Conditions: Urinary Tract Infections, Recurrent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 92
Healthy volunteers: yes

Brief summary:
Several methods are available for use in the prevention of recurrent urinary tract infections (UTIs) over the past few decades. These methods include suppressive antibiotics, estrogen cream, methenamine hippurate, d-mannose, cranberry, probiotics, and vitamin C. Of these, the majority of the literature is in favor of use of suppressive antibiotics for preventing UTIs. However, this data is now about 10 years old. Increasing use of antibiotics over the years has lead to increased resistance of bacteria. In addition, long-term antibiotic use has several adverse effects, some life-threatening. There is recent literature evaluating the use of several of the alternatives to suppressive antibiotics with mixed results. A comparative study of the efficacy of methenamine hippurate to suppressive antibiotics is lacking in the current literature. Several early partly-randomized trials done with methenamine hippurate have shown promising results, but are only as recent as 1987. The primary objective of this prospective, randomized study is to determine whether there is a significant difference in the prevention of recurrent UTIs when given either methenamine hippurate or daily suppressive antibiotics. The secondary objective of this study is to determine how well patients are able to tolerate each of these medications and what adverse effects are observed in a given 1 year time period. The long-term goals of this study are to find an alternative to using suppressive antibiotics, potentially with a lower adverse effect profile and less of the dangers of long term antibiotic use. Finding an alternative to suppressive antibiotics would also tackle the issue of antibiotic resistance.

Detailed description:
Hypothesis:

The hypothesis of this study is that the group taking trimethoprim will have a lower recurrence rate than those taking methenamine hippurate based on the literature. The investigators aim to identify to what degree that difference is and whether or not it is an acceptable difference given the greater degree of an antibiotic resistance.

Objectives:

The primary objective of this prospective, randomized study is to determine whether there is a significant difference in the prevention of recurrent UTIs when given either methenamine hippurate or daily suppressive antibiotics independent of vaginal estrogen use.

The secondary objective of this study is to determine how well patients are able to tolerate each of these medications and what adverse effects are observed in a 1 year time period.

Specific Aims:

1. Identify if there is a differential impact on prevention of recurrent UTIs when treated with either trimethoprim or methenamine hippurate in a 6 and 12 month period.
2. Identify adverse reactions in each group.
3. Determine whether or not estrogen has a more additive effect to trimethoprim or methenamine hippurate in post-menopausal women.
4. Identify how well tolerated the study medications are and whether or not the size of the pills or the frequency of taking them prevents patients from continuing therapy.

Arms:
arm 1: Patients are randomized to receive methenamine hippurate in one arm if they are diagnosed with recurrent urinary tract infections. arm 2: Patients are randomized to receive trimethoprim in the other arm if they are diagnosed with recurrent urinary tract infections.

Interventions: intervention 1: Trimethoprim intervention 2: Methenamine hippurate
Intervention descriptions: intervention 1: suppressive antibiotic. Estrogen cream may be prescribed if the patient is post-menopausal (but not as a part of this study). intervention 2: antiseptic used in the prevention of recurrent UTIs. Estrogen cream may be prescribed if the patient is post-menopausal (but not as a part of this study).

Protocol document:
Prot_SAP_000.pdf: 
February 8th, 2016
Project Title: Methenamine Hippurate versus Suppressive Antibiotics in the Prevention
of Recurrent Urinary Tract Infections
NCT03077711


Project Title: Methenamine Hippurate versus Suppressive Antibiotics in the Prevention
of Recurrent Urinary Tract Infections
Introduction: Recurrent urinary tract infections (UTIs) are common bacterial infections
seen in women of all ages across disciplines. Several treatment options are now
available for prevention, but the gold standard is considered to be suppressive
antibiotics. Considering increasing antibiotic resistance in treating UTIs, we are looking
for viable alternatives. There has not yet been a head-to-head comparison of the
treatment options for the last 2 decades.
Hypothesis: Our hypothesis is that methenamine hippurate will have less or equal
recurrences of UTI’s as suppressive antibiotics and have a lower side effect proﬁle.
Literature review:
Urinary tract infections (UTIs) are one of the most common bacterial infections in
women and account for a signiﬁcant number of ofﬁce and emergency room visits per
year1-2. UTIs can cause vomiting, pain, dysuria, septicemia, fever, fatigues, and
occasionally renal failure in the worst cases. Elderly patients, long-term catheter use, or
patients with renal disease are examples of those at high risk of repeated UTIs, and
patients more likely to have serious complications3. The risk of recurrence has been
shown to be between 20-30% after one infection4. One study by Ikaheimo showed that
recurrent infections occurred in 44% of women presenting in a primary care setting that
had been treated for UTI within the prior 12 months5.
Several methods are available for use in the prevention of recurrent urinary tract
infections (UTIs). One review of management of recurrent UTIs stated that there is
lacking evidence for cranberry, Vitamin C, and methenamine hippurate and concluded
that antibiotic prophylaxis remains the most effective method of management1.
However, long-term use of antibiotics can lead to resistance, in addition nausea and
candidiasis. Several antibiotics have been used in the prevention of recurrent UTIs
including most commonly trimethoprim and nitrofurantoin. Trimethoprim can lead to
Lyell’s syndrome, Stevens-Johnson syndrome and pancytopenia. Even at low doses,
long-term nitrofurantoin use may result in hepatotoxicity and pneumonitis, although
usually reversible1.
Methenamine hippurate is one such alternative that is currently used in practice. The
last randomized control trial however comparing methenamine hippurate to suppressive
antibiotics was in 1985. Earlier randomized control trials had promising results showing
methenamine hippurate to be effective without long-term adverse effects. However,
these studies had very small populations and did not follow patients for longer than 6
months to 1 year. The Cochrane review of the literature concluded that there is not
enough evidence to support the use of methenamine hippurate for prevention of
suppression of recurrent UTIs and encouraged large randomized trials to answer this
question6. Methenamine hippurate may be a good alternative to suppressive antibiotics
if it is as effective with a better adverse effect proﬁle.


Primary Aim(s): Identify if there is a differential impact on prevention of recurrent UTIs
when treated with either trimethoprim or methenamine hippurate in a 6 and 12 month
period.
Secondary Aim(s):
1. Identify adverse reactions of study medications in each group.
2. Determine whether or not estrogen has a more additive effect to antibiotics or
methenamine hippurate in post-menopausal women.
3. Identify tolerability of the study medications and whether the size of the pills or the
frequency of taking them prevents patients from continuing therapy.
Methods:
This will be a prospective randomized control trial comparing the efﬁcacy of
methenamine hippurate versus trimethoprim, a suppressive antibiotic used in the
prevention of recurrent UTIs. The deﬁnition of a UTI will include patients who have had
symptoms including dysuria, suprapubic pain, increased frequency and urgency,
malodorous urine, and hematuria plus a positive urine culture with any degree of
bacteriuria.
Women with a diagnosis of recurrent UTIs, having had at least two UTIs in the past 6
months or 3 in the past year that are proven culture positive with symptoms, will be
included in the study. Upon entry into the study, the patient must have been treated for
their last infection and have a negative urine culture before enrollment. Women who
have received previous prophylaxis for recurrent UTIs but have not taken it for a
minimum of 30 days, will be eligible for enrollment. The patients will be prospectively
followed for one year.
After a patient is diagnosed with recurrent UTIs, she will be evaluated with a repeat
urine culture to conﬁrm a negative prior to enrollment. Informed consent will then be
obtained from the patient by the investigator or designate, who will then randomize the
patient to prophylaxis with either methenamine hippurate or trimethoprim. The groups
will be randomized in a 1:1, methenamine hippurate to trimethoprim. The randomization
will be done by research coordinator and computer-generated sequence prior to the
initiation of the study. Randomization will be provided in sequentially-numbered, sealed
envelopes. Because estrogen is a known confounding factor, we will periodically assess
the number of estrogen users in each arm at 3 month intervals. If there is a large
discrepancy, we will adjust the randomization to include a stratiﬁcation method assigned
equal amounts of estrogen users to each arm moving forward. Most likely,
randomization itself will control for the number of estrogen users in each group. Each
envelope will remain sealed until inclusion and exclusion criteria are met and informed
consent obtained. Patient identiﬁcation including initials and date of birth, envelope
numbers, and treatment designation will be recorded on the enrollment form.
This study will not include a placebo arm as it would be unethical to not treat a patient
with recurrent UTIs, given known treatment. Our patients and investigators will not be
blinded due to cost it would entail to blind the study medications. Investigators will have


to order the speciﬁc medication at the patient’s requested pharmacy. Patients will have
to know which medications they are picking up from the pharmacy. The two medications
differ in frequency and size and would be difﬁcult to blind the patient to. Investigators
may choose to crossover to the opposing medication or add it to the patient’s current
regimen if she continues to have recurrences.
Inclusion:
1. age greater than 18-99
2. recurrent UTI: at least 2 in the past 6 months or 3 in past year (culture positive,
any CFU/mL)
3. must have been symptomatic with dysuria, urgency, frequency, suprapubic pain,
hematuria, malodorous urine
4. treated for last UTI and negative urine culture on entry into study
5. English speaking
Exclusion:
1. pregnancy
2. urinary tract abnormalities (eg kidney stones)
3. pyelonephritis
4. renal insufﬁciency or failure
5. known allergy to medications
6. prophylaxis for post-coital recurrent UTIs
Interventions: The groups will be randomized in a 1:1 of methenamine hippurate to
trimethoprim once diagnosed with recurrent UTIs, inclusion and exclusion criteria are
met, and patient consents to participate in study.
Outcomes
Primary:
1. Time to subsequent infection
2. Number of patients infection-free after 6-12 months
3. Number of infections in 6-12 months per patient
Secondary:
1. Adverse effects of medications
2. Additive effect of estrogen
3. Patient tolerability of medications
Sample Size:
There are very few prior studies which compared methenamine hippurate to
trimethoprim currently published. One randomized control trial from 1982 by
Kasanen et al, allocated patients with recurrent UTIs to one of 4 groups: placebo,
nitrofurantoin 75 mg, methenamine hippurate 1 gm, or trimethoprim 100 mg. At
one year, 63.2% of those in the placebo group had a recurrence, compared to
34.2% in the methenamine hippurate group, 25% in the nitrofurantoin group, and
10.4% in the trimethoprim group7. In a Cochrane review by Aydin et al, current


prevention strategies were reviewed for the prevention of recurrent UTIs.
Prophylactic antibiotics reduced the rate of recurrence to 0.4 UTIs/patient/year. A
crossover study done by Cronberg et al found that the recurrence rate was
reduced to 0.8 UTIs/patient/year using long term methenamine hippurate
prophylaxis6. Based on the results of these prior studies, we performed a power
and sample size calculation. It was determined that 41 subjects per arm would be
required to detect the expected difference in response with 80% power at a 0.05
signiﬁcance level. We predict a 30% attrition rate, and therefore determine that
we should have 65 subjects per arm.
Proposed Analyses:
We will determine:
1. The time to subsequent UTI recurrence among patients with the diagnosis of
recurrent UTIs under suppressive therapy with either methenamine hippurate
or Trimethoprim. Differences in time to subsequent infection will be compared
and assessed for statistical signiﬁcance using a paired, two-tailed Student’s
t-test.
2. At 12 months, the percentage of patients enrolled to either arm that are
infection-free. We will count patients who discontinued the study
medications, added the opposing study medication, or crossed over to using
the opposing study medication as failures and include them in the total
number of patients in the denominator. The percentages will be compared
using a one sample t-test.
3. The number of recurrences in each group at 12 month intervals. We
will determine the rate of recurrences in each arm and compare them using a
student’s t-test.
4. The additive effect of estrogen will be determined at 12 months. A logistic
regression model will be used to compare the two groups to determine if a
combination of the study drug to estrogen further prevented recurrences in
post-menopausal women.
5. The percentages of adverse effects of each of the study medications will be
compared between the two groups using a one sample t-test.
6. Patient tolerability to the study medications. A tolerability survey will be
administered at subsequent follow up visits to the enrollment into the study.
Percentage of patients who discontinue the study medications will be
compared between both groups using a one sample t-test.
References:
1. Abdullatif A, Ahmed K, Zaman I, Khan MS, Dasgupta P. Recurrent urinary tract
infections in women. Int Urogynecol J (2015) 26:795–804.
2. Eells SJ, Bharadwa K, McKinnell JA, Miller LG. Recurrent urinary tract infections
among women: comparative effectiveness of 5 prevention and management
strategies using a Markov chain Monte Carlo model. Clin Infect Dis. 2014 Jan;
58(2):147-60.
3. Mody L, Juthani-Mehta M. JAMA patient page. Urinary tract infections in older
women. JAMA. 2014 Feb 26;311(8):874.


4. Geerlings SE, Beerepoot MA, Prins JM. Prevention of recurrent urinary tract
infections in women: antimicrobial and nonantimicrobial strategies. Infect Dis
Clin North Am. 2014 Mar;28(1):135-47.
5. Ikäheimo R, Siitonen A, Heiskanen T, Kärkkäinen U, Kuosmanen P, Lipponen P,
Mäkelä PH. Recurrence of urinary tract infection in a primary care setting:
analysis of a 1-year follow-up of 179 women. Clin Infect Dis. 1996 Jan;22(1):
91-9.
6. Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing
urinary tract infections. Cochrane Database Syst Rev. 2012 Oct 17;10.
7. Kasanen A, Junnila SY, Kaarsalo E, Hajba A, Sundquist H. Secondary prevention
of recurrent urinary tract infections. Comparison of the effect of placebo,
methenamine hippurate, nitrofurantoin and trimethoprim alone. Scand J Infect
Dis. 1982;14(4):293-6.