Topic: UTI prevention in hospitalized older adults
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https://doi.org/10.1177/1060028019886308
Annals of Pharmacotherapy
2020, Vol. 54(4) 359 –363
© The Author(s) 2019
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DOI: 10.1177/1060028019886308
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Research Report
Introduction
Urinary tract infections (UTIs) cause significant morbidity
and mortality in older adults, accounting for an estimated
15.5% of hospitalizations and 6.2% of infectious disease–
related deaths in patients 65 years and older.1 Among insti-
tutionalized adults, UTIs are the most common type of
infection and account for one-third of all infections.1 Older
adults are at higher risk for UTI because of increasing inci-
dence of urinary incontinence and retention, use of urinary
catheters, vaginal atrophy in postmenopausal women, long-
term institutionalization, and reduced immune function.1,2
Prophylactic antibiotics are often utilized in older
adults with recurrent UTIs. A retrospective cohort study
evaluated more than 19 000 patients ≥65 years old with
recurrent UTI who received prophylaxis with either trim-
ethoprim, cephalexin, or nitrofurantoin.3 Prophylaxis was
associated with a reduction in the risk of UTIs and UTI-
related hospitalizations.3
Currently, there are no treatment guidelines for the pre-
vention of recurrent UTIs. A major concern with use of
prophylactic antibiotics is antimicrobial resistance and
other adverse effects, including Clostridioides difficile.1
Antimicrobial resistance in community-acquired urinary
organisms is increasing in the United States. In nursing
home settings, colonization with multidrug-resistant organ-
isms is common.1
Methenamine is a Food and Drug Administration (FDA)-
approved medication used for the prevention of UTIs in
persons 6 years and older.4 The recommended dosing of
886308AOPXXX10.1177/1060028019886308Annals of PharmacotherapySnellings et al
research-article2019
1University of Colorado, Aurora, CO, USA
Corresponding Author:
Danielle R. Fixen, Department of Clinical Pharmacy, Skaggs School
of Pharmacy and Pharmaceutical Sciences, University of Colorado,
Anschutz Medical Campus Mail Stop C238, 12850 E Montview Blvd,
Aurora, CO 80045, USA.
Email: [email protected]
Effectiveness of Methenamine for UTI
Prevention in Older Adults
Marina S. Snellings, PharmD1, Sunny A. Linnebur, PharmD1,
Scott M. Pearson, PharmD1, Jeff I. Wallace, MD, MPH/MSPH1,
Joseph J. Saseen, PharmD1, and Danielle R. Fixen, PharmD1
Abstract
Background: Methenamine is a drug used for the prevention of lower urinary tract infections (UTIs). However, efficacy
has not been established in older adults or patients with varying degrees of kidney function. Objective: To evaluate the
effectiveness of methenamine for the prevention of UTI in adults 60 years and older. Methods: This was a retrospective,
pre-post, observational study. The study included primary care patients 60 years and older who were taking methenamine
between January 1, 2015, and September 30, 2018. The primary outcome was the time to first UTI after methenamine
initiation compared with the average time between UTIs in the 12 months prior to methenamine initiation. Results: Of
434 patients reviewed, 150 met inclusion criteria. The average time to UTI was 3.3 months prior to methenamine initiation
compared with 5.5 months after methenamine initiation (P = 0.0004). There were 33 patients (22%) who did not have
a UTI after methenamine initiation. Also, 14 patients (9.3%) had a calculated CrCl <30 mL/min at baseline. The average
time to UTI in these patients was 3.3 months prior to methenamine initiation compared with 12.7 months after initiation
(P < 0.0001). Conclusion and Relevance: Methenamine use was associated with a longer time to UTI in older adults
with varying degrees of kidney function. The effectiveness of methenamine appeared to be similar regardless of kidney
function, which is new evidence. Because of a lack of acquired resistance, methenamine may be an effective option for UTI
prophylaxis in older adults.
Keywords
methenamine, urinary tract infections, geriatrics, renal insufficiency
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360 Annals of Pharmacotherapy 54(4)
methenamine hippurate for UTI prophylaxis according to
FDA labeling is 1 g by mouth twice daily. Methenamine
acts via conversion of hexamine to formaldehyde in the
bladder, which in turn acts as a bacteriostatic agent.4 Unlike
other antimicrobials, acquired resistance has not been dem-
onstrated with methenamine use, making it an attractive
option for UTI prophylaxis.5 FDA labeling for methena-
mine states that use is contraindicated in patients with a cre-
atinine clearance (CrCl) less than 30 mL/min; therefore, the
safety and efficacy of methenamine in this population
remains largely unknown.4
Prior studies evaluating the efficacy of methenamine for
UTI prophylaxis were often small and/or had mixed results.6
Furthermore, efficacy of methenamine has not been studied
specifically in older adults with varying degrees of kidney
function. The objective of this study was to determine the
effectiveness of methenamine for the prevention of UTIs in
older adults.
Methods
Study Design and Setting
This was a retrospective, pre-post, observational study of
methenamine for UTI prevention in older adults receiving
primary care at University of Colorado Health (UCHealth).
UCHealth is an integrated health system across Colorado
with more than 900 primary care clinics utilizing the elec-
tronic health record (EHR) EPIC (Verona, WI). Patients
aged 60 to 89 years prescribed methenamine between
January 1, 2015, and September 30, 2018, were identified
through an EHR report. Manual verification of study crite-
ria was completed via EHR review. Patients had to be
actively prescribed methenamine during the study period,
but records were reviewed for the entire time the patient
was prescribed methenamine. The study protocol was
reviewed and determined to be exempt by the Colorado
Multiple Institutional Review Board.
Participants
Patients were included if they were 60 years and older,
were prescribed methenamine for UTI prophylaxis, and
received care in a UCHealth primary care clinic. Patients
were required to have documentation of recurrent UTI,
defined as 2 or more UTIs in the 12 months prior to methe-
namine initiation. In addition, participants had to be a
UCHealth patient for at least 12 months prior to methena-
mine initiation or have outside records available in the
EHR. Exclusion criteria included spinal cord or urological
structural abnormalities, immunocompromised state, use
of other antimicrobial agents for UTI prophylaxis, no
serum creatinine (SCr) in the EHR within 12 months of
methenamine initiation, or evidence that the patient was
not adherent to methenamine.
Outcomes
The primary outcome was time to first UTI after methena-
mine initiation compared with the time between UTIs in the
12 months prior to methenamine initiation. UTI was defined
as one of the following: (1) antibiotic prescription with an
associated International Classification of Diseases diagno-
sis code for UTI, (2) bacteriuria with >100 000 colony-
forming units (cfu)/mL plus either an antibiotic prescription
or urinary symptoms, or (3) emergency department visit or
hospitalization for UTI. Secondary outcomes included
effectiveness of methenamine in patients with CrCl <30
mL/min compared with CrCl ≥30 mL/min and adverse
effects associated with methenamine.
Data Collection and Analysis
Patients were identified from an EHR report, and demo-
graphic data, pertinent lab values, methenamine prescribing
information, and UTI data were collected and recorded
using Microsoft Excel. Number of UTIs in the 12 months
prior to methenamine initiation and time to first UTI after
methenamine initiation were determined. Time between
UTIs in the 12 months prior to methenamine initiation was
calculated by dividing 12 months by the number of UTIs
during that time period to determine an average. In patients
who did not have a UTI after initiation of methenamine,
time to UTI was measured from methenamine initiation
date to date of data collection. Other variables collected
during the EHR review included the following: methena-
mine index (date first prescribed) and discontinuation dates,
height, weight, SCr at index date and highest SCr while on
methenamine, methenamine dose, provider type for methe-
namine prescription, reason for discontinuation, adverse
effects, type of UTI (symptomatic or asymptomatic), bacte-
ria identified in urine culture, antibiotics used for treatment
of UTI, source of antibiotic prescription, use of antibiotics
for other indications, catheter use, and use of other medica-
tions that increase risk of UTI (eg, corticosteroids, sodium-
glucose cotransporter-2 inhibitors). The baseline and lowest
CrCl were manually calculated using the Cockroft-Gault
equation by using the SCr at initiation and highest SCr
while on methenamine.
As our data were normally distributed, a 2-tailed paired
t-test was used for the primary outcome, with a P value of
<0.05 considered statistically significant. Descriptive sta-
tistics were used for demographic and clinical data.
Proportions were used for nominal data.
Results
A total of 434 patients were screened, of whom 150 patients
were included (Figure 1). Baseline characteristics are sum-
marized in Table 1. The mean age was 77 years, and the
majority of patients were white and female. The mean CrCl
Snellings et al 361
at time of methenamine initiation was 54 mL/min.
Urologists (66.7%) were the most common prescriber of
methenamine, followed by primary care physicians
(16.7%). The majority of patients (88.7%) were prescribed
methenamine hippurate 1 g by mouth twice daily, with 1 g
by mouth once daily being the second most common dosing
at the time of methenamine initiation (10.7%). There were
25 patients (16.7%) who used antibiotics for other indica-
tions while taking methenamine, and 17 patients (11.3%)
were taking medications that increased risk for UTIs (eg,
corticosteroids). Urinary catheters were utilized in 26
patients (17.3%) prior to methenamine initiation.
Primary Outcome
The average time to recurrent UTI was 3.3 months prior to
methenamine initiation compared with 11.2 months after
methenamine initiation (P < 0.0001; Table 2). There were 33
patients (22%) who did not have a UTI after methenamine
initiation. Of the 117 patients who had a UTI after methena-
mine initiation, 98 (83.8%) were symptomatic, 6 (5.1%) were
asymptomatic, and in 13 (11.1%), it was unknown.
Escherichia coli was the most common bacteria on urine cul-
ture (47%), followed by Klebsiella pneumoniae (12.8%).
Secondary Outcomes
A total of 14 patients (9.3%) had a calculated CrCl <30
mL/min at baseline. The average time to UTI recurrence in
these patients was 3.3 months prior to methenamine initia-
tion compared with 12.7 months after initiation (P <
0.0001). Of the 136 patients with CrCl ≥30 mL/min, the
average time to UTI was 3.3 months prior to methenamine
initiation compared with 11 months after initiation (P <
0.0001; Table 2). Adverse events occurred in 16 patients
(10.7%) and led to discontinuation of methenamine in 15
of these patients. The most common adverse events
included gastrointestinal effects and dysuria (Table 3). Of
the 16 patients with adverse effects, 1 patient had CrCl
<30 mL/min.
Discussion
In this retrospective analysis, the use of methenamine for
UTI prophylaxis led to a significantly longer time to UTI
recurrence in older adults with varying degrees of kidney
function. Our results are consistent with prior studies that
have found benefit of using methenamine for UTI prophy-
laxis.5-8 Importantly, the effectiveness and tolerability of
methenamine appeared to be similar regardless of kidney
function. Therefore, the avoidance of methenamine pre-
scribing in patients with decreased kidney function because
of lack of data may not be justified.
Our study evaluated average time to UTI recurrence
before and after methenamine initiation, whereas previous
studies have mostly evaluated the reduction in incidence of
UTI or bacteriuria after initiation of methenamine. A review
of adults 58 years and older, using methenamine for UTI
prophylaxis, found a reduction in incidence of UTI or bac-
teriuria.7 A Cochrane systematic review that included 13
studies and a total of 2032 patients found that methenamine
was effective for UTI prophylaxis in patients without renal
tract abnormalities (symptomatic UTI: RR = 0.24, 95% CI
= 0.07 to 0.89; bacteriuria: relative risk (RR) = 0.56, 95%
CI = 0.37 to 0.83).6 Another analysis evaluated rates of
reinfection during a 6-month period of prophylaxis with
methenamine compared with infection rates in the 6 months
prior to methenamine in 52 older women with recurrent
434 pa�ents
screened
150 pa�ents
included
284 pa�ents excluded
• Unclear if ≥2 UTIs prior to methenamine
ini�a�on (n=104)
• Lack of informa�on in EHR (n=104)
• No SCr (n=21)
• Taking other an�bio�cs for prophylaxis (n=20)
• Documenta�on of methenamine non-
adherence (n=18)
• Immunocompromised (n= 13)
• Other (n=4)
Figure 1. Patient screening.
Abbreviations: EHR, electronic health record; SCr, serum creatinine;
UTI, urinary tract infection.
Table 1. Baseline Characteristics at the Time of Methenamine
Initiation.
Characteristic Patients (n = 150)
Age: mean (years) ± SD 77 ± 8
Sex, n (%)
Female 133 (88.7)
Race, n (%)
White 142 (94.7)
CrCl, mean (mL/min) ± SD 54.3 ± 21
Catheter use, n (%) 26 (17.3)
Patients taking medications that increase
risk of UTI, n (%)
17 (11.3)
Methenamine dose, n (%)
1 g Twice daily 133 (88.7)
1 g Daily 16 (10.7)
500 mg Twice daily 1 (0.7)
Provider type for prescription, n (%)
Urologist 100 (66.7)
Primary care physician 25 (16.7)
Urogynecologist 15 (10)
Infectious disease 5 (3.3)
Inpatient provider 4 (2.7)
Oncologist 1 (0.7)
Abbreviations: CrCl, creatinine clearance; UTI, urinary tract infection.
362 Annals of Pharmacotherapy 54(4)
UTI hospitalized in a long-term care facility.8 Patients were
categorized into 1 of 3 groups based on degree of inconti-
nence and immobility (normal, partial, or total). There was
a lower rate of total reinfection cases per person in each
group over the 6-month period of prophylaxis with methe-
namine compared with when not on treatment (normal
[0.45 vs 2.82], partial [0.58 vs 4.33], and total [0.29 vs
5.24]).8 Finally, a case series of 4 patients, 89 years or older,
with history of multidrug-resistant UTIs found that methe-
namine appeared to be safe and effective for prevention of
recurrent UTIs.5
Our study found that patients had a mean of 4.4 UTIs per
year prior to methenamine initiation. This is similar to pre-
vious studies evaluating effectiveness of other prophylactic
agents. A retrospective analysis of 82 renal transplant recip-
ients with recurrent UTI showed that prophylaxis with cran-
berry juice significantly reduced annual number of UTI
episodes from 3.6 ± 1.4 per year to 1.3 ± 1.3 per year (P <
0.001).9 Prophylaxis with l-methionine also significantly
reduced annual UTIs from 3.9 ± 1.8 per year to 2.0 ± 1.3
per year (P < 0.001).9 Another study of 252 postmeno-
pausal women with recurrent UTI randomized patients to
either trimethoprim-sulfamethoxazole or lactobacillus for
prophylaxis.10 The mean number of symptomatic UTIs in
the 12 months prior to initiation of prophylaxis was 7 in the
trimethoprim-sulfamethoxazole group and 6.8 in the lacto-
bacillus group compared with 2.9 (95% CI = 2.3 to 3.6) and
3.3 (95% CI = 2.7 to 4.0) during 12 months of prophylaxis,
respectively. Median time to first UTI was 6 months for
trimethoprim-sulfamethoxazole and 3 months for lactoba-
cillus.10 Our study found a longer mean time to first UTI of
11.2 months with methenamine prophylaxis.
Regardless of kidney function, patients in our study
tolerated methenamine treatment with minimal adverse
effects. Our data are consistent with previous studies that
have shown low rates of adverse events with use of methe-
namine with adequate kidney function, but the finding in
patients with a CrCl <30 mL/min is new.5-8 Other antibiot-
ics that are used for UTI prophylaxis (trimethoprim-sulfa-
methoxazole, nitrofurantoin, and cephalexin) often have
higher rates of adverse effects, drug-drug interactions, and
concern for antimicrobial resistance.9-12
FDA labeling for methenamine states that use is contrain-
dicated in patients with CrCl <30 mL/min because of lack of
data and potential for adverse effects, with no dosage adjust-
ments provided for patients with kidney dysfunction.4 Our
study included 14 patients (9.3%) with CrCl <30 mL/min.
Although overall numbers were small, we found that methe-
namine was effective in patients with CrCl <30 mL/min.
Only 1 of 14 patients (7%) with CrCl <30 mL/min had a
documented adverse event, compared with 15 of 136 patients
(11%) with higher levels of kidney function. Interestingly, 16
patients were prescribed a reduced dose of methenamine 1 g
by mouth daily, but only one had a CrCl <30 mL/min.
Despite FDA labeling stating that use is contraindicated in
renal impairment, our results suggest that methenamine was
safe and effective in persons with reduced renal function.
Future studies with a larger number of patients are needed to
determine true efficacy and safety of methenamine in patients
with moderate to severe kidney dysfunction.
Our study has several advantages. In contrast to other
published studies, we used a pre-post study design, where
patients served as their own controls to assess effectiveness
of methenamine for UTI prophylaxis. We also collected
data on other potential confounders that could increase risk
of UTI, including catheter use and use of other medications
(eg, corticosteroids) known to cause UTI. In addition, our
study categorized patients based on CrCl at the time of
methenamine initiation. Our study specifically evaluated
effectiveness in adults 60 years of age and older, which is a
population at high risk for recurrent UTIs as well as for
negative outcomes from antibiotic use.
Our study has some limitations. The observational nature
of the study with retrospective analysis and manual EHR
review may have introduced bias. Determination of methena-
mine adherence, discontinuation, and adverse effects relied
on record review alone, which may have underreported these
measures. Determination of UTI relied on patients reporting
a UTI to a provider within the health system or having an
Table 2. Study Outcomes Based on Renal Function.
n (%)
Average Time to UTI Prior to
Methenamine Initiation (months)
Average Time to UTI After
Methenamine Initiation (months) P Value
All patients 150 (100) 3.3 11.2 <0.0001
CrCl <30 mL/min 14 (9.3) 3.3 12.7 <0.0001
CrCl ≥30 mL/min 136 (90.7) 3.3 11.0 <0.0001
Abbreviations: CrCl, creatinine clearance; UTI, urinary tract infection.
Table 3. Adverse Events.
Adverse Event n (%)
Gastrointestinal effects 9 (56.3)
Dysuria 3 (18.8)
Hand/feet swelling 1 (6.3)
Insomnia 1 (6.3)
Fatigue 1 (6.3)
Elevated liver function tests 1 (6.3)
Snellings et al 363
office visit or emergency department visit where a UTI was
diagnosed. Additionally, some antibiotic prescriptions may
not have been captured if they were prescribed outside the
UCHealth system. Because this was a retrospective study, not
all patients had a UTI at the time of methenamine initiation,
which may have underestimated time to first UTI. In addi-
tion, there were 33 patients who did not have a UTI after
methenamine initiation. For these patients, time to first UTI
was measured from methenamine initiation date to date of
data collection, which likely underestimated time to first
UTI. Finally, asymptomatic bacteriuria was treated in several
patients, which may have overestimated the time to first UTI
after methenamine initiation.
Conclusion and Relevance
Our findings suggest that use of methenamine for UTI pro-
phylaxis in older adults was effective by significantly
extending time to UTI. This benefit was observed in patients
with normal and reduced kidney function, which is a new
finding. Clinicians should consider prescribing methena-
mine for UTI prophylaxis in older adults. Future prospec-
tive randomized controlled trials in patients with impaired
kidney function are needed to confirm efficacy and safety
of methenamine in this patient population.
Acknowledgments
The authors wish to thank the Health Data Compass Colorado
Center for Personalized Medicine for their help in creating a data
report to identify eligible patients.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Danielle R. Fixen https://orcid.org/0000-0002-7193-1756
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https://orcid.org/0000-0002-7193-1756
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