Topic: UTI prevention in hospitalized older adults
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Annals of Pharmacotherapy
2020, Vol. 54(4) 359 –363
© The Author(s) 2019
Article reuse guidelines:
DOI: 10.1177/1060028019886308
Research Report
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
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
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 mailto:[email protected] 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 References 1. Cortes-Penfield NW, Trautner BW, Jump RLP. Urinary tract infection and asymptomatic bacteriuria in older adults. Infect Dis Clin North Am. 2017;31:673-688. doi:10.1016/j. idc.2017.07.002 2. Rowe TA, Juthani-Mehta M. Urinary tract infection in older adults. Aging Health. 2013;9(5). doi:10.2217/ahe.13.38 3. Ahmed H, Farewell D, Jones HM, Francis NA, Paranjothy S, Butler CC. Antibiotic prophylaxis and clinical outcomes among older adults with recurrent urinary tract infection: cohort study. Age Ageing. 2019;48:228-234. doi:10.1093/ageing/afy146 4. Hiprex [package insert]. Parsippany, NJ: Validus Pharmaceuticals LLC; 2017. 5. McAllister R, Allwood J. Recurrent multidrug resistant uri- nary tract infections in geriatric patients. Fed Pract. 2014;31: 32-35. 6. Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2012;(10):CD003265. doi:10.1002/14651858.CD003265. pub3 7. Chwa A, Kavanagh K, Linnebur SA, Fixen DR. Evaluation of methenamine for urinary tract infection prevention in older adults: a review of the evidence. Ther Adv Drug Saf. 2019;10:2042098619876749. doi:10.1177/2042098619876749 8. Parvio S. Methenamine hippurate (“Hiprex”) in the treatment of chronic urinary tract infections: a trial in a geriatric hospi- tal. J Int Med Res. 1976;4:111-114. 9. Pagonas N, Horstrup J, Schmidt D, et al. Prophylaxis of recurrent urinary tract infection after renal transplanta- tion by cranberry juice and L-methionine. Transplant Proc. 2012;44:3017-3021. doi:10.1016/j.transproceed.2012.06.071 10. Beerepoot MA, ter Riet G, Nys S, et al. Lactobacilli vs anti- biotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012;172:704-712. doi:10.1001/archin- ternmed.2012.777 11. Dueñas-Garcia OF, Sullivan G, Hall CD, Flynn MK, OʼDell K. Pharmacological agents to decrease new episodes of recur- rent lower urinary tract infections in postmenopausal women: a systematic review. Female Pelvic Med Reconstr Surg. 2016;22:63-69. doi:10.1097/SPV.0000000000000244 12. Geerlings SE, Beerepoot MA, Prins JM. Prevention of recurrent urinary tract infections in women: antimicrobial and nonantimicrobial strategies. Infect Dis Clin North Am. 2014;28:135-147. doi:10.1016/j.idc.2013.10.001

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