What does the literature say about the the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections (UTI) in women, as compared to standard low dose antibiotics (nitrofurantoin, trimethroprim, or cefalexin)?

Comment by InpharmD Researcher

Preventative treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections.

Background

According to the American Urological Association, the following is recommended for recurrent uncomplicated UTI's in women:

- Clinicians should use first-line therapy (i.e., nitrofurantoin, TMP-SMX, fosfomycin) dependent on the local antibiogram for the treatment of symptomatic UTIs in women.
- Clinicians should treat recurrent UTI patients experiencing acute cystitis episodes with as short a duration of antibiotics as reasonable, generally no longer than seven days.
- In patients with recurrent UTIs experiencing acute cystitis episodes associated with urine cultures resistant to oral antibiotics, clinicians may treat with culture-directed parenteral antibiotics for as short a course as reasonable, generally no longer than seven days. [1]

The Recurrent Urinary Tract Infections in Women: Diagnosis and Management Guidelines in The Family Physician state the following regarding UTI prevention:

- Continuous and postcoital antimicrobial prophylaxis have demonstrated effectiveness in reducing the risk of recurrent UTIs.
- Cranberry products may reduce the incidence of recurrent symptomatic UTIs.
- Use of topical estrogen may reduce the incidence of recurrent UTIs in postmenopausal women.
- The following agents have been listed for continuous prophylaxis: Cephalexin (Keflex) Ciprofloxacin (Cipro), Nitrofurantoin (Macrodantin) , Norfloxacin (Noroxin), Trimethoprim (Proloprim), Trimethoprim/sulfamethoxazole (Bactrim, Septra). [2]

Recommendations for prevention of recurrent UTIs were not specifically stated in the American Diseases Society of America (IDSA) treatment guidelines.

Potential measures and treatments for UTIs include behavioral changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), non-steroidal anti-inflammatories (NSAIDs), probiotics, D-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. While potential results are promising, higher-level evidence is required before firm recommendations can be made. [3], [4]

Relevant Prescribing Information

Methenamine hippurate (Hiprex, Urex) is a urinary tract antiseptic, and is indicated for prophylactic or suppressive treatment of frequently recurring UTI's when long-term therapy is considered necessary.

Contraindications include patients with renal insufficiency, severe hepatic insufficiency, or severe dehydration. It should not be used as the sole therapeutic agent in acute parenchymal infections causing systemic symptoms. Patients with pre-existing hepatic insufficiency may suffer adverse effects from the small amounts of ammonia and formaldehyde that are produced, and acute hepatic failure may occur.

Large doses of methenamine (8 g daily for 3 to 4 weeks) have caused bladder irritation, painful and frequent micturition, albuminuria and gross hematuria. The tablet contains 1g of drug and the general dose in adults is one tablet twice daily. Children over 12 years of age can take one tablet twice daily. Children 6 to 12 years of age can take one-half or one tablet twice daily.

The concomitant administration of methenamine hippurate and sulfamethizole or sulfathiazole is liable to result in the formation of a precipitate in the urine.

Adverse effects of methenamine hippurate tablets have been reported in fewer than 3.5% of patients treated. These reactions have included the following, in decreasing order of frequency: nausea, vomiting and rarely pruritus, rash, dysuria.

This drug should be stored at controlled room temperature 15°-30°C (59°-86°F). [1]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Please see Table 1 for your response.

Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial

The ALTAR Trial

Design

pragmatic, multicenter, randomized, open label, non-inferiority trial

n= 240

Objective

To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections (UTI) with the current standard prophylaxis of daily low dose antibiotics.

Study Groups

Experimental group: Methanamine Hippurate (n= 120)

Control group: Nitrofurantoin, trimethroprim, or cefalexin (n= 120)

Nitrofurantoin: n= 66
Trimethroprim: n= 30
Cefalexin: n= 24

Group Analyses:

Modified intention-to-treat: n= 205
Intention-to-treat: n= 240
Per protocol: n= 170

Inclusion Criteria

Adult women aged 18 years and over with recurrent UTI who had decided with their clinician that prophylaxis was appropriate.

Recurrent UTI was defined as at least three episodes of symptomatic UTI in the previous 12 months or at least two episodes in the past six months

Women already taking antibiotic prophylaxis or methenamine hippurate were allowed to take part after a three-month washout period.

Exclusion Criteria

Correctable urinary tract abnormalities contributory to recurrent UTI (eg, urinary tract calculi), neurogenic dysfunction of the lower urinary tract

Methods

This study took place across eight urology and urogynacology centers in the UK.

Participants were randomly assigned (1:1) to receive antibiotic prophylaxis or methenamine hippurate. Permuted blocks of variable length (2/4/6/8) were used, stratified by menopausal status and UTI frequency in the preceding year (<4 v ≥4).

For patients assigned to the control group, drugs used included nitrofurantoin (50 or 100 mg), trimethoprim (100 mg), or cefalexin (250 mg) given orally once daily. The antibiotic was chosen depending on previous urine culture results and patients’ history of allergy or intolerance.

For patients assigned to the experimental group, 1g of Methenamine Hippurate taken orally twice daily was prescribed.

Treatment allocation was not masked and crossover between arms was allowed.

An episode of UTI was defined as the presence of at least one symptom reported by patients or clinicians from a predefined list produced by Public Health England, together with the taking of a discrete treatment course of antibiotics for UTI. The end of one UTI episode was defined as 14 days after the final antibiotic dose. If symptoms restarted or further antibiotics were prescribed within 14 days, this event was counted as the same episode.

Duration

Recruitment: 2016-2018

Treatment: 12 months

Final Follow Up: 2020

Outcome Measures

Primary outcome: Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment.

Baseline characteristics

	Intention-to-treat		Modified Intention-to-treat
	Antibiotic Prophylaxis (n=120)	Methenamine Hippurate (n=120)	Antibiotic Prophylaxis (n=102)	Methenamine Hippurate (n=103)
Mean (standard deviation) age (years)	50.3 (18.1)	49.9 (19.1)	51.1 (17.7)	51.1 (18.9)
Mean (standard deviation) weight (kg)	70.1 (15.3)	75.1 (18.5)	69.4 (14.6)	75.5 (18.5)
Menopausal status
Pre-menopausal	49 (41)	50 (42)	40 (39)	41 (40)
Peri-menopausal/post-menopausal	71 (59)	70 (58)	62 (61)	62 (60)
No (%) of self-reported urinary tract infections in previous 12 months before trial entry
<4	14 (12)	16 (13)	12 (12)	16 (16)
≥4	106 (88)	104 (87)	90 (88)	87 (84)
Median (interquartile range)	6 (4-8)	6 (4-8)	6 (4-8)	6 (4-8)
Mean (standard deviation)	6.8 (3.8)	7.0 (3.4)	6.6 (3.8)	6.7 (3.3)
No of positive urine culture reports in previous 12 months before trial entry
Median (interquartile range)	2 (1-4)	3 (1-5)	2 (1-4)	3 (1-5)
Previous use of antibiotic prophylaxis	28 (23)	27 (23)	23 (23)	22 (21)
Nitrofurantoin	20 (17)	20 (17)	17 (17)	17 (17)
Trimethoprim	16 (13)	11 (9)	13 (13)	9 (9)
Cefalexin	6 (5)	13 (11)	2 (2)	9 (9)
Co-amoxyclav	2 (2)	5 (4)	0 (0)	4 (4)
Amoxycillin	3 (3)	3 (3)	0 (0)	2 (2)
Ciprofloxacin	1 (1)	4 (3)	0 (0)	3 (3)
Pivmecillinam	1 (1)	3 (3)	1 (1)	3 (3)
Three month washout period required before randomisation	16 (13)	16 (13)	15 (15)	14 (14)
Previously taken methenamine hippurate	2 (2)	4 (3)	2 (2)	3 (3)
Results of central laboratory urine culture at baseline
No growth	93 (78)	98 (82)	82 (80)	84 (82)
Growth of one or two isolates	18 (15)	13 (11)	16 (16)	13 (13)
No sample	9 (8)	9 (8)	4 (4)	6 (6)
Isolates identified from central laboratory urine culture at baseline
Escherichia coli	15 (13)	7 (6)	14 (14)	7 (7)
Coliform—other	1 (1)	2 (2)	1 (1)	2 (2)
Enterobacter cloacae group	1 (1)	0	0	0
Pseudomonas aeruginosa	0	1 (1)	0	1 (1)
Enterococcus faecalis	1 (1)	0	1 (1)	0
Staphylococcus aureus	0	1 (1)	0	1 (1)
Streptococcus agalactiae	1 (1)	2 (2)	1 (1)	2 (2)

Results

Study population	No of participants included in analysis	Incidence rate (95% CI)	Absolute difference (90% CI)
Modified intention to treat
Antibiotic prophylaxis	102	0.89 (0.65 to 1.12)	—
Methenamine hippurate	103	1.38 (1.05 to 1.72)	0.49 (0.15 to 0.84)
Strict intention to treat
Antibiotic prophylaxis	120	0.88 (0.65 to 1.11)	—
Methenamine hippurate	120	1.40 (1.08 to 1.73)	0.53 (0.20 to 0.86)
Per protocol
Antibiotic prophylaxis	84	0.87 (0.61 to 1.13)	—
Methenamine hippurate	86	1.29 (0.93 to 1.66)	0.42 (0.05 to 0.79)

Safety

	Antibiotic Prophylaxis (n= 142) no. (% or SD)	Methenamine Hippurate (n= 127) no. (% or SD)
No of adverse events reported per participant	1.9 (2.8)	1.8 (2.4)
Worst grade adverse event reported per participant
None	59 (42)	45 (35)
Mild	41 (29)	47 (37)
Moderate	34 (24)	29 (23)
Severe	8 (6)	6 (5)
No of adverse reactions reported per participant	0.4 (0.7)	0.4 (0.7)
No of participants reporting an adverse reaction	34 (24)	35 (28)
Worst grade adverse reaction reported per participant
None	108 (76)	92 (72)
Mild	24 (17)	26 (20)
Moderate	9 (6)	9 (7)
Severe	1 (1)	0
No of participants affected by each adverse event
Lower respiratory tract infection	10 (7)	9 (7)
Nausea	12 (8)	5 (4)
Abdominal pain	7 (5)	9 (7)
Diarrhea	8 (6)	4 (3)
Increase in Alanine aminotransferase	5 (4)	5 (4)
Back pain	7 (5)	3 (2)
Headache	3 (2)	7 (6)
Candida infection	4 (3)	5 (4)
Dyspepsia	5 (4)	4 (3)
Rash	3 (2)	5 (4)
Abdominal discomfort	3 (2)	4 (3)
Dyspnoea	5 (4)	2 (2)
Fall	3 (2)	4 (3)
Vomiting	3 (2)	4 (3)
Depressed mood	1 (1)	4 (3)
Herpes zoster	5 (4)	0

Study Author Conclusions

Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial.

InpharmD^TM Researcher

Critique

While non-inferiority was observed, crossover from methenamine hippurate to antibiotic prophylaxis occurred in 18% of patients, whereas only 6% crossed over to methenamine. This may have tipped the scales in favor of showing non-inferiority. Additionally, the lack of blinding could introduce bias. Furthermore, the trial was not powered to be able to examine specific subgroups to determine if methenamine may be better for certain people or compared to specific antibiotics. The heterogenity of antibiotics and wide inclusion criteria prevent meaningful subgroup analyses.

References:

Harding C, Mossop H, Homer T, Chadwick T, King W, Carnell S et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial BMJ 2022; 376 :e068229 doi:10.1136/bmj-2021-0068229