Case Study 2
A man aged > 89 years with BPH and urinary incontinence managed with an external urinary device worn continuously had a history of 4 UTIs within a 6-month period. His renal function was normal with a creatinine clearance of 37 mg/dL. He was diagnosed with a symptomatic UTI culturing > 100,000 CFU Proteus mirabilis (resistant to ciprofloxacin, nitrofurantoin, and septra).
Due to resistance of the organism to available oral antibiotics, the patient’s desire to avoid hospitalization, and his caregiver’s inability to learn to administer IV antibiotics in the home, methenamine hippurate 500 mg bid was initiated. Within 21 days, the patient’s urinalysis was negative, indicating no bacterial growth. He was treated for 4 months with no recurrence of a UTI. No symptomatic UTIs recurred during the ongoing methenamine treatment.
Case Study 3
A man aged > 89 years with end-stage renal disease and a history of bladder cancer declined dialysis, indicating that his goals for care were palliative. He was followed at home by a hospice team. He had 3 recurrent symptomatic MRSA UTIs in a 9-month period (resistant to ciprofloxacin, levofloxin, penicillin, and oxacillin). The antibiotics the bacteria was sensitive to, nitrofurantoin and septra, could not be given because his creatinine clearance was merely 8 mg/dL. He was prescribed 500 mg methenamine with 1,000 mg ascorbic acid bid. Within 4 weeks, his urinalysis had changed from > 100,000 CFU to > 50,000 CFU (< 100,000 CFU). One month later with the only treatment the methenamine and ascorbic acid, there was no bacterial growth in the patient’s urine culture. He had no recurrence of a symptomatic UTI while receiving methenamine.
Case Study 4
An 89-year-old man with BPH and recurrent MRSA UTIs had 3 hospitalizations within 1 year. He had stage 3 chronic kidney disease with a creatinine clearance of 43 mg/dL. The patient had a symptomatic UTI > 100,000 CFU MRSA. He was treated with 500 mg methenamine and 1,000 mg ascorbic acid bid. Urinalysis results 2 months later revealed the bacterial count had dropped to the colonization range (< 50,000 CFU). His urinalysis was positive for leukocyte esterase with high white blood cell (WBC) counts, but it was negative for nitrites. He continued without recurrent UTIs while receiving the medication.
Discussion
Patients with similar profiles to those discussed in this report were treated with less dramatic results. Several remained free of symptomatic UTIs with urine cultures showing bacterial counts in the colonization range of < 50,000 CFU, as noted in case 4. Frequently, patients treated with methenamine have urinalyses with negative nitrites, positive leukocyte esterase, high WBCs, and few bacteria, but cultures show no growth. Some patients who did not reliably take medications as prescribed had recurrent symptomatic UTIs. Some had a subsequent UTI culturing a different organism or a change in the sensitivity profile of the same organism. This phenomenon suggests that formaldehyde disrupts the manufacture and transmission of the proteins and enzymes responsible for bacterial resistance factors.
Freeman and colleagues conducted a prospective study of 249 men with bacteruria followed for up to 10 years.18 Continuous therapy with methenamine delayed recurrence of bacteruria. Nilsson found that recurrent UTIs were reduced by 25% with long-term treatment (> 3 months) with methenamine.19
Bacteria do not develop resistance to methenamine.20 Reports of AEs are low, and drug interactions are limited to sulfamethizole, which can cause crystallization in the urine. Daily dosing used in studies ranged from 1 g to 4 g daily.21 Nilsson conducted research over 16 months with geriatric patients and found no changes in renal function or crystallization in urine.19
Severe hepatic impairment is also a contraindication, as methenamine can be hydrolyzed to ammonia. Studies have shown a reduced effectiveness with lower urinary tract abnormalities, although those studies administered the medication for short periods of time.21 Because the action of the medication relies on ≥ 2 hours of exposure to urine in the bladder, patients with indwelling catheters or patients who urinate frequently experience little benefit.22 Ideal candidates for methenamine are those with urinary retention and recurrent UTIs.
Although the use of methenamine has increased in Norway and Sweden by 24% since 2000, the use of methenamine in the U.S. remains low, perhaps because of conflicting reports in the literature regarding effectiveness and use with limited populations (ie, noncatheterized patients, those able to retain urine for ≥ 2 hours, and a creatinine clearance > 50 mg/dL).3
Some health care providers use methenamine for UTI prophylaxis, but this practice is less common in the U.S. than it is in Scandinavian countries.3 However, no published studies have explored the action of methenamine on MRSA, ESBL, and VRE bacteria or on the enzymes and proteins that enable and transmit bacterial resistance factors.