Clinical Review

Have you tried these innovative alternatives to antibiotics for UTI prevention?

OBG Manag. 2013 February;25(2):17-26

References

1. Raz R, Stamm W. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329(11):753-756.

2. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008;2:CD005131.-

3. Mayrer AR, Andriole VT. Urinary tract antiseptics. Med Clin North Am. 1982;66(1):199-208.

4. Jepson RG, Craig JC. A systematic review of the evidence for cranberries and blueberries in UTI prevention. Mol Nutr Food Res. 2007;51(6):738-745.

5. Salvatore S, Salvatore S, Cattoni E, et al. Urinary tract infections in women. Eur J Obstet Gynecol Reprod Biol. 2011;156(2):131-136.

6. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2008;1:CD001321.-

7. Stapleton AE, Dziura J, Hooton TM, et al. Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc. 2012;87(2):143-150.

8. Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, DeBusscher J, Foxman B. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis. 2011;52(1):23-30.

9. Beerepoot MAJ, Reit G, Nys S, et al. Cranberries vs antibiotics to prevent urinary tract infections. Arch Intern Med. 2011;171(14):1270-1278.

10. McMurdo MET, Argo I, Phillips G, Daly F, Davey P. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother. 2009;63(2):389-395.

11. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clinical Therapeutics. 2008;30(3):453-468.

12. Miller JL, Krieger JN. Urinary tract infections: cranberry juice underwear, and probiotics in the 21^st century. Urol Clin N Am. 2002;29(3):695-699.

13. Osset J, Bartolome R, Garcia E, et al. Assessment of the capacity of Lactobacillus to inhibit the growth of uropathogens and block their adhesion to vaginal epithelial cells. J Infect Dis. 2001;183(3):485-491.

14. Stapleton AE, Au-Yeung M, Hooton TM, et al. Randomized, placebo-controlled phase 2 trial of Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis. 2011;52(10):1212-1217.

15. Castello T, Girona L, Gomez MR, Mena Mur A, Garcia L. The possible value of ascorbic acid as a prophylactic agent for urinary tract infection. Spinal Cord. 1996;34(10):592-593.

16. Gleckman R, Alvarez S, Joubert DW, Matthews SJ. Drug therapy reviews: methenamine mandelate and methenamine hippurate. Am J Hosp Pharm. 1979;36(11):1509-1512.

17. Vainrub B, Musher DM. Lack of effect of methenamine in suppression of or prophylaxis against, chronic urinary tract infection. Antimicrob Agents Chemother. 1977;12(5):625-629.

18. Lee BB, Simpson JM, Craig JC, Bhuta T. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2007;4:CD003265.-

19. Kevorkian CG, Merritt JL, Ilstrup DM. Methenamine mandelate with acidification: an effective urinary antiseptic in patients with neurogenic bladder. Mayo Clin Proc. 1984;59(8):523-529.

20. Wainwright M, Stanforth A, Jones R, Loughran C, Meegan K. Photoantimicrobials as a potential local approach to geriatric UTIs. Lett Appl Microbiol. 2010;50(5):486-492.

21. Bannwart C, Hagmaier V, Straumann E, Hofer H, Buillemier JP, Trutishauser G. Modification of urinary pH through ascorbic acid. Helv Chir Acta. 1981;48(3-4):425-428.

22. Hetey SK, Kleinberg ML, Parker WD, Johnson EW. Effect of ascorbic acid on urine pH in patients with injured spinal cords. Am J Hosp Pharm. 1980;37(2):235-237.

23. Ochoa-Brust GJ, Fernandez AR, Villanueva-Ruiz GJ, et al. Daily intake of 100 mg ascorbic acid as urinary tract infection prophylactic agent during pregnancy. Acta Obstet Gynecol Scand. 2007;86(7):783-787.

24. Turi M, Turi E, Kotjalg S, Mikelsaar M. Influence of aqueous extracts of medicinal plants on surface hydrophobicity of Escherichia coli strains of different origin. APMIS. 1997;105(12):956-962.

25. Beaux D, Fleurentin J, Mortier F. Effect of extracts of Orthosiphon stamineus Benth Hieracium pilosellaL., Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in rats. Phytother Res. 1999;13(3):222-225.

26. Kubo M, Ito M, Nakata H, Matsuda H. Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. I. Combined effect of 50% methanolic extract from Arctostaphylos uva-ursi (L.) Spreng. (bearberry leaf) and prednisolone on immuno-inflammation [article in Japanese]. Yakugaku Zasshi. 1990;110(1):59-67.

27. Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: a preliminary report. Curr Ther Res. 1993;53(4):441-443.

28. Christenson JT, Thulesius D, Nazzal MM. The effect of forskolin on blood flow platelet metabolism, aggregation and ATP release. Vasa. 1995;24(1):56-61.

29. Bishop BL, Duncan MJ, Song J, Li G, Zaas D, Abraham SN. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat Med. 2007;13(5):625-630.

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Advantages of methenamine include the fact that it produces no changes in gut flora, poses no risk for antimicrobial resistance, and has low toxicity. It also is low in cost.¹⁷

Methenamine is contraindicated in patients with renal insufficiency or severe hepatic disease.

Adverse reactions are generally mild and include gastrointestinal disturbances, skin rashes, dysuria, and microscopic hematuria.¹⁶

Methenamine hippurate

A 2007 Cochrane review, deemed up to date in 2010, analyzed 13 randomized, controlled trials involving 2,032 participants. Subgroup analyses suggested that methenamine hippurate may be of some benefit to patients without renal tract abnormalities; these patients experienced significantly reduced symptoms after short-term treatment of 1 week or less.

Patients with spinal injury do not appear to benefit from treatment, according to a randomized, double-blind, placebo-controlled trial by Lee and colleagues.¹⁸

Methenamine mandelate

This agent is commonly used to prevent recurrent UTI, although there is a paucity of randomized, controlled trials to support its use. One such trial in patients with neurogenic bladder found that methenamine mandelate with acidification was superior to placebo (P <.02) for preventing UTI.¹⁹ Beyond this population, however, it’s difficult to assess methenamine’s efficacy in the prevention of recurrent UTI.

Methylene blue may be useful in the elderly

Methylene blue is a light-activated compound described as “photodynamic antimicrobial chemotherapy” (PACT). Once illuminated, it becomes a bactericide, causing excitation of electrons followed by one of two reactions:

reduction oxidation
formation of a labile singlet oxygen and then oxidation.

This makes resistance unlikely.

In an in vitro study, methylene blue was as effective as levofloxacin against Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Enterococcus, and Staphylococcus aureus when illuminated.

Potential benefits of this mode of treatment include local exposure and no drug interactions.

We suggest that methylene blue be placed and illuminated with a special catheter that would target UTI in the elderly population, among whom 52% of UTIs are associated with use of catheters.²⁰ In vivo effects, adverse effects, and cost are not known, which limits current applicability of this compound.

Vitamin C may reduce UTI in pregnancy

The proposed mechanism for the efficacy of vitamin C for the treatment of UTI is the acidification of urine, which is believed to reduce the proliferation of bacteria. However, several studies have shown that vitamin C, at various doses, does not reliably reduce urine pH.^15,21,22 Nonetheless, ascorbic acid was tested for its effect on UTI prevention during pregnancy.

In a single-blind trial, 110 pregnant women were divided into two groups (55 in each group):

One group received ferrous sulfate (200 mg), folic acid (5 mg), and vitamin C (100 mg) daily for 3 months
The other received ferrous sulfate (200 mg) and folic acid (5 mg) daily for 3 months.

Urine was cultured monthly. The incidence of UTI was significantly lower in the group receiving vitamin C (12.7%), compared with the control group (29.1%) (P=.03; odds ratio [OR], 0.35).²³

Uva ursi may have a prophylactic effect

Uva ursi (UVA-E) is one of the most commonly used herbal supplements for treatment of UTI. The crude extract from Bearberry or Arctostaphylos uva-ursi has been shown to act as an antimicrobial by decreasing bacterial adherence.²⁴ In addition, investigators have found the extract to have diuretic and anti-inflammatory properties.^25,26 However, few studies have explored its efficacy. One randomized, controlled trial that included 57 women (30 allocated to UVA-E and 27 to placebo) found a statistically significant reduction in the rate of recurrence at 1 year among women taking UVA-E, compared with those who did not.²⁷

Note that the women in this trial were given UVA-E for 1 month only. Long-term use of this herb has not been studied and may cause liver damage.

In a mouse model, forskolin reduced urinary-tract E. coli

This herb is derived from Indian coleus (Coleus forskohlii), a member of the mint family. It has been used primarily for its antiasthmatic, spasmolytic, and antihypertensive effects. It is believed to activate adenylate cyclase, increasing intracellular cyclic AMP (cAMP) concentrations and activating a number of key enzymatic pathways.²⁸

The findings of a recent observational study have spurred the use of forskolin in the treatment of recurrent UTI.²⁹ In the study, conducted on mice, when forskolin was injected into the bladder, intracellular E. coli decreased.

It is theorized that the incorporation of bacteria into intracellular vesicles of the bladder prevents exposure to antibiotics. When combined with an antibiotic, forskolin may increase bacterial elimination and thus lower the risk of recurrent infection. However, no randomized trials have evaluated the efficacy of this treatment.