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Powder or Capsules and understanding D-Mannose formulations

D-mannose is sold as both as a powder or as capsules. Which type you use, is up to you and personal preference.  Suppliers include

Sweet Cures – Waterfall D-mannose

Now Foods D Mannose 

West Coast Mint

However it is important to understand the differences between D-mannose formulations, particularly for those with allergy issues.

Manufacturers can use various raw sources for the production of D-mannose or D-mannose can be synthetically produced. Manufacturers refer to this as pure or synthetic production. Natural sources can be from birch trees, palm kernels, potato, corn or fruits such as cranberries and pineapples. Synthetic sources such d-fructose or d-glucose or pure starch through bio-conversions are inexpensive starting materials and widely available.

For those with corn allergies, always check with the manufacturer as to the source of their D-mannose before purchasing and the environment in which the product has been packaged. If you have a known corn allergy or suffer a reaction after using D-Mannose, consider an alternate that is made from pineapples or cranberries or derived from birch/beech wood hydrolysate.

The production of D-mannose can also introduce additives, in particular if taken in capsule form. Silica, magnesium stearate, rice flour, artificial sweeteners and heavy metals can all be included as bulking agents or form the body of an individual tablet. This ensures cheaper mass production. Do your research first especially if you have allergy issues or are following a preferred regime of avoidance such as soy, gluten or GM products.

Sadly sometimes price does reflect quality of manufacture and purity of product so buyer beware.

When researching a brand look at the amount of pure D-mannose in each pot or tablet. The higher the better. A teaspoon of powder should offer around 2000 mg of D-Mannose and a tablet around 500mg. And remember Cranberry products are not the same as D-Mannose. Cranberry extract and juice has been shown not to be effective against recurrent and chronic UTI.

We debunk the cranberry myth here.

Your type of period sanitary protection can make things worse

Human blood is comparatively alkaline, with a pH of around 7.35 – 7.45. During menstruation, the presence of blood in the vagina raises the vaginal pH above normal, disrupting the usual environment, and favouring the growth of Candida. With tampons resting in the vaginal tract and no immediate outlet for the menstrual flow, for some this can alter PH levels leading to an upsurge of candida or bacterial vaginosis during or shortly after menstruation has finished. Tampons can also be drying on the vaginal tract.

Try using unscented sanitary towels as the bleach, scent and plastic in most high street and brand name sanitary towels can irritate vulval and vaginal tissue for some people. The following are recommended:

Natracare

Time of the Month

Alternatively Boots and Sainsbury’s in the UK sell their own branded sanitary protection that is unscented. These products are much cheaper than Natracare or Time of the Month but they are still bleached and contain plastics. However the major irritant – the scent – has been removed.

More evidence for Hiprex when treating recurrent & chronic UTI

More recent data has come from a ten year patient study by the Lower Urinary Tract Symptoms Clinic at the Whittington Hospital, London, published in the International Urogynecology Journal in 2018.

The study reviewed 624 women between 2004 and 2014 where Hiprex was prescribed alongside high dose, long-term antibiotics. 64 percent of the women said that their symptoms were very much better, with another 20 percent reporting that they were much better. The mean treatment time was just over one year.

In 2019 a trial of 86 adult patients was undertaken at Chicago’s NorthShore University Health System in the US comparing low dose prophylaxis Trimethoprim against Hiprex for recurrent UTI within a 12 month period. Results of the study showed that there was no difference between groups with regard to recurrent urinary tract infections, with 65% recurrence in the trimethoprim group versus 65% recurrence in the methenamine hippurate group. The authors concluded that methenamine hippurate may be an alternative for the prevention of recurrent urinary tract infections, with similar rates of recurrence and adverse effects to trimethoprim.

In December 2021 a published patient trial study at Newcastle University Hospitals in the UK recruited women from eight secondary care urology and urogynaecology centres in the UK from June 2016 and incorporated a 12 month treatment period followed by a six month follow-up period. Participants were adult women aged 18 years and over with recurrent UTI who had decided, in conjunction with their responsible clinician, that prophylaxis was appropriate, were eligible for inclusion. The study noted that 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.

Between 23 June 2016 and 20 June 2018, 240 participants were recruited and randomly assigned to antibiotic prophylaxis or methenamine hippurate. For those allocated to antibiotic prophylaxis, 66 (55%) received nitrofurantoin, 30 (25%) trimethoprim, 24 (20%) cefalexin. A total of 22 (18%) participants allocated to methenamine hippurate switched to receive antibiotic prophylaxis and seven (6%) vice versa. Patient follow-up was completed in January 2020.

The results of this trial noted that “incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.9 episodes per person year in the antibiotics group and 1.4 in the methenamine hippurate group confirming non-inferiority”.

The authors concluded “In the ALTAR trial, we have demonstrated high levels of efficacy from methenamine hippurate in terms of UTI prevention, and have shown that this efficacy is comparable to the current guideline recommended prophylaxis (that is, around six month, low dose antibiotic treatment)”.

Swabs were taken during the trial to check for antibiotic-resistant bacteria. During the treatment period, more women in the antibiotic group tested positive for bacteria that were resistant to one or more antibiotics. But in the 6 months after treatment had finished, more women in the methenamine group tested positive for resistant bacteria. This unexpected (secondary) finding could be because women on methenamine received more short-course antibiotics after the study finished. More research is needed to determine whether methenamine reduces antibiotic resistance.

In 2023 the UK National Institute for Health and Care Research concluded in a published paper discussing the ALTAR trial that the results have led to an ongoing review by the National Institute for Health and Care Excellence (NICE) in the UK on whether methenamine can be offered to women with recurrent urinary tract infections. The researchers say that guidelines, such as European Association of Urology Urological Infections Guidelines, could be updated to include methenamine as an option for preventing recurrent infections. This study, along with the NICE review, will allow clinicians and patients to make shared decisions and consider using methenamine rather than antibiotics.

What issues are there with bladder instillations?

  • There are no large randomised control studies to demonstrate long term efficacy for the management of chronic urinary tract infections using bladder instillations.
  • Studies relating to patients without neurogenic bladder problems or those who have undergone renal surgery focus on the replenishment of the GAG layer in the bladder. The European Urological Association noted:“A recent review of 27 clinical studies concluded that large-scale trials are urgently needed to assess the benefit of this type of therapy. Therefore, no general recommendation is possible at this stage”. This Cochrane Review published in 2016 confirms these findings.
  • There are no standardised treatment regimes – instillations in trials have been offered daily for a week, every third day or once a week
  • Antibiotics used in instillations are often generic medications (rather than those that are exclusively patented) thus no pharmaceutical manufacturing company has carried out its own trials on generic antibiotics used in instillations. This means that clinicians often have to develop their own treatment regimes – you may come across the words “rescue instills” which can include not only an antibiotic but also a steroid and gag layer replenishment agent.
  • It is invasive which makes it logistically awkward and adds to the treatment expense offered to patients by local clinical commissioning groups and hospitals
  • The usage of catheters may introduce further bacteria into an infected bladder

D Mannose further reading and references

Further reading:

Adhesive Pili in UTI Pathogenesis and Drug Development Spaulding CN, Hultgren SJ. Adhesive Pili in UTI Pathogenesis and Drug Development. Pathogens. 2016;5(1):30. Published 2016 Mar 15. doi:10.3390/pathogens5010030

D-Mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial Altarac, S. and Papeš, D. World J Urol. 2014 Feb;32(1):79-84. doi: 10.1007/s00345-013-1091-6. Epub 2013 Apr 30.

D-mannose: a promising support for acute urinary tract infections in women. A pilot study Domenici L, Monti M, Bracchi C, Giorgini M, Colagiovanni V, Muzii L, Benedetti Panici P. Eur Rev Med Pharmacol Sci. 2016 Jul;20(13):2920-5.

Oral D-mannose in recurrent urinary tract infections in women: a pilot study Porru, Daniele & Parmigiani, A. & Barletta, Davide & Choussos, D. & Bassi, Silvia & Miller, O. & Gardella, Barbara & Nappi, Rossella & Spinillo, A. & Rovereto, B.. (2013). European Urology Supplements. 12. e894-e895. 10.1016/S1569-9056(13)61373-1.

The efficacy of D-mannose in the prevention of recurrent urinary tract infections compared to long- term antibiotic therapy Stompro, Kristine. (2017).

Use of D‐mannose in prophylaxis of recurrent urinary tract infections (UTIs) in womenAltarac, S. and Papeš, D. (2014), Comment. BJU Int, 113: 9-10. doi:10.1111/bju.12492

References:

1. Foxman B. Urinary tract infection syndromes: Occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect. Dis. Clin. N. Am. 2014;28:1–13. doi: 10.1016/j.idc.2013.09.003.

Griebling T.L. Urinary tract infection in women. In: Litwin M.S., Saigal C.S., editors. Urologic Diseases in Amerca. U.S. Government Printing Office; Washington, DC, USA: 2007. pp. 587–620.

Flores-Mireles A.L., Walker J.N., Caparon M., Hultgren S.J. Urinary tract infections: epidemiology, mechanims of infection and treatment options. Nat. Rev. Microbiol. 2015;13:269–284. doi: 10.1038/nrmicro3432.

2. Adhesive Pili in UTI Pathogenesis and Drug Development Caitlin N. Spaulding and Scott J. Hultgren Pathogens. 2016 Mar; 5(1): 30.

How to use D Mannose

  • Take a half to one teaspoon of D-mannose in no more than half of a glass of water. Then wait for about 45 mins to an hour. After that, drink plenty of water. Once the D-mannose has been absorbed into the bloodstream and flushed through the kidneys, this will concentrate the D-mannose in your urine allowing it to bind to the UPEC bacteria. Continue this every two to three hours for up to five days.
  • Only use D-mannose at the very beginning of symptoms. If symptoms have not diminished or completely disappeared after a short period, do not wait any longer and go to the doctor. A full-blown UTI might benefit from D-Mannose supplementation, but there is a risk that bacteria are growing at a faster rate than can be cleared through D-mannose especially if the bacteria are resistant to it. Remember, D-mannose only works for UTIs caused by E. coli bacteria.  A delay in seeking treatment if symptoms worsen or do not significantly improve can result in worsening the infection leading to possible kidney infection or at worse sepsis.
  • If antibiotics are prescribed, supplementing with D-mannose could be an option to speed up recovery, but do not stop the antibiotic treatment to switch to D-mannose. A course of antibiotics should always be completed unless side effects are experienced and a medical professional advises cessation.
  • Some find it beneficial to follow up a flare up or acute attack by taking a preventive D-mannose dose daily. This is usually one teaspoon 2-3 times daily. Consider taking D-mannose every time you think your vaginal flora or immune system are compromised (with the first signs of a yeast infection, after sex, illness etc.).
  • Take the DM away from any acidic food or drink as it will counteract its effects and the urine must be kept alkaline. This includes the use of Hiprex, a urinary antiseptic which is activated when urine is very concentrated and acidic. Gram-negative bacteria such as e coli reproduce more slowly in an alkaline environment allowing for the potential of greater attachment to the D-mannose molecules in your urine.
  • Initial usage of D-mannose can lead to loose stools for a few days.  If diarrhoea continues, consult with your specialist as to continued usage.  Users also report gas and bloating as other side effects.  It may potentially exacerbate symptoms for those with small intestinal bowel overgrowth (SIBO).  If this applies to you consider adjusting your dosage or discuss its usage with your consultant.

Urine Test References

(i) O’Brien K, Hillier S, Simpson S, et al. An Observational Study of Empirical Antibiotics for Adult Women with Uncomplicated UTI in General Practice. J Antimicrob Chemother 2007; 59(6): 1200–1203.

Little P, Merriman R, Turner S, et al. Presentation, pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic resistance among patients presenting with suspected Uncomplicated urinary tract infection in primary care: observational study. BMJ 2010; 340: b5633.

McIsaac WJ, Low DE, Biringer A, et al. The impact of empirical management of acute cystitis on unnecessary antibiotic use. Arch Intern Med 2002; 162(5): 600–605.

Nazareth I, King M. Decision making by general practitioners in diagnosis and management of lower urinary tract symptoms in women. BMJ 1993; 306(6885): 1103–1106.

Vellinga A, Cormican M, Hanahoe B, et al. Antimicrobial management and appropriateness of treatment of urinary tract infection in general practice in Ireland. BMC Fam Pract 2011; 12(1): 108.

(ii) Kass, E.H. Asymptomatic infections of the urinary tract. Transactions of the Association of American Physicians Volume 69, 1956, Pages 56-64

(ii) Kass EH. Bacteriuria and pyelonephritis of pregnancy. Arch. Intern. Med. 105, 194–198 (1960).

(iii) Paul C. Schreckenberger, Travis K. Price, Evann E. Hilt, Tanaka Dune, Cynthia Brincat, Linda Brubaker, Elizabeth R. Mueller, Alan J. Wolfe. Detecting clinically relevant micro-organisms: we can do better 2015

(iii) Evann E. Hilt, Kathleen McKinley, Meghan M. Pearce, Amy B. Rosenfeld, Michael J. Zilliox, Elizabeth R. Mueller, Linda Brubaker, Xiaowu Gai, Alan J. Wolfe, Paul C. Schreckenberger, Urine is Not Sterile: Use of Enhanced Urine Culture Techniques to Detect Resident Bacterial Flora in the Adult Female Bladder. Journal of Clinical Microbiology. 2014 52(3):871-6

(iii) Natasha Curtissa, Aswini Balachandrana, Louise Krskab, Claire Peppiatt-Wildmanb, Scott Wildmanb, Jonathan Ducketta, A case control study examining the bladder microbiome. 2017

(iii) Lisa Karstens, Mark Asquith, Sean Davin, Patrick Stauffer, Damien Fair, W.Thomas Gregory, James T.Rosenbaum, Shannon K.McWeeney and Rahel Nardos. Does the Urinary Microbiome Play a Role in Urgency Urinary Incontinence and its Severity? 2016

(iii) Ahmed Moustafa, Harinder Singh, Weizhong Li, Kelvin J. Moncera, Manolito G. Torralba, Yanbao Yu, Oriol Manuel, William Biggs, J. Craig Venter, Karen E. Nelson, Rembert Pieper, Amalio Telenti. Microbial Metagenome of Urinary Tract Infection. 2017

(iii) Marcus J. Drake, Nicola Morris, Apostolos Apostolidis, Mohammad S. Rahnama and Julian R. Marchesi. The Urinary Microbiome and its Contribution to LUTS. 2015

(iii) Travis K. Price, Tanaka Dune, Evann E. Hilt, Krystal J. Thomas-White, Stephanie Kliethermes, Cynthia Brincat, Linda Brubaker, Alan J. Wolfe, Elizabeth R.Mueller, and Paul C. Schreckenberger. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Micro-organisms. Journal of Clinical Microbiology. May, 2016

(iv) Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK. Diagnosis of coliform infection in acutely dysuric women. N. Engl. J. Med. 307(8), 463–468 (1982).

(iv) Latham RH, Stamm WE. Urethral syndrome in women. Urol. Clin. North Am. 11(1), 95–101 (1984).

(v) Sathiananthamoorthy S, et al J. Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection. 2018, J. Clin. Microbiol., doi:10.1128/JCM.01452-18

(vi) Dukes C., Some Observations on Pyuria. Proc R Soc Med 1928; 21: 1179–83

(vii) Forte Medical FOI Request April 2016 to each UK NHS Hospital Trust

(viii) https://www.wyevalley.nhs.uk/visitors-and-patients/county-hospital-(acute)/a-z-departments/pathology.aspx

(x) Kupelian AS, Horsley H, Khasriya R, Amussah RT, Badiani R, Courtney AM, Chandhyoke NS, Riaz U, Savlani K, Moledina M, Montes S, O’Connor D, Visavadia R, Kelsey M, Rohn JL, Malone-Lee J. Discrediting microscopic pyuria and leucocyte esterase as diagnostic surrogates for infection in patients with lower urinary tract symptoms: Results from a clinical and laboratory evaluation. BJU International 2013

Rabinovitch A. Urinalysis and collection, transportation, and preservation of urine specimens: approved guideline. 2d ed. Wayne, Pa.: National Committee for Clinical Laboratory Standards, 2001. NCCLS document GP16-A2.

Urine culture – the case against

These research studies have been challenged for the following reasons

  • The usage and study of pregnant women with acute kidney infections rather than those suffering from lower urinary tract infections of the bladder and urethra. Kass’s test was never, in its creation, validated for use in lower urinary tract infections for the bladder or urethra.  But it has been readily adopted globally for all infections of the urinary and renal tracts and has not been revised or updated since the 1950s.
  • Kass’s belief that the normal bladder is sterile and bacteria introduced via the urethra are the cause of infection. Researchers have refuted that belief in recent years now more is understood about the urinary microbiome (the community of microbes in the urinary tract). Read more about the urinary microbiome. Are infections solely attributable to bacteria and in particular one bacteria introduced into the bladder?  What part do viruses, fungi or other microbes in this urinary soup play?
  • Kass also noted that sufferers of a UTI tend to over-dilute their urine by drinking too much water. This means that any sample is not sufficiently concentrated to identify the growth of a single bacterial species let alone multiple infection causing bacteria.
  • The failure to recognise polymicrobial infections in Kass’s research (an infection comprising of one or more bacteria) with his belief that the urinary tract infection is caused by a single bacteria. Because of this, samples with multiple organisms or lactobacillus are labelled as ‘contaminated’ or ‘mixed growth’ as it is assumed that these bacteria came from other sources. In reality, these bacteria are not contaminants and may well be contributors to the infection, as in some cases infections can be polymicrobial.
  • The culture numbers are likely to depend on the ease of growth of bacteria in a laboratory. Bacterial species react differently to an oxygenated environment. The bacteria residing in your bladder have a limited oxygen source but when a urine sample is placed on a petri dish in the laboratory, the oxygen they are exposed to increases. This means that bacteria which flourish beneficially in this type of environment will grow. An example of this is E-coli whereas those that prefer the ecosystem and oxygen levels of the bladder will grow in limited numbers and are often dismissed as contamination.
  • The standard urine culture also does not pick up on viral or fungal causes of infection, which have been proven to be the cause for certain symptomatic patients with negative culture tests, even in patients that are not immunocompromised.
  • The E. coli focused design of a standard culture could explain our current E. coli centric view of UTI we have today, since so many other organisms remain undetected. Indeed in one study that analysed 157,000 urine samples using a different technology, E.coli was the dominant species in only 28% of cases.

 

Dipsticks – the case against

  • The use of any existing antibiotics will reduce bacterial growth leading to no evidence of infection on dip
  • Drinking too much liquid before providing a sample thus diluting it.
  • The dipsticks are calibrated to detect white blood cells counts of >10 5 (100,000) bacteria per millilitre of urine or greater. For someone with a bacterial infections lower than this cut off range, the dipstick will report a false negative.
  • Bacteria require a minimum of four hours to reduce the nitrate in urine to nitrites. Not all bacteria responsible for UTIs contain nitrite reductase, the enzyme responsible for this conversion. Examples of Nitrite reducing bacteria including E-coli, Proteus and Klebsiella. But if your infection is caused by Enterococcus or Pseudomonas, this enzyme conversion will not occur.
  • Various chemicals can also interfere with urine dipstick analysis. Some chemicals that may cause false-negative results include ascorbic acid (such as vitamin C) and oxalic acid (an organic compound found in many plants such as leafy greens, vegetables, fruits, cocoa, nuts and seeds).
  • Biofilm or embedded bladder wall infections mean that the bacteria are embedded and hidden away from the urine, not floating in it. When you urinate, the bacteria will not transfer into the sample pot resulting in lack of detection on a dipstick.

Fresh urine microscopy more information

A sample of fresh urine taken at the clinic is dropped onto a plate for immediate analysis under a microscope.

White blood cells and epithelial cells are counted as markers of an infection.

When infection occurs in the urinary tract, the immune system tries to remove infected cells by shedding the cells in the bladder lining (the epithelium) to be excreted during urination – these are known as epithelial cells.

A high white blood cell count usually indicates that the body is fighting an infection. White blood cells rush in to help destroy the harmful substance and prevent the infection developing further as part of the immune system response to pathogenic bacteria.

The need for immediate analysis of a urine sample is because white blood cells degrade very quickly. Studies have shown this occurs in as little as four hours unless collected in an appropriate sample bottle containing a boric acid preservative.  A sample sent for analysis at the laboratory may not identify sufficient or any white blood cells if there is a delay in the delivery and analysis within a four hour period or urine collection does not involve a sample container that utilises boric acid to help preservation.