Who Can Benefit From Bladder Instillations?

There are different definitions of chronic/recurrent urinary tract infections (rUTIs) but the most established definition is having at least three episodes of UTI with a documented number of bacteria being over 1000 CFUs (colony forming units) per ml of urine (1).  The rate of recurrences is high.  After just one UTI, more than 25 percent of women will have a repeat infection within 3-6 months.  At least 15 percent of all prescriptions given to outpatients are for the treatment of UTI. 

Because UTIs are so common, particularly in women, and because they are so expensive to treat, there is a need to consider therapies that will reduce the incidence of UTIs. The traditional method has been to use chronic low-dose antibiotic therapy as a form of chronic suppression of bacterial growth.  The biggest problem is that this practice encourages bacterial resistances and creates “superbugs” that become difficult to treat, not to mention suppressing the growth of beneficial bacteria. For this reason, researchers are looking for ways to prevent UTIs that don’t involve antibiotic therapy at all. 

The bladder has several defense mechanisms by itself to resist bacterial infection. The inside layer of the bladder has cells that are connected tightly to one another so as to prevent bacteria from invading the bladder lining. There is a glycosaminoglycan layer that prevents bacterial invasion inside the bladder. The urine has a low pH that inhibits the proliferation of bacteria. Therefore, every time a healthy person urinates, they also flush out the bladder and prevent infections. 

Some researchers have suspected that problems with the GAG (glycosaminoglycan) layer are linked to UTIs. Later on, we will talk about using hyaluronic acid and chondroitin sulfate (4), which are components of the GAG layer as an instillation into the bladder to reduce UTI rates. Currently, instillation with hyaluronic acid and chondroitin sulfate are used successfully for painful bladder syndrome and bladder inflammation. Heparin (a blood thinner) has also been used to treat painful bladder syndrome (2).

Bladder instillation, also called bladder wash or bladder bath, is a process of filling the bladder via a catheter with a cocktail of medicines, holding these medicines in the bladder for 10-60 minutes and then peeing all out naturally.

Some researchers have considered using heparin for recurrent UTIs, with the idea that it builds up the GAG layer, preventing bacteria from taking hold (2).  Heparin is cheap, readily available, and makes up about 15 percent of the human GAG layer.  It has a strong negative electrical charge, which may prevent adherence of bacteria. Heparin also has a down-regulating effect on inflammation. 

Heparin Instillations

This research study (2) looked at 18 women who had a history of recurrent UTIs and who were resistant to conservative antibiotic therapies. They were given instillations inside the bladder of heparin (40,000 Units) plus bicarbonate and lidocaine. Each woman had once weekly instillations for a total of six weeks, needing to hold the heparin inside the bladder for one hour before voiding. If they complained of symptoms before or after the treatments they received urinalysis and urine cultures to see if they really had an infection. Patients with positive cultures received antibiotics.

Patients who received heparin instillations were felt to respond positively to treatment if they had a 50 percent or greater reduction in the rate of infection after the instillation therapy. Of the 18 women in the study, 13 (78 percent) responded to therapy with a fifty percent reduction in UTIs after therapy. Of those that didn’t respond, these women had 4.6 UTIs within the 6 months prior to instillation, compared to 4.2 UTIs in women who did respond.  Non-responders had 3 infections in the six months after instillation therapy, versus 0.6 infections on average in responders after treatment.

So, what did the study show? Heparin instillations were given to the toughest-to-treat patients in the study—women who had frequent UTIs unresponsive to other therapies. This is just 5 percent of all UTI patients. Even so, 78 percent of the woman responded with a significant reduction in UTIs after heparin instillation into the bladder. When all of the women were clumped together, the infection rate went from 4.4 in the six months before treatment to 1.1 infections in the six months after treatment. 

It all seems to be related to the GAG layer, which prevents bacterial adherence. GAGs will stimulate the immune system by promoting the movement and activation of bacterial-killing white blood cells in inflamed bladder tissue. The GAG layer also adds to the chemical activators of the immune system so the bladder can resist infection. This may be why the treatment lasts for several months after treatment.

A Second Research Study on Heparin Instillations

Another research group wanted to study the effect of “intravesical”—inside the bladder—instillations with heparin to treat patients with chronic UTIs. This study (3) was published in February of 2018. They looked at patients with both chronic UTIs and recurrent UTIs. The women had the frequency of their UTIs studied during and for six months after treatment with heparin instillations.

This time, 39 women have treated with heparin intravesical installations for their recurrent/chronic UTIs. They received weekly instillations for six weeks (which were completed by 85 percent of women). A total of 69 percent when onto a “maintenance phase”. After six months, 46 percent had at least 1 UTI with only 18 percent of women having recurrent UTIs (more than 1 UTI in a six-month period. 

The basic idea was the same. Heparin is cheap and widely available; it is believed to restore the GAG layer in the inner lining of the bladder and is thought to be helpful in patients who have interstitial cystitis (also called bladder pain syndrome). The same or similar problem with the GAG layer is thought to lead to recurrent UTIs. 

The women in this study received just 10,000 units of heparin, which was mixed with lidocaine, solumedrol, and sterile water. The rest of the protocol was the same as with the previous study.  The solution was kept in the bladder for an hour after receiving the instillation.  The researchers were a little stricter on the definition of UTI, requiring cultures of greater than 100,000 CFU per ml to have a UTI.

Of the 39 patients, 69 percent had maintenance instillations every two weeks after the initial six instillations. Twelve patients (31 percent) had a culture-proven UTI during the treatment phase. About 46 percent had at least one UTI after the treatment course. About 18 percent of patients had at least two UTIs after treatment. In this study, 54 percent of recurrent UTI patients had no UTIs after instillation therapy.

So, what was wrong with this study? Unlike the first study, they didn’t check the UTI rate in the women before getting instillation therapy so it’s difficult to know if the treatment actually worked.  Most importantly, they didn’t use a control group (randomized or double-blinded). What if instilling anything in the bladder makes a difference? Maybe there’s a placebo effect? These are questions only answerable with a control group.  The first study didn’t use a control but measured the UTI rate before and after heparin instillation and used more heparin in the instillation so this may be why they had better results.

Intravesicular Instillation of Hyaluronic Acid and Chondroitin Sulfate

This study looked at instilling hyaluronic acid (HA) and chondroitin sulfate (CS) in the bladders of women with recurrent bacterial bladder infections (4). They wanted to know if this treatment plan worked better than low-dose antibiotic therapy for women who had at least 2 UTIs within the previous six months. HA and CS are part of the glycosaminoglycan (GAG) layer in the epithelium (inner lining layer) of the bladder. A good GAG layer prevents adherence of bacteria and toxins onto the bladder wall. A damaged GAG layer, on the other hand, causes bacterial adherence and infection. (Next: Read about supplements that help restore bladder lining).

Patients who were included in the study were those women who had at least three UTIs within the previous year. A positive culture involved those having 1000 CFUs of a single uropathogen in the urine. The “experimental” group got hyaluronic acid and chondroitin sulfate in 50 ccs of water with a culture performed three days before instillation. If a woman got a UTI during treatment, the instillations were delayed until the urine culture was negative. They retained the fluid for at least 2 hours before voiding. Each woman got weekly instillations for a month and then monthly instillations for 4 months.

This study had a “control” group who didn’t receive any instillations for their recurrent cystitis but instead got Bactrim (trimethoprim/sulfamethoxazole) for six weeks. The outpatient visits were done at one month, three months, six months, and a year after the end of treatment.

So, what happened? A total of 98 women got instillations and 76 women stayed on Bactrim as a preventative against UTIs. While the previous two studies involved mainly women in the 50-70-year age group, the mean age of these women were just 35 years. During the 12 months after the treatment, 69 UTIs were detected in the instillation group with 109 episodes discovered in the control group. Most patients had E. coli (at 69 percent) and Klebsiella (28 percent).

More patients in the experimental/installation group had one recurrence, while more people in the control group had 2 or 3 recurrences. Thirteen women in the control group had 3 UTIs in the next year with only 2 women had 3 UTIs in the next year after treatment. The conclusion was that HA and CS intravesical instillation was better than having prophylactic antibiotics. About 37 percent of the women who received instillations had no UTI episodes within a year after receiving their HA and CS.  Only 21 percent of women on antibiotic prophylaxis could say they didn’t have any UTIs within a year of starting therapy.

The major downside of this research study is that there isn’t the same availability of hyaluronic acid and chondroitin sulfate in the United States when compared to Europe. This means that, while this appears to be good therapy, women with recurrent UTIs in the US can’t use this treatment. In addition, the study that used 10,000 units of heparin wasn’t nearly as good as the study that used 40,000 units of heparin.  Not only was the study design better in the first study, but the results were better.

Not every woman has the availability of a urologist that will do these instillations as they are still being investigated. Women really wanting instillation therapy may need to join a clinical trial that uses heparin or the combination of hyaluronic acid and chondroitin sulfate (as this isn’t approved in the US except for clinical trials). Even so, this is promising research that indicates the GAG layer is probably much more important in preventing bacterial adhesion and infection than previously thought.  The added bonus is that instillation therapy won’t add to the large burden of resistant organisms that come out of taking prophylactic antibiotics.

Antibiotic Instillations for Recurrent UTIs

There are surprisingly few studies on instilling actual antibiotics for recurrent UTIs. One study (5) looked at eighteen women who had recurrent UTIs and taught them how to catheterize themselves.  They instilled an antibiotic called gentamicin into their bladders. The women placed 30 ml of the antibiotic solution into the bladder once a day for the first week, 4 times per week for the second week, and then 3 times per week (Monday, Wednesday, Friday) during the following 6 weeks, completing 2 months of regular bladder instillations.

The most common recurrent bacterial organism each woman had was Escherichia coli (6 women), followed by Klebsiella (5 women), and Enterococcus (2 women). Five women had infections caused by multiple organisms. All of the organisms were sensitive to gentamicin.

Of the 18 women who received treatment with the gentamicin sulfate solution, 12 had no other documented UTI, and 3 were lost to follow-up. The 3 other women had a poor outcome, with ongoing recurrences of UTIs associated with E. coli in 1 patient and mixed flora in the other 2 patients. Of these 3 women, 2 had radiographically demonstrated urologic abnormalities (multiple bilateral renal calculi and bilateral hydronephrosis) at the time of treatment.

So, what does this mean? If you’re willing to catheterize yourself frequently to instill gentamicin (it can’t be given orally), then it might work for you if you don’t tolerate oral antibiotic prophylaxis. The only women for whom it didn’t work were those who had some type of structural urologic abnormality. Gentamicin is readily available and if you can find a urologist to teach you to self-catheterize and will prescribe you gentamicin it may be the best treatment for you without a huge risk of resistance.

References

1. Albert X, et al. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. 2003; Cochrane Database Syst Rev 3: CD001209.
2. Ablove T, et al. Prevention of recurrent urinary tract infections by intravesical administration of heparin: a pilot study. Ther Adv Urol. 2013 Dec; 5(6): 303–309.
3. Dutta S, Lane F. Intravesical instillations for the treatment of refractory recurrent urinary tract infections. Ther Adv Urol. 2018 Feb; 10(5): 157-163.
4. Gugliotta G, et al. Is intravesical instillation of hyaluronic acid and chondroitin sulfate useful in preventing recurrent bacterial cystitis? A multicenter case-control analysis. Taiwanese Journal of Obstetrics and Gynecology. 2015 Oct; 54(5): 537-540.
5. Arap M, et al. Efficacy of Intermittent Intravesical Gentamicin Sulfate Solution for Recalcitrant Recurrent Cystitis in Women. https://www.medscape.com/viewarticle/458850_2.  Accessed 7/19/2018.