11. Intravesical Therapies
Antibiotic intravesical instillations can be used in the prevention of UTIs. The use of gentamicin, neomycin/polymyxin, neomycin and colistin has been reported in literature.
Non-antimicrobial instillations, such as Cystistat ®or laluril ®, restores the bladder glycosaminoglycans (GAG) layer and can be used in UTI prophylaxis.
Intravesical therapies bypasses the oral or intravenous route and thus minimises systemic side effects.
The main limitations of intravesical therapy is that administration requires a course of in/out urinary catheterisation, which is invasive in nature and causes discomfort and its administration needs to be done in an outpatient clinical setting by a trained healthcare professional.
Intravesical therapy is a localised treatment where a liquid drug is administered directly into the bladder via a urinary catheter, bypassing the oral or intravenous route and thus minimising side effects, as its effect is solely limited to the bladder where it needs to act. Intravesical therapies are already widely used in clinical practice as an adjuvant additional treatment for non-muscle invasive bladder cancer, following surgical endoscopic resection. In recent years, intravesical therapy has also been used to in the treatment of chronic cystitis and prophylactic treatment for recurrent UTIs. This involves either intravesical antibiotic irrigation or instillations of Cystistat® or Ialuril® to restore the bladder glycosaminoglycans (GAG) layer.
11.2 The Procedure Itself
Intravesical therapy involves urinary catheterisation into the bladder using a local anaesthetic lubricating gel. Once inserted and the bladder is emptied, the catheter can then be used to administer a liquid drug formulation directly to the bladder. After this, the catheter is removed and the patient is advised to refrain from passing urine in the next hour or so, to allow the medication enough time in the bladder to have an optimal effect.
Depending on the type of intravesical instillation agents and the underlying causes of recurrent UTIs, the frequency of treatments may vary.
Generally, the initial treatment regimen is once a week for 4 weeks, then every 2 weeks for two treatments. After this time, treatments are usually given once a month until patient’s symptoms resolve, with a whole course lasting up to 6 months, or even 12 depending on local policies.
11.3 Intravesical Antibiotics (IVA)
Intravesical antibiotics (IVA) have been used for prophylaxis and treatment of recurrent UTIs since the 1960s, however there is still a lack of comprehensive evidence and consensus on its use.
11.4 Clinical Evidence
A recent 2018 review investigated the efficacy of IVA. They identified 285 patients in 11 clinical studies who received IVA either as treatment or as prophylaxis for UTIs.
The authors reported that the antibiotics used were mainly gentamicin, but also neomycin/polymyxin, neomycin or colistin. Furthermore, 78.2% (n = 223) of participants who underwent the antimicrobial instillation showed a beneficial response with reduction of symptomatic UTI, with success seen over 3–6 months in both the treatment (88% success) and prophylaxis (71% success) group.
Interestingly, the sensitivities of the organisms in the bladder also changed with IVA—either the multi-resistant organism was eradicated or antibiotics the bacteria were previously resistance to have now become effective and the bacteria has developed sensitivities. This occurred both in the treatment group (30% changed sensitivities) and prophylaxis group (23% changed sensitivities).
Importantly there were minimal side effects reported, with discontinuation rates of 5% and 8% in the treatment and prophylaxis group respectively. Gentamicin IVA patients had the lowest discontinuation rates of all the antibiotics.
Interestingly, the majority of patients had indwelling catheters, does intermittent self-catheterisation or had neurogenic bladders. This suggests IVA may be an effective treatment option in complex recurrent UTIs. Furthermore, the patient already knowing self-catheterisation or has an indwelling catheter may eventually mean the more able patients may be able to self-administer this treatment at home once taught and supervised initially.
11.5 Non-antibiotic Instillations (GAG Layer Replacement)
In a healthy bladder there is a natural barrier, called the glycosaminoglycan (GAG) layer, which protects the bladder lining epithelial cells from the urine, preventing bacterial adherence. If GAG layer is damaged, urine comes into direct contact with the bladder epithelial cells. Over time this causes irritation and inflammation, which result in urinary symptoms such as pain, urgency and frequency, and increases the risk of infections due to easier bacterial adhesion and invasion.
One option to repair this damaged layer is instillations of Hyaluronic Acid (HA) or Chondroitin Sulphate (CS) via a catheter. Upon instillation, patients hold the treatments within their bladders for 2 hours before passing the urine/bladder instillation out and recommencing normal daily activities.
11.6 Clinical Evidence
HA +/− CS intravesical instillations have been shown to lower rates of UTI recurrence and increase duration of UTI-free time between acute attacks. Small studies have found intravesical therapies reduced cystitis recurrence when compared against antibiotics [1, 2], and placebo .
A larger European retrospective study in 276 women compared intravesical GAG replacement to “standard therapy”. This was defined as antibiotic prophylaxis, cranberry or probiotics. A 49% reduction in UTI risk was found in the 12-month follow up, with effectiveness correlating with increasing numbers of instillations. A bacterial recurrence odds ratio of 0.81 was found in patients who underwent five or more instillations. If the patient had seven or more instillations, this dropped to 0.63 .
Cystistat® (Bioniche Life Sciences Inc., Belleville, Ontario, Canada) and Ialuril® (Aspire Pharma, UK) are a couple of commercially available HA + CS instillation options. Both have shown effectiveness in lowering rates of recurrent UTIs with minimal side effects.
Overall, the strength of the current evidence is limited by the small sample size in these studies. For this reason, the current EAU guidelines do not have any recommendation on GAG replacement and more large-scale trials and clinical data are required on this front.
11.7 Limitation of Intravesical Therapies
The main constraints for intravesical therapies are the need for in/out urinary catheters, an invasive process that can cause discomfort. Furthermore patients cannot self-medicate at home, rather the patient is required to regularly attend the specialist outpatient clinic where a trained healthcare professional is required to deliver this treatment.
Interestingly, Ialuril has recently developed a “catheter free” delivery method, which is a prefilled syringe with a unique adaptor that allows the reagent to be injected directly into the bladder to administer treatment without the need for a catheter. The process is very similar to injected Instillagel (a local lubricant anaesthetic) prior to a cystoscopy or catheterisation into the urethra. We eagerly await further clinical trials on this new delivery device and whether its use is taken up into routine clinical practice and negates the above limitations.