Clinical trial NCT06387329: Bladder Botox UTI Antibiotic Prophylaxis
Official title: Urinary Tract Infection Prophylaxis In Intradetrusor OnabotulinumtoxinA Procedures: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Overactive Bladder
Bladder Pain Syndrome
Keywords: Intradetrusor Onabotulinumtoxin A
Urinary tract infection
Antibiotic prophylaxis
Lead sponsor: Walter Reed National Military Medical Center
Sponsor class: FED
First posted: 2024-04-29
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Nonblinded, randomized, noninferiority trial of single dose nitrofurantoin vs 3 day twice daily course of nitrofurantoin for prevention of post-procedure urinary tract infections after intradetrusor onabotulinumtoxinA injections for OAB and IC/BPS.
Primary purpose: PREVENTION

Brief summary: Overactive bladder (OAB) is a common condition with a prevalence of 17% in the general population that significantly affects quality of life. Intradetrusor onabotulinumtoxinA injections are an advanced therapy for OAB as well as interstitial cystitis/bladder pain syndrome (IC/BPS). The most common adverse event following intradetrusor injection of onabotulinumtoxinA in urinary tract infection (UTI), which occurs in 8.6-48.1% of patients. To prevent UTIs, patients are given a course of antibiotics, however the ideal prophylactic regimen has not been determined for the timing, duration, and type of antibiotic. Four retrospective studies in the literature address this question with variable conclusions, and there are no prospective studies. Identifying the ideal regimen is important for preventing UTIs as well as minimizing antibiotic use to prevent adverse effects and development of antibiotic resistance.

The population to be studied will be female patients 18 years and older who are patients of the urogynecology and urology clinics at Walter Reed National Military Medical Center with a diagnosis of OAB or IC/BPS and have chosen to be treated with intradetrusor onabotulinumtoxinA injections. It will be a non-blinded randomized controlled noninferiority trial in which the patients are randomly placed into 2 groups. The first group will receive a 3 day course of twice daily oral nitrofurantoin 100mg starting at the time of the procedure, and the second group will receive a single dose of 100mg oral nitrofurantoin at the time of the procedure.

The patients will be screened at the clinic at the time that they schedule their intradetrusor onabotulinumtoxinA injection appointment or by phone 1-2 weeks prior to their procedure. If the patient agrees to participate in the study then they will be instructed to give a urine sample for urinalysis and culture 1 week prior to the procedure appointment to exclude existing UTI. If a UTI is diagnosed at this time they must complete treatment prior to the procedure or will need to reschedule their procedure. On the day of the procedure patients will receive the clinic standard 10ml of 2% viscous lidocaine through the urethra 10-20 minutes prior to the procedure, and may be offered 5-10mg oral diazepam at the discretion of the treating physician. All patients will be given 200mg of phenazopyridine and 100mg of nitrofurantoin prior to the initiation of the procedure. The procedure will take place as directed by the treating physician per standard operating procedure.

A urinalysis and urine culture will be placed for all study participants at time of their procedure appointment in case they have symptoms of UTI, and they will be instructed to follow up with the research team by phone if they have concerns for a UTI. Patients will be contacted 30-45 days after the procedure by phone, email, or message through genesis and asked about any UTI symptoms, UTI diagnoses and secondary outcomes during the 30 days following the procedure. Data will be analyzed for the primary outcome of UTI rates in the 30 days following intradetrusor onabotulinumtoxinA injection.

Detailed description: Overactive bladder (OAB) is a common condition with a prevalence of 17% in the general population that significantly affects quality of life (1). It is characterized by urinary urgency, urinary frequency as well as nocturia in the absence of infection or other proven pathology. Approximately a third of patients with OAB also experience incontinence with urgency while the remaining two thirds do not experience incontinence. Average annual per capita costs estimated to be around $80 billion (2). First line treatment is behavioral and lifestyle modifications along with pelvic floor strengthening. Oral medications are considered second line treatment. Of patients that initiate oral pharmacotherapy, less than 50% will remain on it by one year after initiation due to lack of efficacy, inability to tolerate side effects or other reasons. Many patients will go on to advanced treatment options, such as neuromodulation or onabotulinumtoxinA (Botox®, Allergan Inc.) (3-6). A large body of evidence has demonstrated the efficacy of onabotulinumtoxinA for treatment of both idiopathic and neurogenic OAB and it has increasingly become the advanced therapy of choice for OAB by clinicians and patients (7-20). In 2013 onabotulinumtoxinA was approved by the FDA for treatment of both idiopathic and neurogenic OAB. OnabotulinumtoxinA is also commonly used to treat urinary urgency and frequency in interstitial cystitis/bladder pain syndrome (IC/BPS).

Urinary tract infection (UTI) is a well-documented adverse event following intradetrusor injection of onabotulinumtoxinA. Prior studies have demonstrated that UTI occurs in 8.6% - 48.1% of patients, for which data was collected for between 1 and 6 months after the procedure (7-9, 12, 13, 21-24). The package insert states that "oral prophylactic antibiotics, except aminoglycosides, should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI" (25). However, this recommendation is supported by little evidence as few studies have addressed antibiotic prophylaxis for intradetrusor onabotulinumtoxinA procedures. Furthermore, the American Urological Association best practice recommendations state that in cystourethroscopy procedures with minor break in mucosal barriers such as with biopsy or fulguration it is uncertain whether UTI prophylaxis is required, however if given, then a single dose of antibiotics is recommended (26). In practice, urologists and urogynecologists have a wide range of regimens used for UTI prophylaxis with timing ranging from starting before the procedure or initiated at the time of the procedure, variable duration ranging from 1 to 7 days, and choice of antibiotic including nitrofurantoin, trimethoprim-sulfamethoxazole, ciprofloxacin, amoxicillin/clavulanate, and others.

Four retrospective studies have evaluated variable antibiotic regimens for intradetrusor onabotulinumtoxinA injection procedures and rate of UTIs. Martin, et al. studied 290 patients undergoing 896 injections of intradetrusor onabotulinumtoxinA receiving either no antibiotics, a single day of antibiotics, or a multi-day course of antibiotics (21). Antibiotics used included ciprofloxacin (64.4%), sulfamethoxazole-trimethoprim (15.1%), nitrofurantoin (10.6%), and cephalexin (5.6%). The primary outcome was UTI within 30 days by culture, or by empiric treatment with improvement in symptoms. The overall UTI rate was 11.4%. With no prophylaxis it was 23.2%, with single day prophylaxis it was 8.6%, and with multi day prophylaxis it was 13.2%. Use of any antibiotic was significantly associated with a lower risk of UTI (OR 0.34, P\<.001), but there was no significant difference between groups (23).

Bickhaus, et al. retrospectively reviewed 2 cohorts of patients (n=111), one of which received ciprofloxacin for 1-3 days starting at the time of the procedure and the second of which received 3 days of ciprofloxacin starting the day prior to the procedure (22). The primary outcome was UTI within 90 days of the procedure, and they found no statistical difference between the groups (p=0.18) with 34% of the group receiving postprocedure antibiotics only developing a UTI versus 22% of the group that received pre- and postprocedure antibiotics (24).

Eckhardt, et al. performed a secondary analysis of a retrospective cohort study on women undergoing intradetrusor onabotulinumtoxinA injection for OAB (23). 565 patients were studied of which 44.4% received intravenous (IV) antibiotics only, 8.9% received oral (PO) antibiotics only, and 39.7% received combination IV and PO. 7.1% received no antibiotics. For the primary outcome of UTI within 3 months determined by International Classification of Diseases(ICD) codes for cystitis, 30.4% of patient developed a UTI with no significant difference between the groups (25).

Houman, et al. reviewed the use of intramuscular ceftriaxone immediately prior to intradetrusor onabotulinumtoxinA injections versus a 3-day course of ciprofloxacin starting the day prior to the procedure (24). UTI was defined as a positive culture or new onset urgency, frequency, or dysuria within 30 days of the procedure. 284 patient charts were reviewed. They found that the UTI rate for patients who received ciprofloxacin was 20% versus 36% for patients who a single received ceftriaxone injection, p=.04 (26 ).

Antibiotic resistance is increasingly becoming a problem in modern medicine. Notably, almost 15% of all antibiotics used are to treat UTIs (27). Among all bacteria isolated in UTI, resistance to nitrofurantoin is low at 8%, but resistance to trimethoprim-sulfamethoxazole has increased to over 20% in some areas and resistance to ciprofloxacin has more than tripled to 11.8% (28-30). Minimizing unnecessary antibiotic use and shortening antibiotic courses is an important part of antibiotic stewardship programs and can help reduce antibiotic resistance to ensure that treatment for UTIs in the future remains effective (31).

The Infectious Diseases Society of America recommends that based on resistance rates and patient tolerance that the first line antibiotics for uncomplicated UTI are nitrofurantoin, trimethoprim sulfamethoxazole, and fosfomycin (32). The American Urologic Association's antimicrobial prophylaxis recommendations state that for "cystourethroscopy with minor manipulation, break in mucosal barriers, biopsy, fulguration, etc." it is uncertain whether prophylaxis is indicated, but if given should be done with a single dose of antibiotics (33).

Based on the lack of level 1 evidence on antibiotic prophylaxis after intradetrusor onabotulinumtoxinA injections, we propose a randomized controlled trial comparing nitrofurantoin given as a single dose at the time of the procedure to a 3 day course started at the time of the procedure. The primary outcome is to evaluate the rate of culture proven urinary tract infections within 30 days after the procedure.

Eligibility criteria: Inclusion Criteria:

* All patients 18 years or older being seen at the WRNMMC Urogynecology clinic
* Diagnosis of OAB or IC/BPS
* Planning to undergo intradetrusor onabotulinumtoxinA injection for treatment of their OAB or IC/BPS
* Ability to follow instructions and complete follow up

Exclusion Criteria:

* Contraindication to nitrofurantoin (allergy, CrCl \<30mL/minute)
* If performed in the operating room, the patient cannot undergo a concurrent procedure that would increase the risk of UTI or require an alternate antibiotic regimen (such as hysterectomy, prolapse repair, or anti-incontinence procedure)
* Active UTI at the time of procedure
* Neurogenic bladder
* Recurrent UTI (3 in 12 month period or 2 in 6 months)
* Post void residual bladder volume ≥150mL
* Patient is already taking antibiotics at the time of the procedure
* Contraindication to onabotulinumtoxinA (allergy, pregnancy, greater than 400 units of onabotulinumtoxinA received in the last 3 months)

Primary outcomes:
measure: Urinary tract infection
timeFrame: Within 30 days after intradetrusor injection of onabotulinumtoxinA
Secondary outcomes:
measure: Urinary tract infection symptoms
timeFrame: Within 30 days after intradetrusor injection of onabotulinumtoxinA
measure: Urinary retention
timeFrame: Within 30 days after intradetrusor injection of onabotulinumtoxinA
measure: Adverse effects
timeFrame: Within 30 days after intradetrusor injection of onabotulinumtoxinA
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
Study officials:
affiliation: Walter Reed National Military Medical Center
name: Jordan Gisseman, MD
role: PRINCIPAL_INVESTIGATOR
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