Bladder Botox UTI Antibiotic Prophylaxis

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.