Nitrofurantoin Prophylaxis During Catheter-managed Acute Urinary Retention After Pelvic Reconstructive Surgery

Study Overview
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Brief Summary
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The specific aim of this randomized double-blind placebo-controlled trial is to determine if extended release nitrofurantoin antibiotic prophylaxis decreases the incidence of symptomatic urinary tract infection (UTI) compared with placebo for patients undergoing short term indwelling or clean intermittent self-catheterization (CISC) for acute postoperative urinary retention following pelvic organ prolapse and/or urinary incontinence surgery. Consented patients who undergo urogenital surgery and fail their post-operative voiding trial will be randomized to either extended release nitrofurantoin 100mg or an identical appearing placebo capsule to be taken daily while performing CISC or while indwelling catheter is in place. The primary outcome will be symptomatic and culture confirmed UTI within six weeks of surgery. Secondary outcomes include adverse events associated with nitrofurantoin use, and incidence of nitrofurantoin-resistant isolates from urine culture of symptomatic women. Primary and secondary outcomes will be evaluated with Student t test and chi squared or Fisher exact test as appropriate. Assuming a decrease in symptomatic UTIs attributable to nitrofurantoin prophylaxis from 33% to 13%, with 80% power, and a two-sided alpha of 0.05, and a 10% dropout rate, we should recruit a total of 154 patients.

Detailed Description
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Urinary tract infections (UTI) occur frequently following surgery for urinary incontinence or pelvic organ prolapse (POP), with reported incidence up to 48%. This high rate is frequently attributed to intraoperative factors, such as manipulation of the genitourinary tract and instrumentation of the bladder and urethra, as well as an approximately 50% rate of short term postoperative catheterization following urogynecologic surgery. As American women have a 20% lifetime risk of surgery for POP or urinary incontinence, the absolute number of women at risk for urinary infectious morbidity associated with these procedures is quite high. The substantial risk of UTI following POP or incontinence surgery, combined with the well-established risk associated with catheterization, leads many practitioners to prescribe oral antibiotics to women undergoing catheterization in the postoperative period. However, there is minimal Level I evidence to support or refute this practice. The Infectious Disease Society of America (IDSA) Guideline acknowledges that prophylactic antibiotics have been shown to reduce UTI rates among patients using short term postoperative catheterization in randomized trials. However, they recommend against routine antibiotic prophylaxis use due to concerns regarding anti-microbial resistance, cost, and potential for adverse effects, even among high risk groups including women undergoing urogynecologic surgery. This recommendation is based on expert opinion, given a paucity of trial data to guide clinical care. Nitrofurantoin is a commonly used antibiotic for UTI prophylaxis during catheterization, is well-tolerated with few adverse effects, and is known to have a very low rate of associated resistance. After decades of use, it remains active against the most common UTI pathogens that have gained resistance to other antimicrobials. For example, in the 2013 Magee-Womens Hospital Adult Antibiogram, 98% of E-coli specimens were sensitive to Nitrofurantoin, which has been consistent since at least 2007. The drug has a half-life of 20 minutes and 40% is concentrated in and excreted into the urine in a therapeutically unchanged form. Thus it has minimal impact on vaginal and bowel flora. Nitrofurantoin has been shown to reduce the incidence of positive urine cultures and symptomatic UTIs in women with a suprapubic catheter after pelvic organ prolapse and/or urinary incontinence surgery. No trials have evaluated nitrofurantoin prophylaxis for women using short term indwelling catheters or CISC following urogynecologic procedures. Given the large number of women at risk for urinary infectious morbidity associated with short term catheterization for acute urinary retention following POP and/or incontinence surgery, and the paucity of data on the impact of antibiotic prophylaxis in this setting, we propose to demonstrate the efficacy of nitrofurantoin prophylaxis through an adequately-powered, placebo-controlled trial. Secondary outcomes will include adverse events associated with nitrofurantoin use, and incidence of nitrofurantoin resistant bacterial isolates from urine culture. Primary Aim: To determine if extended release nitrofurantoin administered daily to patients using indwelling or clean intermittent self-catheterization (CISC) after pelvic organ prolapse and/or urinary incontinence surgery will decrease the incidence of symptomatic and culture proven urinary tract infection (UTI) when compared to placebo in a randomized, double-blind trial. Secondary Aim(s): To determine how nitrofurantoin antibiotic prophylaxis administered to patients using an indwelling catheter or CISC after pelvic organ prolapse and/or urinary incontinence surgery affects frequency of adverse events related to daily nitrofurantoin exposure, and frequency of urine cultures positive for nitrofurantoin-resistant isolates. The Null Hypotheses: Nitrofurantoin antibiotic prophylaxis administered to patients using an indwelling catheter or CISC after pelvic organ prolapse and/or urinary incontinence surgery does not change the incidence of symptomatic and culture proven urinary tract infection (UTI) compared with placebo.

Official Title
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A Randomized, Double-blind, Placebo-controlled Trial of Nitrofurantoin Prophylaxis During Catheterization for Acute Postoperative Urinary Retention After Pelvic Reconstructive Surgery

Conditions
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Pelvic Organ Prolapse

Intervention / Treatment
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* Drug: Nitrofurantoin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Women who have undergone surgery for the correction of pelvic organ prolapse and/or urinary incontinence and failed a postoperative voiding trial Exclusion Criteria: Known drug allergy to nitrofurantoin History of renal insufficiency Renal transplant Renal nephropathy Recent history of more than 3 UTIs per year History of nitrofurantoin-induced pulmonary injury or nitrofurantoin associated cholestatic jaundice/hepatic dysfunction Known immunocompromised condition (organ transplant, chemotherapy, immune suppression associated with autoimmune disease).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nitrofurantoin<br>Receives once daily nitrofurantoin 100mg | Drug: Nitrofurantoin<br>* Patients will receive nitrofurantoin 100mg once daily or a placebo. Pills will be identical.<br>* Other names: Macrobid;|
| Placebo Comparator: Placebo<br>Receives matching placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Urinary Tract Infection Within 6 Weeks of Surgery | Frequency of symptomatic, culture-proven UTI; included participants who were empirically treated outside of protocol (symptoms but no culture) within 6 weeks of surgery. Positive culture was defined as at least 100,000 colony forming units (cfu)/ml of uropathic bacteria in a catheterized or midstream clean catch voided urine specimen. | within 6 weeks of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least One Adverse Event Symptom While Requiring Catheterization | This is the number of participants who experienced at least one adverse symptom as reported on the diary completed daily while requiring catheterization. These adverse symptoms included: constipation, nausea/vomiting, drowsiness, headache, flatulence, abdominal pain, dizziness, diarrhea, rash/itching, dyspepsia, fever/chills, amblyopia and other. | within 6 weeks of surgery | 
| Frequency of Urine Cultures Positive for Nitrofurantoin-resistant Isolates | Frequency of urine cultures with one or more organisms resistant to nitrofurantoin. Positive culture was defined as at least 100,000 colony forming units (cfu)/ml of uropathic bacteria in a catheterized or midstream clean catch voided urine specimen. | within 6 weeks of surgery |