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

Sponsor
Halina M Zyczynski, MD (Other)
Overall Status
Completed
CT.gov ID
NCT02727322
Collaborator
(none)
154
2
2
21.3
77
3.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
154 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
A Randomized, Double-blind, Placebo-controlled Trial of Nitrofurantoin Prophylaxis During Catheterization for Acute Postoperative Urinary Retention After Pelvic Reconstructive Surgery
Study Start Date :
Aug 1, 2016
Actual Primary Completion Date :
Mar 27, 2018
Actual Study Completion Date :
May 12, 2018

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Nitrofurantoin

Receives once daily nitrofurantoin 100mg

Drug: Nitrofurantoin
Patients will receive nitrofurantoin 100mg once daily or a placebo. Pills will be identical.
Other Names:
  • Macrobid
  • Placebo Comparator: Placebo

    Receives matching placebo

    Drug: Placebo
    Placebo

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Experiencing Urinary Tract Infection Within 6 Weeks of Surgery [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.

    Secondary Outcome Measures

    1. Number of Participants Who Experienced at Least One Adverse Event Symptom While Requiring Catheterization [within 6 weeks of surgery]

      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.

    2. Frequency of Urine Cultures Positive for Nitrofurantoin-resistant Isolates [within 6 weeks of surgery]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Georgetown/MedStar Hospital Center Washington District of Columbia United States 20007
    2 Magee-Womens Hospital of UPMC Pittsburgh Pennsylvania United States 15213

    Sponsors and Collaborators

    • Halina M Zyczynski, MD

    Investigators

    • Principal Investigator: Erin S Lavelle, MD, University of Pittsburgh

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Halina M Zyczynski, MD, Professor, University of Pittsburgh
    ClinicalTrials.gov Identifier:
    NCT02727322
    Other Study ID Numbers:
    • PRO15110557
    First Posted:
    Apr 4, 2016
    Last Update Posted:
    May 29, 2019
    Last Verified:
    May 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Nitrofurantoin Placebo
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily during catheter use. Receives matching placebo Placebo: Patients will receive identical appearing placebo once daily during catheter use.
    Period Title: Overall Study
    STARTED 77 77
    COMPLETED 75 76
    NOT COMPLETED 2 1

    Baseline Characteristics

    Arm/Group Title Nitrofurantoin Placebo Total
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily during catheter use. Receives matching placebo Placebo: Patients will receive identical appearing placebo once daily during catheter use. Total of all reporting groups
    Overall Participants 75 76 151
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.7
    (11.9)
    60.5
    (12.0)
    60.9
    (11.9)
    Sex: Female, Male (Count of Participants)
    Female
    75
    100%
    76
    100%
    151
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (participants) [Number]
    Caucasian
    64
    85.3%
    60
    78.9%
    124
    82.1%
    African American
    5
    6.7%
    11
    14.5%
    16
    10.6%
    Native American
    1
    1.3%
    1
    1.3%
    2
    1.3%
    Hispanic
    5
    6.7%
    4
    5.3%
    9
    6%
    Body Mass Index (kg/m^2) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    26.8
    (4.4)
    27.5
    (5.3)
    27.2
    (5.1)
    Gravidity (number of pregnancies) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [number of pregnancies]
    3
    (2)
    3
    (2)
    3
    (2)
    Parity (pregnancies delivered after 20 weeks) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [pregnancies delivered after 20 weeks]
    3
    (1)
    3
    (1)
    3
    (1)
    Current Smoker (Count of Participants)
    Count of Participants [Participants]
    4
    5.3%
    3
    3.9%
    7
    4.6%
    Menopausal Status (Count of Participants)
    Premenopausal
    15
    20%
    17
    22.4%
    32
    21.2%
    Postmenopausal, No Hormone Replacement therapy
    56
    74.7%
    57
    75%
    113
    74.8%
    Postmenopausal, Oral Hormone Replacement Therapy
    4
    5.3%
    2
    2.6%
    6
    4%
    Vaginal Estrogen Use (Count of Participants)
    Count of Participants [Participants]
    20
    26.7%
    22
    28.9%
    42
    27.8%
    Diabetes, on medication (Count of Participants)
    Count of Participants [Participants]
    4
    5.3%
    9
    11.8%
    13
    8.6%
    History of Urinary Tract Infection in past year (Count of Participants)
    Count of Participants [Participants]
    2
    2.7%
    6
    7.9%
    8
    5.3%
    Preoperative POP-Q Stage (Count of Participants)
    0
    2
    2.7%
    3
    3.9%
    5
    3.3%
    1
    4
    5.3%
    6
    7.9%
    10
    6.6%
    2
    27
    36%
    16
    21.1%
    43
    28.5%
    3
    38
    50.7%
    37
    48.7%
    75
    49.7%
    4
    1
    1.3%
    5
    6.6%
    6
    4%
    unknown
    3
    4%
    9
    11.8%
    12
    7.9%
    Preoperative Postvoid Residual Volume (ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml]
    87.4
    (147.5)
    66.4
    (129.4)
    72.8
    (95.3)
    Indication for surgery (Count of Participants)
    Prolapse
    38
    50.7%
    31
    40.8%
    69
    45.7%
    Incontinence
    12
    16%
    19
    25%
    31
    20.5%
    Prolapse and Incontinence
    25
    33.3%
    26
    34.2%
    51
    33.8%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Experiencing Urinary Tract Infection Within 6 Weeks of Surgery
    Description 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.
    Time Frame within 6 weeks of surgery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Nitrofurantoin Placebo
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily during catheterization. Receives matching placebo Placebo: Patients will receive identical appearing placebo daily during catheterization.
    Measure Participants 75 76
    Count of Participants [Participants]
    13
    17.3%
    13
    17.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Nitrofurantoin, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.97
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 1.1
    Confidence Interval (2-Sided) 95%
    0.50 to 2.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Number of Participants Who Experienced at Least One Adverse Event Symptom While Requiring Catheterization
    Description 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.
    Time Frame within 6 weeks of surgery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Nitrofurantoin Placebo
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily during catheter use. Receives matching placebo Placebo: Patients will receive identical appearing placebo once daily during catheter use.
    Measure Participants 75 76
    Count of Participants [Participants]
    51
    68%
    46
    60.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Nitrofurantoin, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.665
    Comments
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 1.12
    Confidence Interval (2-Sided) 95%
    0.885 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Frequency of Urine Cultures Positive for Nitrofurantoin-resistant Isolates
    Description 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.
    Time Frame within 6 weeks of surgery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Nitrofurantoin Placebo
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily or a placebo. Pills will be identical. Receives matching placebo Placebo: Placebo
    Measure Participants 75 76
    Measure Positive urine cultures 12 15
    Number [nitrofurantoin resistant urine cultures]
    4
    3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Nitrofurantoin, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 1.0
    Comments
    Method Fisher Exact
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 1.32
    Confidence Interval (2-Sided) 95%
    0.31 to 5.68
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame 6 weeks since randomization
    Adverse Event Reporting Description Participants completed daily diaries during catheterization in which they reported adverse effects. Study coordinators also solicited adverse events from participants at 6 weeks, and reviewed medical records for adverse events.
    Arm/Group Title Nitrofurantoin Placebo
    Arm/Group Description Receives once daily nitrofurantoin 100mg Nitrofurantoin: Patients will receive nitrofurantoin 100mg once daily during catheter use. Receives matching placebo Placebo: Patients will receive identical appearing placebo once daily during catheter use.
    All Cause Mortality
    Nitrofurantoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/75 (0%) 0/76 (0%)
    Serious Adverse Events
    Nitrofurantoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/75 (4%) 2/76 (2.6%)
    Blood and lymphatic system disorders
    Transfusion 1/75 (1.3%) 1 0/76 (0%) 0
    Renal and urinary disorders
    Voiding Dysfunction Requiring Surgery 2/75 (2.7%) 2 1/76 (1.3%) 1
    Vascular disorders
    Transient Ischemic Attack 0/75 (0%) 0 1/76 (1.3%) 1
    Other (Not Including Serious) Adverse Events
    Nitrofurantoin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 18/75 (24%) 16/76 (21.1%)
    Blood and lymphatic system disorders
    Anemia 0/75 (0%) 0 1/76 (1.3%) 1
    Gastrointestinal disorders
    Nausea 1/75 (1.3%) 1 1/76 (1.3%) 1
    General disorders
    0/75 (0%) 0 2/76 (2.6%) 2
    Infections and infestations
    Infection of Incision 2/75 (2.7%) 2 3/76 (3.9%) 3
    Vulvovaginal Yeast Infection 1/75 (1.3%) 1 0/76 (0%) 0
    Infected Hematoma 1/75 (1.3%) 1 0/76 (0%) 0
    Nervous system disorders
    Headache 1/75 (1.3%) 1 1/76 (1.3%) 1
    Lower Extremity Symptoms 1/75 (1.3%) 1 0/76 (0%) 0
    Renal and urinary disorders
    Dysuria 1/75 (1.3%) 1 2/76 (2.6%) 2
    Hematuria 3/75 (4%) 3 1/76 (1.3%) 1
    Prolonged Urinary Retention 1/75 (1.3%) 1 2/76 (2.6%) 2
    Catheter Discomfort or Obstruction 3/75 (4%) 3 0/76 (0%) 0
    Hydronephrosis 0/75 (0%) 0 1/76 (1.3%) 1
    Skin and subcutaneous tissue disorders
    Rash 3/75 (4%) 3 2/76 (2.6%) 2

    Limitations/Caveats

    The per protocol analysis did not meet power. Not powered for secondary outcomes - antibiotic resistance and adverse symptoms.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Halina Zyczynski
    Organization University of Pittsburgh
    Phone 421-641-1440
    Email hzyczynski@upmc.edu
    Responsible Party:
    Halina M Zyczynski, MD, Professor, University of Pittsburgh
    ClinicalTrials.gov Identifier:
    NCT02727322
    Other Study ID Numbers:
    • PRO15110557
    First Posted:
    Apr 4, 2016
    Last Update Posted:
    May 29, 2019
    Last Verified:
    May 1, 2019