Nitrofurantoin Prophylaxis During Catheter-managed Acute Urinary Retention After Pelvic Reconstructive Surgery
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
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:
|
Placebo Comparator: Placebo Receives matching placebo |
Drug: Placebo
Placebo
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
- 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
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.- PRO15110557
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
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 |
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 |
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
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 |
hzyczynski@upmc.edu |
- PRO15110557