A Randomized, Double-blind, Placebo-controlled Trial of Nitrofurantoin Prophylaxis During Catheterization for Acute Postoperative Urinary Retention After Pelvic Reconstructive Surgery
Phase: PHASE4
Conditions: Pelvic Organ Prolapse
Sponsor: Halina M Zyczynski, MD

Fellows’ Pelvic Research Network (FPRN)  
MANUAL OF PROCEDURES/PROTOCOL  
 
 
A randomized, double-blind, placebo-controlled trial of nitrofurantoin prophylaxis 
in women undergoing short-term catheterization for acute postoperative urinary 
retention after pelvic reconstructive surgery  
 
 
PI: Erin Seifert Lavelle, MD 
Mentor: Gary Sutkin, MD 
 
 
Data Coordinating Center  
Magee Womens Hospital of UPMC 
University of Pittsburgh 
Pittsburgh, PA 
 
 
Version 1, November 2015 
 
 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
ABSTRACT  
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. 
 
 
SPECIFIC AIMS 
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. 
 
BACKGROUND 
Urinary tract infections (UTI) occur frequently following surgery for urinary 
incontinence or pelvic organ prolapse (POP), with reported incidence up to 48% (Albo 
2007, Chai 2009, Sutkin 2010, Nygaard 2011, Wei 2012).  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 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
term postoperative catheterization following urogynecologic surgery (Sutkin 2010, 
Nygaard 2010, Dieter 2014).  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 (Wu 2014).   
 
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 (Hooton 2009).  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 (Shaw 1989).  After decades of use, it remains active 
against the most common UTI pathogens that have gained resistance to other 
antimicrobials (Guay 2001). 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 
(Rogers 2004).  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.  
 
 
 
SIGNIFICANCE 
This prospective, randomized control study is uniquely feasible in the Fellows’ 
Research Pelvic Network, where data from a large and diverse patient population can be 
collected.  
 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
STUDY DESIGN 
Women who undergo surgery for urinary incontinence and/or pelvic organ 
prolapse who fail a post-operative voiding trial will be eligible to participate in this a 
double blind, randomized trial.  Randomization will be a block randomization stratified 
by site with 1:1 allocation to either extended release nitrofurantoin 100mg or an identical 
appearing placebo capsule to be taken daily while using an indwelling catheter or 
performing CISC.  Neither the patient, nor her physician nor the research staff will know 
her allocation. The diagram below outlines randomization details: 
 
 
 
 
Inclusion criteria: Women who have undergone surgery for the correction of pelvic 
organ prolapse and/or urinary incontinence and failed a postoperative voiding trial and 
provide informed consent will be randomized.   
 
 
Exclusion criteria: Known drug allergy to nitrofurantoin, a history of renal 
insufficiency, renal transplant, renal nephropathy, preoperative urinary retention, a recent 
history of more than 3 UTIs per year, a previous 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).  
 
Intervention:  Extended release nitrofurantoin 100mg or an identical appearing placebo 
capsule to be taken daily while using an indwelling catheter or performing CISC.   
 
Women Undergoing Surgery for POP and/or SUI 
Void trial failure 
A 
Placebo daily during 
catheter use 
N=77
Voiding trial per institution protocol 
Randomization 
Consent for participation 
B 
Nitrofurantoin 100mg daily 
during catheter use 
N=77 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
Primary outcome: The frequency of symptomatic UTIs confirmed with a positive urine 
culture within 6 weeks of surgery. UTI definition will be culture growth of ≥103 colony 
forming units (cfu)/mL of uropathogenic bacteria in in a single catheter urine specimen or 
a midstream voided urine specimen and the presence of symptoms or signs compatible 
with UTI without other identifiable source.  This is consistent with the American Urology 
Infectious Disease Society of America (IDSA) and National Surgical Quality 
Improvement Program (NSQIP) guidelines, with the exception that postoperative UTI 
will be diagnosed with a colony count of >103 instead of >105 for symptomatic women, 
given the increased risk in this population. 
 
Secondary outcomes:  
1. Frequency of adverse events related to daily nitrofurantoin exposure, primarily 
nausea, vomiting, headache and flatulence, but including diarrhea, dyspepsia, 
abdominal pain, constipation, emesis, dizziness, drowsiness, amblyopia, pruritis, 
urticaria, hair loss, fever, chills, and malaise as well as acute pulmonary, 
dermatologic or hepatic reactions.  
2. Frequency of urine cultures positive for nitrofurantoin-resistant isolates, defined 
as a single organism of 103 or greater colony forming units with resistance (not 
including intermediate sensitivity) on susceptibility testing. 
 
Protocol in Detail: 
Women scheduled for surgical correction of urinary incontinence or prolapse can 
be introduced to the study pre-operatively in the clinical office or immediately prior to 
surgery, and will be consented and randomized post-operatively should they fail their 
voiding trials. Voiding trials may be performed per protocol at the participating 
institution.  At our institution, the bladder is back filled through a Foley catheter with 
300cc sterile water.  Patients are considered to pass the voiding trial when they 
spontaneously void with a post-void residual (PVR) that is 100cc or less.  Patients who 
‘fail’ a voiding trial are either taught CISC prior to discharge, or are otherwise discharged 
with an indwelling catheter.  A documented PVR of 100cc or greater is preferred for 
study inclusion.  
 
Screening for study inclusion will be performed at the time of diagnosis of 
postoperative urinary retention after pelvic reconstructive surgery.  Women who agree to 
potential study participation will be approached by an investigator from the research 
team.  The investigator will review the inclusion/exclusion criteria to determine the 
patient's eligibility.  Informed consent will be reviewed and signed with eligible patients.  
 
At enrollment, baseline clinical data and information on voiding symptoms will 
be abstracted from the clinical chart or collected when not current within six months (see 
Enrollment Data Abstraction Sheet).   
 
Study drug and placebo will be prepared by the UPMC investigational drug 
service and shipped to participating sites.  A ten day supply of study drug will be placed 
in identical pill bottles with labels indicating that they are part of this study and contain 
either nitrofurantoin 100 mg tabs or placebo, and instructions to take one capsule daily 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
during catheter use.  Study drug and a block randomization log will be provided to 
participating sites in blocks of 8 patients.  When patients are enrolled, they will receive a 
study ID number from the randomization log and receive the study drug pre-labeled with 
the study ID number.  The pharmacy, investigational drug service, or other personnel of 
each site will administer the randomization log and provide the participant with study 
drug at enrollment.   
 
Medication (nitrofurantoin or placebo) will be self-administered by the patient 
once daily beginning on postoperative day one and continuing each day the patient 
requires catheterization.  Patients who must take a study drug while under hospital care 
will self-administer study drug with a physician order that they may do so, and under 
supervision of the nursing staff, or per hospital protocol of participating institutions.   
 
Patients using indwelling catheters will be seen for repeat voiding trial at the 
discretion of the treating provider.  All women will be asked to complete a simple daily 
diary for each day they use a catheter to document compliance with study drug, 
symptoms of UTI, or adverse effects from study drug (see Daily Diary).  Criteria for 
discontinuing indwelling catheter use will be passing a voiding trial per policy of 
participating sites.  Criteria for discontinuing CISC will per policy of participating sites.   
At our institution, patients may discontinue CISC when they are able to void 
spontaneously with a PVR of less than 100cc on two consecutive voids, and this will be 
the preferred criteria.  Patients will return the diary by mail in pre-addressed envelopes 
when they discontinue catheter use.   
 
Patients will be strongly encouraged to seek care for possible UTI symptoms from 
their study physician.  A symptom survey and urine specimen for culture will be 
collected.  Catheterized specimens are preferred although clean catch specimens will be 
accepted.  UTI symptoms will be treated with antibiotics (other than Nitrofurantoin) at 
the discretion of the treating physician; type, duration and strength of antibiotic will be 
recorded.  When symptoms occur outside of business hours, patients may reach an on-
call study staff member who can help them facilitate urine culture collection as well as 
clinical care.  Empiric prescription of antibiotics prior to obtaining urine for culture will 
be strongly discouraged.  Patients will be given a prescription and specimen cup for a 
urine culture so they can drop off a specimen if empiric treatment is necessary.  They will 
also be given a card identifying them as study participants with a request to send a urine 
culture and to forward results to their physician should they present for care to an outside 
facility.   
 
An episode of UTI symptoms will only be considered a UTI if confirmed by a 
positive urine culture, as defined below.  If empiric treatment occurs, the episode will be 
counted as a UTI.  
 
All patients will be seen by a physician and a research staff at a 6-week 
postoperative visit.   At the 6-week visits patients will return their diary if it has not yet 
been sent in, and return any unused study drug.  The study team will review the chart for 
any adverse events or UTIs not previously reported, and patients will fill out a brief 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
questionnaire to confirm the same.  Duration of catheterization will be confirmed 
between the patient diary and the patient chart.  If the patient is still using an indwelling 
catheter or performing CISC at the end of the study, we will not break the randomization 
code until the study is completed. The decision to continue or initiate antibiotics will be 
made by the patient and her treating physician.  
 
During the six week study period, the central Study Coordinator will track patient 
participation.  They will contact the patient at three to four day intervals to answer any 
study related questions, confirm patient is filling out the daily diary, and remind patients 
to return their diary when catheterization is completed.  They will remind patients to 
follow-up six weeks following surgery and to contact their study physician for any UTI 
symptoms. 
 
The study will end 6 weeks after surgery of the last recruited patient.   
 
DATA COLLECTION 
 
Data will be collected by participating sites using data collection forms (see 
appendix).  All paper forms will be sent via encrypted email to the Data Coordinating 
Center.  Forms will be reviewed for errors and completion by the Study Coordinator and 
entered into a central database.   
 
CONFIDENTIALITY 
Extensive efforts will be made to ensure and maintain participant confidentiality. 
All identifying information must be maintained in a secure area at all times in accordance 
with participating site Institutional Review Board policy.  When documentation is 
transferred to the Data Coordinating Center (DCC), data sheets must include the Subject 
ID number without personal patient identifiers.  
 
 
Participants will be assigned a Study ID number at study enrollment.  Study ID 
number will be taken from the randomization log provided to the participating sites.  This 
Study ID number should be used label all data collection sheets.  All communication 
between the DCC and participating sites regarding patient data will occur via the Subject 
ID number. The staff at the DCC will not have access to any identifying information 
available to the participating site. The DCC staff will have access to the Subject ID 
number for data management purposes. Once a Subject ID number has been assigned, it 
should never, for any reason, be reassigned.  
 
 
The DCC will maintain the randomization log.  They will maintain a record of the 
block randomization including which Study ID numbers have been assigned to which 
clinical site.   Only the onsite pharmacy or other research staff personnel for each clinical 
site will maintain patient identifiers associated with the Study ID number.  This 
information must be kept in a secure area in accordance with each site’s IRB policy and 
approval. 
 
 

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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
POWER ANALYSIS  
In a study by Rogers et al, the rate of UTIs with placebo in women with 
suprapubic catheters was 33%. In a study at Magee Womens Hospital, 13% of those 
performing CISC post-operatively developed a symptomatic UTI, despite daily 
prophylactic nitrofurantoin (Sutkin, 2010). Assuming a 60% decrease attributable to 
nitrofurantoin from 33% to 13%, with 80% power and a two-sided alpha of 0.05, we will 
need 69 patients per arm. Allowing for a 10% dropout rate, we will recruit a total of 154 
patients, 77 per arm. 
 
 
DATA ANALYSIS 
Demographics and baseline data will be analyzed by Student’s t-test and chi-squared test 
or Fisher’s Exact test as appropriate. 
 
Primary outcome: The frequency of urinary tract infection within 6 weeks of surgery 
will be analyzed by intention to treat using a chi squared test.  This primary outcome 
includes symptomatic, culture-proven UTI as well as women who were empirically 
treated outside of protocol.  Women who were diagnosed with multiple urinary tract 
infections during the study period will be counted, but only the first UTI for each patient 
will be included.  A secondary analysis of symptomatic, culture-proven UTIs, excluding 
those who were empirically treated, will be performed by chi square test.  In addition, 
frequency of urinary tract infection among women undergoing urinary incontinence (UI) 
surgery only, pelvic organ prolapse (POP) surgery only, or a combination of UI/POP 
surgeries will be performed using chi squared or Fisher’s Exact test as appropriate.  
 
Secondary outcomes:  
1. Frequency of adverse events related to daily nitrofurantoin exposure as defined 
above will be compared with chi-squared test or Fisher’s Exact test as 
appropriate. 
2. Frequency of urine cultures positive for nitrofurantoin-resistant isolates will be 
analyzed by chi-squared test or Fisher’s Exact test as appropriate. 
 
        
 
PROJECT SCHEDULE: 
 
- 
February 8, 2016: Final confirmation of participating sites 
- 
February 8 to April 4, 2016: Start up including IRB approval at all sites 
- 
April 2016 until April 2017: Recruitment 
- 
May through July 2017: Data analysis, manuscript completion 
 
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colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med 
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Lavelle & Sutkin. RCT of nitrofurantoin prophylaxis during short-term postop catheterization.  
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