Uncomplicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Uncomplicated Urinary Tract
Infections: Developing Drugs
for Treatment
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Clinical/Antimicrobial

Uncomplicated Urinary Tract
Infections: Developing Drugs
for Treatment
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Clinical/Antimicrobial

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DEVELOPMENT PROGRAM ....................................................................................... 2
A. 	General Considerations .................................................................................................................2
1. Drug Development Population .........................................................................................................2
2. Efficacy Considerations ...................................................................................................................2
3. Safety Considerations .......................................................................................................................3
4. Pharmacokinetic and Dose Selection Considerations .....................................................................3
B. 	Specific Efficacy Trial Considerations .........................................................................................3
1. Clinical Trial Designs, Populations, and Enrollment Criteria ........................................................3
2. Clinical Microbiology Considerations .............................................................................................4
3. Specific Populations .........................................................................................................................4
4. Choice of Comparators ....................................................................................................................5
5. Efficacy Endpoints............................................................................................................................5
a. 	Primary efficacy endpoint .........................................................................................................5
b. 	Efficacy endpoints for a finding of superiority .........................................................................6
c. 	Secondary endpoints ..................................................................................................................6
6. Trial Procedures and Timing of Assessments ..................................................................................6
a. 	Entry visit ..................................................................................................................................6
b. 	On-therapy and end-of-therapy visits ........................................................................................6
c. 	Post-treatment visits ..................................................................................................................6
7. Statistical Considerations.................................................................................................................6
a. 	Analysis populations..................................................................................................................7
b. 	Noninferiority margins ..............................................................................................................7
c. 	Sample size ................................................................................................................................7
8. Labeling Considerations ..................................................................................................................8
REFERENCES.............................................................................................................................. 9
APPENDIX: JUSTIFICATION FOR NONINFERIORITY MARGIN FOR
UNCOMPLICATED URINARY TRACT INFECTIONS...................................................... 10

Contains Nonbinding Recommendations
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Uncomplicated Urinary Tract Infections:
Developing Drugs for Treatment
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the
treatment of uncomplicated urinary tract infections (uUTIs).2 Specifically, this guidance
addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall
development program and clinical trial designs for drugs to support an indication for the
treatment of uUTIs.
We consider the treatment of uUTIs to be an indication distinct from the treatment of
complicated urinary tract infections (cUTIs). This guidance addresses uUTIs only. The FDA
issued a separate guidance on cUTIs.3 This guidance does not contain discussion of the general
issues of statistical analysis or clinical trial design. Those topics are addressed in the ICH
guidances for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10
Choice of Control Group and Related Issues in Clinical Trials (May 2001), respectively.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
1 This guidance has been prepared by the Division of Anti-Infective Products in the Center for Drug Evaluation and
Research at the Food and Drug Administration.
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological
products unless otherwise specified.
3 See the guidance for industry Complicated Urinary Tract Infections: Developing Drugs for Treatment (June
2018). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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II. 	BACKGROUND
uUTI is defined as a clinical syndrome characterized by pyuria and a documented microbial
pathogen on urine culture, accompanied by local signs and symptoms such as lower abdominal
discomfort and dysuria. uUTIs, also referred to as acute cystitis, occur in females with normal
anatomy of the urinary tract and are not accompanied by systemic signs or symptoms, such as
fever greater than 38 degrees Celsius or costovertebral angle pain. Urinary tract infections in
males are characterized as cUTIs because these infections occur in association with urologic
abnormalities such as instrumentation or bladder outlet obstruction (e.g., benign prostatic
hyperplasia).
III. 	DEVELOPMENT PROGRAM
A. 	General Considerations
1. 	Drug Development Population
The intended clinical trial population should be female patients with uUTIs.
2. 	Efficacy Considerations
Active-controlled trials designed for findings of superiority or noninferiority are potential
options to evaluate antibacterial drugs for the treatment of uUTI. A treatment effect of
antibacterial drug therapy for uUTI has been established (see the Appendix). Therefore, the
noninferiority trial design is acceptable for demonstration of efficacy.
The treatment-delay, placebo-controlled trial design allows for a finding of superiority of the
investigational drug compared to placebo at a time point early in therapy, after which patients
randomized to treatment delay receive antibacterial drug treatment. Sponsors interested in
conducting a placebo-controlled trial should discuss trial design and safety issues with the FDA.
All trial designs should provide appropriate provisions for patient safety.4
If a sponsor seeks only a uUTI indication for an investigational drug, we recommend two
adequate and well-controlled trials. A single adequate and well-controlled trial supported by
other confirmatory evidence, such as a trial in another infectious disease indication, can provide
evidence of effectiveness.5 Sponsors should discuss with the FDA the other independent
evidence that would be used to support the findings from a single trial in uUTI.
4 For examples, see the References section of this guidance for references that include placebo-controlled or
nonantibacterial-controlled trials in uUTI patients.
5 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products (May 1998).

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3. 	Safety Considerations
In general, we recommend a preapproval safety database of at least 800 patients at the proposed
dose and duration for treatment. If the dose and duration of therapy used in clinical trials for
other infectious disease indications are the same or greater than the dose and duration proposed
for treatment of uUTI, the safety information from those clinical trials can be part of the overall
preapproval safety database. Sponsors should discuss the appropriate size of the preapproval
safety database with the FDA during clinical development.
4. 	Pharmacokinetic and Dose Selection Considerations
The pharmacokinetics of the drug should be determined, including its excretion in urine. Urinary
concentrations of the drug are important when bacterial infection is limited to the lower urinary
tract (i.e., uUTI). Drug concentrations in urine over time should be assessed during early stages
of a clinical development program.
Phase 2 dose-ranging studies are recommended. Phase 2 studies should include assessment of
blood and urine drug concentrations to explore exposure-response relationships for safety and
efficacy. Sponsors can consider sparse blood sampling for drug exposure estimates in phase 3
trials.
B. 	Specific Efficacy Trial Considerations
1. 	Clinical Trial Designs, Populations, and Enrollment Criteria
Sponsors should conduct randomized, double-blind, controlled trials in female patients with
uUTI, using a superiority or noninferiority design.
We recommend the following inclusion and exclusion criteria:
• 	Patients should be adult females and, if appropriate, adolescent females with evidence of
pyuria (see section III.B.2., Clinical Microbiology Considerations) and at least two of the
following signs or symptoms of uUTI:
‒ 	Dysuria
‒ 	Urinary frequency
‒ 	Urinary urgency
‒ 	Suprapubic pain
• 	Patients should not have the following:
‒ 	Signs or symptoms of systemic illness such as fever greater than 38 degrees Celsius,
shaking chills, or other clinical manifestations suggestive of cUTI

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‒ 	Treatment with other antibacterial drugs that are effective for treatment of the current
uUTI
2. 	Clinical Microbiology Considerations
Before receipt of drug therapy, all patients should submit a urine specimen for culture and
antimicrobial susceptibility testing.6 A microscopic evaluation for pyuria or dipstick analysis for
leukocytes, nitrites, or a catalase test of the urine specimen should be performed. The urine
specimen should be cultured using standard microbiology laboratory procedures. In general, a
single species of bacteria on pure culture identified at 10 5 colony forming units per milliliter
(CFU/mL) or greater should be considered a true bacterial pathogen,7 and no growth of bacteria
(or growth at a quantitation of less than 103 CFU/mL) should be considered a microbiologic
success for a mid-stream clean-catch urine specimen (see section III.B.5., Efficacy Endpoints).
Antimicrobial susceptibility testing of the isolates to the investigational drug and to other
recommended antimicrobial drugs that may be used to treat uUTIs should be performed using
standardized methods unless other in vitro susceptibility testing is justified.8
Development of new rapid diagnostic tests may facilitate future clinical trial design and
potentially benefit patients by providing earlier diagnosis of causative organisms. Clinical trials
of an investigational antibacterial drug for treatment of uUTI may provide an opportunity to
contribute to the evaluation of a new diagnostic test. Sponsors interested in the development of a
new rapid diagnostic test should discuss this opportunity with the FDA.
3. 	Specific Populations
Sponsors should enroll in the trials patients from across a wide age range, including geriatric
patients.9 Sponsors can enroll patients with hepatic impairment in phase 3 trials provided the
sponsor has evaluated the pharmacokinetics of the drug in these patients and has defined
appropriate dosing regimens.
We encourage sponsors to begin discussions about their pediatric clinical development plans as
early as is feasible because pediatric studies under section 505B of the Federal Food, Drug, and
Cosmetic Act (FD&C Act), if applicable, are a required part of the overall drug development
program and sponsors are required to submit pediatric study plans no later than 60 days after an
6 Proper methods of urine specimen collection for analysis and culture are important enrollment considerations for
clinical trials. See, for example, publications from the American Society for Microbiology, such as the Clinical
Microbiology Procedures Handbook, 3rd Edition, 2010, or a more recent edition; and the Cumitech 2C: Laboratory
Diagnosis of Urinary Tract Infections, 2009, or a more recent edition.
7 Sponsors should prespecify in the protocol how patients who have more than one bacterial species (isolated on a
baseline urine culture) will be handled in the efficacy analysis.
8 Standard methods for in vitro susceptibility testing are developed by organizations such as the Clinical and
Laboratory Standards Institute, Wayne, PA.
9 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics (August 1994) and
E7 Studies in Support of Special Populations: Geriatrics; Questions and Answers (February 2012).

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end-of-phase 2 meeting or such other time as may be agreed upon by the FDA and the sponsor.10
Sponsors can include adolescent patients in phase 3 safety and efficacy trials, if appropriate.
Given the different clinical considerations regarding urinary tract infections in pregnant patients
(Gupta et al. 2011), sponsors should discuss with the FDA if the investigational drug is being
considered for use in pregnant patients who may have the potential to benefit from the
investigational drug.
4. 	Choice of Comparators
In general, sponsors should use an active comparator that is considered standard of care for
treatment of uUTI in the United States for this indication. The active comparator generally
should be approved by the FDA for treatment of uUTI. When evaluating the current standard of
care, we consider recommendations by authoritative scientific bodies (e.g., Infectious Diseases
Society of America) based on clinical evidence and other reliable information that reflects
current clinical practice. For a noninferiority trial, it is important that the analysis population
includes only patients for whom the bacterial pathogen is fully susceptible to the active control
drug on in vitro susceptibility testing.
5. 	Efficacy Endpoints
The following subsections describe the FDA’s recommended primary efficacy endpoint and
secondary endpoints.
a. 	Primary efficacy endpoint
The primary efficacy endpoint should be based on a responder outcome of clinical and
microbiologic response.
• 	Clinical and microbiologic response: Resolution of the symptoms of uUTI (see section
III.B.1., Clinical Trial Designs, Populations, and Enrollment Criteria) present at trial
entry (and no new symptoms) and the demonstration that the bacterial pathogen found at
trial entry is reduced to fewer than 10 3 CFU/mL on urine culture (microbiologic
response) assessed at a fixed time point after randomization that is based on the duration
of investigational antibacterial drug therapy and half-life of the investigational drug.
• 	Clinical or microbiologic failure: Patients who did not meet the definition of clinical
and microbiologic response (see above) or who died during the trial.
10 See section 505B of the FD&C Act and the draft guidance for industry Pediatric Study Plans: Content of and
Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (March 2016).
When final, this guidance will represent the FDA’s current thinking on this topic.

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b. 	Efficacy endpoints for a finding of superiority
Sponsors can use the primary efficacy endpoint discussed in section III.B.5.a., Primary efficacy
endpoint, or discuss with the FDA other endpoints and clinical trial designs for superiority,
including designs that incorporate a delayed treatment group with standard or approved therapies
(see section III.B.4., Choice of Comparators).
c. 	Secondary endpoints
Patients should be evaluated for continued resolution of symptoms and microbiologic success at
a fixed time point approximately 21 to 28 days following randomization. This assessment helps
to evaluate sustained microbiologic success and resolution of all clinical symptoms of uUTI (a
responder outcome) as a secondary endpoint. Sponsors also should evaluate the clinical and
microbiologic responses separately at each fixed time point assessment as secondary endpoints.
6. 	Trial Procedures and Timing of Assessments
a. 	Entry visit
Sponsors should collect baseline demographic and clinical information at the entry visit and
include clinical signs and symptoms, microbiologic specimens (Gram stain and culture of urine;
blood culture), and laboratory tests, as appropriate.
b. 	On-therapy and end-of-therapy visits
Patients should be evaluated at least once during therapy or at the end of prescribed therapy.
Clinical and laboratory assessments for safety should be performed as appropriate. If the
investigational drug needs to be continued beyond the protocol-specified duration, the protocol
should prespecify objective criteria for extending the therapy.
c. 	Post-treatment visits
The responder endpoint should be evaluated at a fixed time point after randomization that is
based on the duration of investigational antibacterial drug therapy and half-life of the
investigational drug. Patients should be evaluated by history and physical examination for
adverse reactions. Symptoms of uUTI should be assessed at this visit and a urine specimen
should be obtained for microscopic examination and culture. An assessment for the maintenance
of clinical and microbiologic response should occur at approximately 21 to 28 days after
randomization.
7. 	Statistical Considerations
In general, before trial initiation the sponsor should develop a detailed statistical analysis plan
stating the trial hypotheses and the analysis methods. The primary efficacy analysis is usually
based on the difference in the proportions of patients achieving a successful response.

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a. 	Analysis populations
The following definitions apply to various analysis populations in uUTI clinical trials:
• 	Intent-to-treat (ITT) population: All patients who were randomized.
• 	The microbiological intent-to-treat population (micro-ITT population): Randomized
patients who did not have growth of a bacterial pathogen on culture of urine at baseline
should be excluded from this population. For a noninferiority trial, the micro-ITT
population should include patients who have growth of bacterial pathogens on culture of
urine at baseline demonstrating susceptibility to the active control drug. Patients should
not be excluded from this population based on events that occurred after randomization
(e.g., loss to follow-up).
• 	Clinically evaluable population: Patients who meet the definition of the ITT population
and who follow important components of the trial as specified in the protocol.
• 	Microbiologically evaluable population: Patients who meet the definition for the
micro-ITT population and who follow important components of the trial as specified in
the protocol.
• 	Safety population: All patients who received at least one dose of the drug during the
trial.
The sponsor should consider the micro-ITT population as the primary analysis population for a
noninferiority trial. The sponsor should evaluate the consistency of the results in all populations,
explore any inconsistencies in the results of these analyses, and provide explanations in the final
report.
b. 	Noninferiority margins
Noninferiority trials can be an appropriate trial design if there is reliable and reproducible
evidence of a treatment effect for the comparator drug.11 For a uUTI trial, a noninferiority
margin of 10 percent is supported by historical evidence (see the Appendix).
c. 	Sample size
An estimate of the sample size for a noninferiority trial with 1:1 randomization is approximately
310 patients per group in the micro-ITT population. This sample size is based on a
noninferiority margin of 10 percent, a clinical success rate in the micro-ITT population of 80
percent in the treatment and control groups, a two-sided α = 0.05 statistical significance level,
and 90 percent power. Approximately 80 percent of patients should have a bacterial pathogen
11 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).

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identified by baseline culture and belong to the micro-ITT population, and thus approximately
388 patients per group may need to be included in the ITT population.
The sample size estimate for a treatment delay superiority trial with 1:1 randomization is
approximately 181 patients per group based on assumed success rates of 80 percent in the
investigational group and 65 percent in the control group (e.g., placebo treatment delay), a two-
sided α = 0.05 statistical significance level, and 90 percent power.
8. 	Labeling Considerations
Generally, the labeled indication should be the treatment of uUTI caused by the specific bacteria
identified in a sufficient number of patients in the clinical trials.

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REFERENCES
Asbach HW, 1991, Single Dose Oral Administration of Cefixime 400mg in the Treatment of
Acute Uncomplicated Cystitis and Gonorrhoea, Drugs, 42 Suppl 4:10–13.
Bleidorn J, I Gágyor, MM Kochen, K Wegscheider, and E Hummers-Pradier, 2010,
Symptomatic Treatment (Ibuprofen) or Antibiotics (Ciprofloxacin) for Uncomplicated Urinary
Tract Infection? — Results of a Randomized Controlled Pilot Trial, BMC Med, 8:30.
Christiaens TC, M De Meyere, G Verschraegan, W Peersman, S Heytens, and JM De Maeseneer,
2002, Randomised Controlled Trial of Nitrofurantoin Versus Placebo in the Treatment of
Uncomplicated Urinary Tract Infection in Adult Women, Br J Gen Pract, 52(482):729–734.
Dubi J, P Chappuis, and R Darioli, 1982, Treatment of Urinary Infection With a Single Dose of
Co-Trimoxazole Compared With a Single Dose of Amoxicillin and a Placebo, Schweiz Med
Wochenschr, 112(3):90–92.
Ferry SA, SE Holm, H Stenlund, R Lundholm, and TJ Monsen, 2007, Clinical and
Bacteriological Outcome of Different Doses and Duration of Pivmecillinam Compared With
Placebo Therapy of Uncomplicated Lower Urinary Tract Infection in Women: The LUTIW
Project, Scand J Prim Health Care, 25(1):49–57.
Gágyor I, J Bleidorn, MM Kochen G Schmiemann, K Wegscheider, and E Hummers-Pradier,
2015, Ibuprofen Versus Fosfomycin for Complicated Urinary Tract Infection in Women:
Randomized Controlled Trial, BMJ, 351:h6544.
Gupta K, TM Hooton, KG Naber, B Wullt, R Colgan, LG Miller, GJ Moran, LE Nicolle, R Raz,
AJ Schaeffer, and DE Soper, 2011, International Clinical Practice Guidelines for the Treatment
of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the
Infectious Diseases Society of America and the European Society for Microbiology and
Infectious Diseases, Clin Infect Dis, 52(5):e103–e120.
Vik I, M Bollestad, N Grude, A Bærheim, E Damsgaard, T Neumark, L Bjerrum, G Cordoba, IC
Olsen, and M Lindbæk, 2018, Ibuprofen Versus Pivmecillinam for Uncomplicated Urinary Tract
Infection in Women — A Double-Blind, Randomized Non-inferiority Trial, PLOS Medicine,
15(5): e1002569.

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APPENDIX:
JUSTIFICATION FOR NONINFERIORITY MARGIN FOR
UNCOMPLICATED URINARY TRACT INFECTIONS
We identified two trials of uncomplicated urinary tract infection (uUTI) that used a placebo
control, assessed a combined clinical and microbiological eradication outcome, and were
published in the English language (Asbach 1991; Ferry et al. 2007). Young adult females with
symptoms such as dysuria and urinary frequency and/or urgency and a baseline urine culture
positive for a bacterial pathogen (e.g., growth of bacteria at a quantitation of greater than 105
colony forming units per milliliter (CFU/mL)) were enrolled in these trials. The responder
efficacy endpoint of both resolution of symptoms (clinical resolution) and microbiological
eradication of the bacterial pathogen from urine (bacterial pathogen found at trial entry is
reduced to fewer than 10 3 CFU/mL on follow-up urine culture) was evaluated in these two trials
(Table 1).
Table 1: Clinical Resolution Plus Microbiological Eradication Outcome Assessment
Study Name
(first author)
Timing of
Outcome
Assessment
Antibacterial
Group Responder
Rate
Control
Group
Responder
Rate
Difference 	95% CI *
Asbach Days 14–17
post therapy
Oral cefixime (400
mg single dose)
50/57 (88%)
Placebo
5/19 (26%) 61.4% 	36.3% to 86.5%
Ferry 	Days 8–10
Oral pivmecillinam
(pooled groups
given 200 mg TID *
x7 days, 200 mg
BID* x7 days, or
400 mg BID * x3
days)
374/657 (57%)
Placebo
30/227 (13%) 43.7% 	37.5% to 49.2%
Random effects meta-analysis 	49.4% 	33.2% to 65.6%
* CI = confidence interval; TID = ter in die or three times per day; BID = bis in die or two times per day
An estimate for the treatment difference for the responder efficacy endpoint of clinical resolution
plus microbiological eradication is approximately 33 percent (the lower bound of the two-sided
95 percent confidence interval from Table 1). Because of the differences between the point
estimate antibacterial group responder rates and what might be expected in prospective
noninferiority trials, we discounted 50 percent of the treatment effect to account for uncertainties
and generalizability issues when translating the historical treatment effect to the effect of a
current active control, as recommended in the guidance for industry Non-Inferiority Clinical
Trials to Establish Effectiveness (November 2016).1 Therefore, an estimated treatment
difference (M 1 ) is approximately 16 percent. Considering preservation of the treatment effect,
we recommend a clinically acceptable noninferiority margin (M 2 ) of 10 percent.
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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Below, we identify five additional published prospective and controlled trials of uUTI and
describe results that are supportive of the treatment effect of an antibacterial drug for uUTI.
These five trials were not included in the meta-analysis above for the responder endpoint for the
following reasons.
1. 	One trial (Bleidorn et al. 2010) compared antibacterial drug treatment to ibuprofen.
Ibuprofen appeared to influence symptom resolution as compared to ciprofloxacin, thus
the trial did not show a significant difference between treatment groups for symptom
resolution at Days 4 and 7. There appeared to be an advantage for the antibacterial group
for the microbiological eradication endpoint on Day 7 (72 percent eradication in the
ciprofloxacin group compared to 49 percent in the ibuprofen group), but this difference
was not statistically significant.
2. 	A second trial (Christiaens et al. 2002) evaluated clinical and microbiologic response
separately, which showed significant differences in favor of the antibacterial drug group
over placebo on Days 3 and 7 for both endpoints. However, this trial was not included in
the analysis because patient level data were not available to assess an individual patient’s
outcome on the combined responder endpoint.
3. 	A third trial (Gágyor et al. 2015) enrolled patients that presented to an outpatient clinic
with signs and symptoms of uUTI, regardless of whether a baseline urine culture
demonstrated a bacterial pathogen. Furthermore, there were no outcome data on
microbiological eradication because the trial did not evaluate urine cultures at a follow-up
visit. A statistically significantly greater proportion of females achieved resolution of
symptoms at Day 7 in the fosfomycin group compared to the ibuprofen group (82 percent
for fosfomycin group and 70 percent for the ibuprofen group).
4. 	A fourth trial (Dubi et al. 1982) was not published in the English language and
approximately 25 percent of the patients enrolled in this trial had only a positive urine
culture with no symptoms of uUTI (i.e., females with asymptomatic bacteriuria). This
trial showed a statistically significant difference in favor of the antibacterial drug on the
responder endpoint compared to placebo (70 percent versus 44 percent, respectively),
although these results were likely driven by the microbiological eradication outcome
measure caused by some patients not having symptoms at baseline.
5. 	A fifth trial (Vik 2018) enrolling females with uUTI, randomized to receive an
antibacterial drug or ibuprofen, included the evaluation of women who did not have a
positive urine culture at baseline. The results showed that ibuprofen was inferior to the
antibacterial drug (74 percent of patients in the antibacterial drug group were free of
symptoms at Day 4 compared to 39 percent of patients in the ibuprofen group).