Urinary Tract Infections
Conditions
Keywords
Urinary Tract Infections, Urinary antiinfective agents
Brief summary
This study will investigate the treatment of urinary tract infection in men. Specifically, the investigators are looking to see if shorter duration of antibiotics (7 days) is any worse than longer duration of antibiotics (14 days). The investigators will also study whether longer treatment leads to an increase in antibiotic resistant bacteria in the large intestine (colon), or an increase in drug side effects.
Detailed description
The proposed study is a randomized placebo-controlled trial of treatment duration for male urinary tract infection (UTI). Specifically, 319 men with a UTI will be randomized to 7 vs. 14 days of antimicrobial treatment. The primary outcome is resolution of UTI symptoms, assessed 14 days after completing active antimicrobial treatment. Secondary outcomes include recurrent UTI in the 4 weeks after treatment, adverse drug events, and intestinal carriage of antimicrobial resistant Gram-negative bacilli. Subjects will be enrolled from the Primary Care Clinic and Emergency Department at the Minneapolis VA Medical Center (MVAMC). Currently, the optimal treatment duration for male UTI is unknown. A clinical trial of 14 vs. 28 days of treatment showed no difference in outcomes, whereas another trial of 3 vs.14 days showed an increase in recurrence with 3 days of treatment. However, current treatment recommendations are to treat men with UTI for 7 to 14 days, and no data exist to favor the shorter or longer duration. Most men with UTI in the VA are treated for more than 7 days, which is associated with a small but significant increase in Clostridium difficile infection. Additionally, other studies of non-UTI infectious diseases have shown that longer-duration treatment leads to increased antimicrobial resistance. Longer-duration treatment is also more costly and inconvenient to patients. Thus, since longer-duration treatment is associated with some adverse outcomes, in order to justify longer-duration treatment thee must be some clinically significant benefit to the extended treatment. Accordingly, the proposed randomized placebo-controlled trial of 319 men with UTI will test the hypothesis that 7 days of antimicrobial treatment is non-inferior for the resolution of UTI symptoms when compared to 14 days of treatment. This study will provide valuable information to VA patients and clinicians regarding a common and understudied clinical decision.
Interventions
14 days of antimicrobial treatment
7 days of antimicrobial treatment
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Must have all * Male gender * New-onset (within 7 days) of at least one of the following symptoms/findings: dysuria, urinary frequency, urgency, hematuria, perineal pain, supra-pubic pain, costovertebral angle tenderness, or flank pain * Treated as an outpatient (Primary Care Center or Emergency Department), with \< 24 hours observation in the hospital or Emergency Department following the time of initial diagnosis * Prescribed treatment with at least 7 days, but not more than 14 days, of either ciprofloxacin or TMP-SMZ
Exclusion criteria
Must have none * Admission to the hospital (for \> 24h) at the time of diagnosis * Documented fever at time of initial evaluation ( 38.0 Celsius) * Previous enrollment in the study * Treatment for UTI in past 14 days * Not able to give informed consent * Unwilling to return for study visit * Symptoms thought more likely to be caused by a non-UTI diagnosis (e.g., urinary calculus, sexually transmitted infection, etc.) * Other antimicrobial therapy (new or ongoing) prescribed for a non-UTI diagnosis (e.g., cellulitis, pneumonia, etc.) * Treatment initiated with an empiric antimicrobial to which the organism isolated in the urine culture is non-susceptible based on standard laboratory criteria * Treatment initiated with an empiric antimicrobial regimen that is underdosed, based on current guidelines and reviews
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resolution of UTI Symptoms 14 Days After Completing Active Antimicrobial Therapy | 14 days | This outcome will be assessed in a binary manner. Subjects with persistent UTI symptoms or having received further antimicrobials because of UTI symptoms will be considered to have not met the primary outcome, whereas those without persistent UTI symptoms and not having received further antimicrobials will be considered to have met the primary outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrent UTI Within 28 Days of Completing Active Study Medication | 28 days | New onset of symptomatic UTI within the 28 day follow-up period |
| Adverse Drug Event in the 28 Days After Completing Study Medication | 28 days | The incidence of adverse drug events, including nausea, vomiting, diarrhea, dizziness, headache, drug allergy, and C. difficile infection, both individually and in aggregate, will be compared between treatment groups This outcome is number of subjects experiencing ANY adverse drug event |
| Intestinal Carriage of Antimicrobial-resistant Gram Negative Bacilli | 7 days | Intestinal carriage of antimicrobial-resistant Gram-negative bacilli after completing study medication, as compared to a baseline sample taken early in treatment. Antimicrobial resistance for this measure was defined as newly detected resistance to either of the study drugs, ciprofloxacin or trimethoprim/sulfamethoxazole. |
Countries
United States
Participant flow
Recruitment details
Enrolled subjects are afebrile men with symptomatic urinary tract infection who were initially treated with 7-14 days of trimethoprim/sulfamethoxazole (TMP/SMZ) or ciprofloxacin by the treating clinician. Subjects were randomized prior to day 8 of treatment to an additional 7 days of their original study drug (14d group) or placebo (7d group.
Pre-assignment details
Primary analysis was per-protocol, and included all subjects who took at least 26 of 28 doses of medication. Intention to treat analysis includes all randomized subjects.
Participants by arm
| Arm | Count |
|---|---|
| Longer (14 Day) Duration Antimicrobial Treatment 14 days of ciprofloxacin or trimethoprim/sulfamethoxazole
Longer therapy duration: 14 days of antimicrobial treatment | 136 |
| Shorter (7 Day) Duration Antimicrobial Treatment 7 days of ciprofloxacin or trimethoprim/sulfamethoxazole, followed by 7 days of placebo
Shorter therapy duration: 7 days of antimicrobial treatment | 136 |
| Total | 272 |
Baseline characteristics
| Characteristic | Longer (14 Day) Duration Antimicrobial Treatment | Shorter (7 Day) Duration Antimicrobial Treatment | Total |
|---|---|---|---|
| Age, Continuous | 67.8 years STANDARD_DEVIATION 11.6 | 67.8 years STANDARD_DEVIATION 11.6 | 67.8 years STANDARD_DEVIATION 11.6 |
| Cerebrovascular accident | 5 Participants | 13 Participants | 18 Participants |
| CKD | 14 Participants | 8 Participants | 22 Participants |
| Diabetes | 60 Participants | 46 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 126 Participants | 127 Participants | 253 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants |
| HIV | 2 Participants | 2 Participants | 4 Participants |
| Incontinence | 52 Participants | 44 Participants | 96 Participants |
| Indwelling catheter use | 8 Participants | 8 Participants | 16 Participants |
| Intermittent catheter use | 23 Participants | 24 Participants | 47 Participants |
| Prior UTI | 78 Participants | 84 Participants | 162 Participants |
| Prostate Cancer | 23 Participants | 21 Participants | 44 Participants |
| Prostatic hypertrophy | 47 Participants | 56 Participants | 103 Participants |
| Prostatitis | 18 Participants | 16 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 26 Participants | 49 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 105 Participants | 107 Participants | 212 Participants |
| Region of Enrollment United States | 136 Participants | 136 Participants | 272 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 136 Participants | 136 Participants | 272 Participants |
| Spinal cord injury | 6 Participants | 5 Participants | 11 Participants |
| Urethral stricture | 16 Participants | 17 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 136 | 0 / 136 |
| other Total, other adverse events | 33 / 136 | 28 / 136 |
| serious Total, serious adverse events | 0 / 136 | 0 / 136 |
Outcome results
Primary
Resolution of UTI Symptoms 14 Days After Completing Active Antimicrobial Therapy
This outcome will be assessed in a binary manner. Subjects with persistent UTI symptoms or having received further antimicrobials because of UTI symptoms will be considered to have not met the primary outcome, whereas those without persistent UTI symptoms and not having received further antimicrobials will be considered to have met the primary outcome.
Time frame: 14 days
Population: Per-protocol analysis (including all subjects who took medication as directed, defined as at least 26 of 28 doses, missing no more than 2 consecutive doses)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Longer (14 Day) Duration Antimicrobial Treatment | Resolution of UTI Symptoms 14 Days After Completing Active Antimicrobial Therapy | 111 Participants |
| Shorter (7 Day) Duration Antimicrobial Treatment | Resolution of UTI Symptoms 14 Days After Completing Active Antimicrobial Therapy | 122 Participants |
Secondary
Adverse Drug Event in the 28 Days After Completing Study Medication
The incidence of adverse drug events, including nausea, vomiting, diarrhea, dizziness, headache, drug allergy, and C. difficile infection, both individually and in aggregate, will be compared between treatment groups This outcome is number of subjects experiencing ANY adverse drug event
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Longer (14 Day) Duration Antimicrobial Treatment | Adverse Drug Event in the 28 Days After Completing Study Medication | 29 Participants |
| Shorter (7 Day) Duration Antimicrobial Treatment | Adverse Drug Event in the 28 Days After Completing Study Medication | 26 Participants |
Secondary
Intestinal Carriage of Antimicrobial-resistant Gram Negative Bacilli
Intestinal carriage of antimicrobial-resistant Gram-negative bacilli after completing study medication, as compared to a baseline sample taken early in treatment. Antimicrobial resistance for this measure was defined as newly detected resistance to either of the study drugs, ciprofloxacin or trimethoprim/sulfamethoxazole.
Time frame: 7 days
Population: of the 163 subjects who participated in the optional intestinal carriage sub-study, 65 had growth in both of the submitted stool samples and are included in this analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Longer (14 Day) Duration Antimicrobial Treatment | Intestinal Carriage of Antimicrobial-resistant Gram Negative Bacilli | 4 Participants |
| Shorter (7 Day) Duration Antimicrobial Treatment | Intestinal Carriage of Antimicrobial-resistant Gram Negative Bacilli | 4 Participants |
Secondary
Recurrent UTI Within 28 Days of Completing Active Study Medication
New onset of symptomatic UTI within the 28 day follow-up period
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Longer (14 Day) Duration Antimicrobial Treatment | Recurrent UTI Within 28 Days of Completing Active Study Medication | 15 Participants |
| Shorter (7 Day) Duration Antimicrobial Treatment | Recurrent UTI Within 28 Days of Completing Active Study Medication | 13 Participants |