Clinical Effectiveness and Bacteriological Eradication of 4 Short-course Antibiotics for Uncomplicated UTIs in Women.

Study Overview
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Brief Summary
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Randomized clinical trial in which women aged 18 or older and with symptoms of uncomplicated lower urinary tract infection and a positive urine dipstick analysis will be randomized to one of the following four groups: 2-day 3 g fosfomycin o.d., 3-day pivmecillinam 400 mg. t.i.d, 5-day nitrofurantoin 100 mg t.i.d. or a single dose of 3 g of fosfomycin. Sample: 1,000 patients. Two co-primary endpoints are considered: clinical effectiveness at day 7 and bacteriological eradication at day 14. Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed.

Detailed Description
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Uncomplicated lower urinary tract infections (LUTI) represent a common problem in primary care. Resistance of uropathogens to common antibiotics has significantly increased in the last years. Current local guidelines recommend the use of a single 3 g dose of fosfomycin for these infections, but most general practitioners prefer short-course therapies to single-dose therapy. No study has compared head-to-head short course antimicrobial agents for uncomplicated LUTIs. Therefore, the aim of this randomized clinical trial is to compare three different short-course antibiotic therapies with single-dose fosfomycin for uncomplicated LUTIs in adult women. This will be a pragmatic, multicenter, parallel group, open randomized trial. Women aged 18 or older and with symptoms of uncomplicated LUTI and a positive urine dipstick analysis will be randomized to one of the following four groups: 2-day 3 g fosfomycin o.d., 3-day pivmecillinam 400 mg. t.i.d, 5-day nitrofurantoin 100 mg t.i.d. or a single dose of 3 g of fosfomycin. Sample: 1,000 patients. Two co-primary endpoints are considered: clinical effectiveness, defined as resolution of symptoms, answered by the patients at day 7, and bacteriological eradication (proportion of patients bacteriologically cured) at day 14. Patients will be given a symptom diary for seven days. Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed. If positive, antibiograms for the 3 antibiotics studied will be performed.

Official Title
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Clinical Effectiveness and Bacteriological Eradication of Three Different Short-course Antibiotic Regimens and Single-dose Fosfomycin for Uncomplicated Lower Urinary Tract Infections in Adult Women.

Conditions
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Urinary Tract Infections

Intervention / Treatment
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* Drug: Fosfomycin Trometamol Salt
* Drug: Nitrofurantoin
* Drug: Pivmecillinam
* Drug: Fosfomycin Trometamol Salt


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women of 18 years of age or older, with clinical features of uncomplicated community-acquired lower urinary tract infection including: At least one of four key symptoms of lower urinary tract infection: dysuria, urgency including nycturia, frequency, and suprapubic tenderness that could be attributed to an uncomplicated lower urinary tract infection, and no alternative explanation (i.e. symptoms suggestive of sexually-transmitted infection or vulvovaginitis), and A urine dipstick analysis positive for either nitrites or leukocyte esterase. Exclusion Criteria: Male sex High suspicion of pyelonephritis (i.e. fever ≥ 37.5°C or flank pain/tenderness) Any condition that may lead or predispose to complicated urinary infection (i.e. indwelling urinary catheter, pregnancy, immunosuppressive therapy, abnormal urinary tracts, recurrent urinary tract infection, severe neurological disease affecting the bladder) Pregnancy or planned pregnancy Symptoms consistent with urinary tract infection in the preceding 4 weeks Patients taking long-term antibiotic prophylaxis Ongoing antibiotic therapy or use of any systemic antibiotic in the previous 7 days Symptoms correlating with differential diagnosis (i.e. vaginal discharge or pain) Hypersensitivity or allergy to β lactams, nitrofurantoin and/or fosfomycin Moderate to severe chronic renal insufficiency Pre-existing polyneuropathy History of lung or liver reaction or peripheral neuropathy after previous use of nitrofurantoin Glucose-6-phosphate dehydrogenase deficiency Porphyria or systemic primary carnitine deficiency or of the type organic aciduria (i.e. methylmalonic aciduria and propionicacidaemia) Esophageal stricture Current intake of allopurinol or probenecid or valproate Currently part of another randomized clinical trial Previous enrolment in the proposed study Patients living in long-term institutions; and/or Difficulty in conducting scheduled follow-up visits

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3 short-course antibiotic regimens and one-dose of fosfomycin
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Short-course fosfomycin<br>3 g of fosfomycin once daily for two days (sachets) | Drug: Fosfomycin Trometamol Salt<br>* Fosfomycin 3 g 2 sachets, taken orally, once daily for two days<br>* Other names: Monurol;|
| Active Comparator: Short-course nitrofurantoin<br>Five-day nitrofurantoin 100 mg t.i.d. (pills) | Drug: Nitrofurantoin<br>* Nitrofurantoin 50 mg pills, taken orally, two pills/8 hours, for five days<br>* Other names: Furantoin;|
| Active Comparator: Short-course pivmecillinam<br>Three-day pivmecillinam 400 mg. t.i.d. (pills) | Drug: Pivmecillinam<br>* Pivmecillinam 400 mg pills. taken orally, one pill/8 hours, for three days<br>* Other names: Selexid;|
| Active Comparator: Single-dose fosfomycin<br>Single 3 g dose of fosfomycin (sachet) | Drug: Fosfomycin Trometamol Salt<br>* Fosfomycin 3 g one sachet, taken orally, for one day<br>* Other names: Monurol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical effectiveness. | Proportion of patients who report being cured, defined as the resolution of the four symptoms, scoring 0 in the symptom diary. | Day 7. | 
| Bacteriological eradication. | Proportion of patients bacteriologically cured, defined as less than 1,000 colony forming units (cfu)/ml. | Day 14. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of symptoms. | Number of days until the last day the patient scores 0 in any of the four symptoms. | From baseline visit to day 7. | 
| Bacteriological eradication. | Proportion of patients bacteriologically cured, defined as less than 1,000 cfu/ml. | Day 28. | 
| Relapse rate. | Proportion of patients presenting a relapse of symptoms within the first four weeks after inclusion in the study and timing of relapse of symptoms and/or bacteriuria. | Days 7, 14 and 28. | 
| Reattendance and complication rate. | Proportion of patients re-attending healthcare services and development of complications within the first 4 weeks (i.e. pyelonephritis, urosepsis). | Days 7, 14 and 28. | 
| Adverse event rate. | Proportion of patients presenting adverse and serious adverse events. | Days 7, 14 and 28. | 
| Change in quality of life. | Change in the quality of life by means of the 5-level EQ-5D version (EQ-5D-5L) validated questionnaire (Spanish version). | Days 0 and 7. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urinary Tract Infections, Women, Patient Outcome Assessment, Bacteriological Eradication, Urinalysis, Anti-Bacterial Agents, Antimicrobial Resistance, Short Course, Primary Health Care