Study Comparing Nitrofurantoin to Fosfomycin for Acute Urinary Tract Infection in Women

Phase 4

• Conditions: Urinary Tract Infections; Cystitis
• Interventions: Drug: nitrofurantoin; Drug: fosfomycin

• Registration Number: NCT01966653
• Lead Sponsor: University Hospital, Geneva

Brief Summary

Developed before the establishment of a structured process for drug assessment, nitrofurantoin is now being prescribed frequently given the rise in multi-resistant gram-negative pathogens. Doubts remain regarding fosfomycin's long-term clinical effectiveness. A randomized, controlled trial is needed to explore the clinical effectiveness and better define the side effect profiles of both nitrofurantoin and fosfomycin. This multi-center open trial will randomize 600 non-pregnant women at three international sites (200 each in Poland, Switzerland, and Israel) at increased risk for carriage of resistant uropathogens and with suspicion of uncomplicated lower urinary tract infection to receive either oral nitrofurantoin 100 mg three times daily for 5 days or a single 3g dose of oral fosfomycin. Patients will be followed for clinical and bacteriologic response at days 14 and 28 post therapy completion. The study hypothesis holds that nitrofurantoin will be superior to fosfomycin in clinical efficacy at final follow-up.

Detailed Description

Developed before the establishment of a structured process for drug assessment, nitrofurantoin is now being prescribed frequently given the rise in multi-resistant gram-negative pathogens. Doubts remain regarding fosfomycin's long-term clinical effectiveness. A randomized, controlled trial is needed to explore the clinical effectiveness and better define the side effect profiles of both nitrofurantoin and fosfomycin. From autumn 2013 through summer 2016, this multi-center open trial will randomize 600 non-pregnant women at three international sites (200 each in Poland, Switzerland, and Israel) at increased risk for carriage of resistant uropathogens and with suspicion of uncomplicated lower urinary tract infection to receive either oral nitrofurantoin 100 mg three times daily for 5 days or a single 3g dose of oral fosfomycin. Patients will be followed for clinical and bacteriologic response at days 14 and 28 post therapy completion. The study hypothesis holds that nitrofurantoin will be superior to fosfomycin in clinical efficacy at final follow-up.

Study Timeline

• Study Start: 2013-10
• Study First Submitted: 2013-10-10
• Study First Submitted QC: 2013-10-16
• Study First Posted: 2013-10-21
• Status Verified: 2017-05
• Primary Completion: 2017-05
• Last Update Submitted: 2017-05-01
• Last Update Posted: 2017-05-02
• Study Completion: 2017-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 600

Inclusion Criteria

• Female gender
• Age ≥ 18 years
• Written informed consent
• At least one of four key UTI symptoms that could be attributed to an uncomplicated UTI, and no alternative explanation (i.e. symptoms suggestive of STI or vulvo-vaginitis):
• Dysuria
• Urgency (including nocturia)
• Frequency
• Suprapubic tenderness
• Urine dipstick test positive for either nitrites or leukocyte esterase
• Patient is at increased risk for resistant pathogens, e.g., FQ-resistant or ESBL-producing Enterobacteriacae

Exclusion Criteria

• Male sex
• Pregnancy or planned pregnancy
• Known carriage of nitrofurantoin- or fosfomycin-resistant uropathogens(s)
• Concomitant antimicrobial therapy
• Use of any antibiotics in the past 7 days
• Known or suspected hypersensitivity or allergy to fosfomycin or nitrofurantoin
• History of lung or liver reaction or peripheral neuropathy after use of nitrofurantoin or other nitrofurans in the past
• Pre-existing polyneuropathy
• G6PD deficiency
• Symptoms consistent with UTI in the preceding 4 weeks
• Active upper UTI (e.g. pyelonephritis, urosepsis: fever > 38.0, flank pain, chills)
• Symptoms/signs suggestive of vaginitis or sexually transmitted infection
• Indwelling catheter, nephrostomy, ureter stent or other foreign material
• Otherwise complicated UTI:
• A history of anatomical or functional abnormalities of the urogenital tract:
• Congenital abnormalities
• Polycystic kidney disease
• Obstruction or stricture of renal pelvis, ureter or urethra
• Kidney stones
• Cystocele
• Cystic diverticulae
• Change of anatomical proportions (e.g. after ureter implantation)
• Chronic vesico-urethral reflux
• Neurogenic bladder
• Severe chronic renal (creatinine clearance < 30 ml/min) or hepatic dysfunction
• Porphyria
• Immunosuppression:
• Untreated infection with the human immunodeficiency virus (HIV)
• Use of high-dose systemic corticosteroids or other immunosuppressive medication
• Chemotherapy
• Treatment with radiation
• Critical illness requiring intensive care
• Planned surgery within the next 6 weeks
• Inability to take oral drugs
• Participation in another prospective clinical trial
• Previous enrolment in the proposed study
• Inability to understand or to follow the study protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
nitrofurantoin	nitrofurantoin	Nitrofurantoin will be given orally at a dose of 100 mg three times daily for 5 days.
fosfomycin	fosfomycin	A single 3g dose of oral fosfomycin will be given.

Primary Outcome Measures

Name	Time	Method
Number of participants with clinical cure, clinical failure, or indeterminate clinical response (see description below)	at 28 days post therapy completion	Clinical response is defined as either (1) clinical cure, which in turn is defined as complete resolution of symptoms with no recurrence of symptoms or signs of urinary tract infection; (2) clinical failure, defined as the need for additional, or change in, antibiotic treatment due to a urinary tract infection, OR discontinuation due to lack of efficacy; or (3) indeterminate response, defined as either persistence of symptoms without objective evidence of infection (absence of bacteriuria or pyuria) OR any extenuating circumstances precluding a classification or clinical cure/failure.

Secondary Outcome Measures

Name	Time	Method
Number of participants with bacteriologic cure and with bacteriologic recurrence	at 28 days post therapy completion	Bacteriologic response is defined as either (1) bacteriologic cure, that is, eradication of the infecting strain with no recurrence of bacteriuria (\<10x3 cfu/mL) during follow-up; or (2) bacteriologic recurrence, defined as bacteriuria \>10x3 cfu/mL. However, bacteriologic recurrence without urinary tract symptoms will be designated asymptomatic bacteriuria and left untreated.

Trial Locations

Locations (3)

Tel Aviv University; 🇮🇱 Tel Aviv, Israel

Lodz University Hospital; 🇵🇱 Lodz, Poland

University Hospitals of Geneva; 🇨🇭 Geneva, Switzerland