Clinical trial NCT02142751: Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli
Official title: Phase 3, Randomized, Controlled Multicentric, Open-label Clinical Trial to Prove Non-Inferiority of Fosfomycin vs Meropenem or Ceftriaxone in the Treatment of Bacteriemic Urinary Infection Due to Multidrug Resistance in E.Coli
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection Due to ESBL Escherichia Coli
Keywords: Escherichia coli
Extended-spectrum β-lactamases (ESBLs)
Bacteremia
Urinary tract infection
Bloodstream infection
Fosfomycin
Meropenem
Pharmacokinetics
intestinal colonization
Recurrence
multidrug resistance E.coli
Ceftriaxone
Lead sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Sponsor class: OTHER
Collaborators: name: Spanish Network for Research in Infectious Diseases
First posted: 2014-05-20
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Enterobacterieaceae (and specially Escherichia coli) showing resistance due to multidrug-resistant Escherichia coli, plasmid mediated AmpC or quinolone resistance caused by chromosomal mechanisms have spread worldwide during the last decades. This is important because many of these isolates are also resistant to other first-line agents such as fluoroquinolones or aminoglycosides, leaving few available options for therapy, and this condition is associated with increased morbidity- mortality and length of hospital stay. While carbapenems are considered the drugs of choice for multidrug-resistant Escherichia coli and AmpC producers, recent data suggests that certain alternatives may be suitable for some types of infections.

At the present time, finding therapeutic alternatives to carbapenems and cephalosporins for the treatment of invasive infections due to multidrug-resistant Escherichia coli is critical. Fosfomycin was discovered more than 40 years ago but was not investigated according to present standards, and thus is not used in clinical practice except in desperate situations. It is one of the so-considered neglected antibiotics with high potential interest for the future.

With the aim of demonstrate the clinical non-inferiority of intravenous fosfomycin compared to meropenem or ceftriaxone in the treatment of bacteraemic urinary tract infections caused by multidrug-resistant Escherichia coli . The investigators propose a "real practise" randomised, controlled, multicentre phase III clinical trial to compare the clinical and microbiological efficacy and safety of intravenous fosfomycin (4 grammes every 6 hours) with meropenem (1 gramme every 8 hours) or ceftriaxone (1 gramme every 24 hours) as targeted therapy of the previously specified infection; change to oral therapy according to predefined options is allowed in both arms after 5 days. Follow-up for the study is planned up to 60 days.

Detailed description: The FOREST study is a phase 3, randomised, controlled, multicentric, open-label clinical trial to prove the noninferiority of fosfomycin versus meropenem in the targeted treatment of bacteraemic UTI due to ESBL-EC, designed as a real practice trial. It is a non-commercial, investigator-driven clinical study funded through a public competitive call by Instituto de Salud Carlos III, Spanish Ministry of Economy (PI13/01282).

The study is coordinated by investigators from Hospital Universitario Virgen Macarena in Seville, Spain; the sponsorship is performed by Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI), of which the sponsor-scientific responsibilities are delegated to the CTU (Clinical Trial Unit-Hospital Universitario Virgen del Rocío, Seville, Spain). All participating patients or their relatives must give written informed consent before any study procedures occur, including the withdrawal of biological samples for the study.

The hypothesis to test is that intravenous fosfomycin is not inferior to meropenem for the targeted treatment of bacteraemic UTI caused by ESBL-EC in terms of efficacy.

The primary objective of the study is to demonstrate that intravenous fosfomycin is not inferior to meropenem for reaching clinical and microbiological cure 5-7 days after the completion of treatment.

Secondary objectives include comparing the early clinical and microbiological response, 30-day mortality, hospital stay, recurrence rate, safety and impact on intestinal colonisation by MDR Gram-negative bacilli, evaluation of the rate of resistance development to fosfomycin and blood level concentration of fosfomycin.

Eligibility criteria: Inclusion Criteria:

* ≥18 years old hospitalized patients
* Negative pregnancy test in fertile women
* Episode of clinically-significant monomicrobial urinary BSI due to multidrug-resistant E.coli susceptible to fosfomycin and meropenem or ceftriaxone
* Urinary sepsis with multidrug resistant E. coli isolation from the blood cultures, requires at least one clinical criteria and one of the following urinalysis criteria:

Clinical criteria

* UTI symptoms (dysuriac, urgency, suprapubic pain or pollakiuria)
* Lumbar back pain
* Cost-vertebral angle tenderness
* Altered mental status in people up to 70 years old
* Intermittent or permanent indwelling foley catheter (or withdrawal during 24 hours previous) even without urinary symptoms urinalysis criteria
* Urine dipstick test positive for either nitrites or leukocyte esterase
* Positive urine culture - Signed informed consent form (ICF) executed prior to protocol screening assessments

Exclusion Criteria:

* Polymicrobial bacteremia
* No drainage of renal abscess or obstructive uropathy unresolved
* Pregnant or careening women
* Haematogenous infection
* Other concomitant infection
* Renal transplantation recipients
* Polycystic kidney
* Hypersensitivity and/or intolerance to meropenem or fosfomycin or ceftriaxone
* Palliative care or life expectance \< 90 days
* Septic shock at time of randomization
* New York Heart Association (NYHA) functional Class IV, hepatic cirrhosis or renal impairment receiving dialysis
* Active empiric treatment \>72 hours
* Late randomization \>24 hours after multidrug resistant.coli blood culture´s identification
* Participation in other clinical trial with active treatment

Primary outcomes:
measure: Clinical and microbiological cure rate
timeFrame: Day 5-7 after end of treatment (test of cure)
Secondary outcomes:
measure: Early clinical response
timeFrame: After 5 -7 days of complete treatment (from the first day of study drugs administration)
measure: Mortality
timeFrame: At day 30 of follow-up
measure: Length of hospital stay
timeFrame: At day 30 of follow-up
measure: Safety of intravenous fosfomycin in this indication
timeFrame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
measure: Recurrences (relapse and reinfection) rate
timeFrame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
measure: Fosfomycin steady-state plasma concentration
timeFrame: At 3 days after treatment started
measure: Microbiota impact of study treatment bacilli
timeFrame: Screening, day 5-7, day 12
measure: Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem
timeFrame: participants will be followed for the duration of fosfomycin, an expected average of 14 days
measure: Early microbiological response
timeFrame: within the first 5 days after treatment started
measure: Safety of intravenous antibiotic administration in this indication
timeFrame: To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Other outcomes:
Locations:
city: Terrassa
country: Spain
facility: Hospital Mutua de Terrassa
state: Barcelona
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrín
state: Gran Canarias
city: Vilanova
country: Spain
facility: Hospital Arnau de Vilanova
state: Lleida
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
state: Murcia
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Tenerife
city: Alicante
country: Spain
facility: Hospital Marina Baixa
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital Parc Salud Mar
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i San Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge
city: Bilbao
country: Spain
facility: Hospital de Cruces
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Royo Villanova
Study officials:
affiliation: Spanish Network for Research in Infectious Diseases
name: JESUS RODRIGUEZ-BAÑO, MD, PhD
role: STUDY_CHAIR
References:
citation: Sojo-Dorado J, Lopez-Hernandez I, Rosso-Fernandez C, Morales IM, Palacios-Baena ZR, Hernandez-Torres A, Merino de Lucas E, Escola-Verge L, Bereciartua E, Garcia-Vazquez E, Pintado V, Boix-Palop L, Natera-Kindelan C, Sorli L, Borrell N, Giner-Oncina L, Amador-Prous C, Shaw E, Jover-Saenz A, Molina J, Martinez-Alvarez RM, Duenas CJ, Calvo-Montes J, Silva JT, Cardenes MA, Lecuona M, Pomar V, Valiente de Santis L, Yague-Guirao G, Lobo-Acosta MA, Merino-Bohorquez V, Pascual A, Rodriguez-Bano J; REIPI-GEIRAS-FOREST group. Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jan 4;5(1):e2137277. doi: 10.1001/jamanetworkopen.2021.37277.
citation: Rosso-Fernandez C, Sojo-Dorado J, Barriga A, Lavin-Alconero L, Palacios Z, Lopez-Hernandez I, Merino V, Camean M, Pascual A, Rodriguez-Bano J; FOREST Study Group. Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial. BMJ Open. 2015 Mar 31;5(3):e007363. doi: 10.1136/bmjopen-2014-007363.