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Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli (FOREST)

Primary Purpose

Infection Due to ESBL Escherichia Coli

Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Fosfomycin sodium intravenous
Meropenem intravenous
Ceftriaxone intravenous
Sponsored by
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infection Due to ESBL Escherichia Coli focused on measuring Escherichia coli, Extended-spectrum β-lactamases (ESBLs), Bacteremia, Urinary tract infection, Bloodstream infection, Fosfomycin, Meropenem, Pharmacokinetics, intestinal colonization, Recurrence, multidrug resistance E.coli, Ceftriaxone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Mutua de Terrassa
  • Hospital Universitario de Gran Canaria Dr. Negrín
  • Hospital Arnau de Vilanova
  • Hospital Clínico Universitario Virgen de la Arrixaca
  • Hospital Universitario de Canarias
  • Hospital Marina Baixa
  • Hospital General Universitario de Alicante
  • Hospital Parc Salud Mar
  • Hospital de la Santa Creu i San Pau
  • Hospital Vall d'Hebron
  • Hospital Universitario de Bellvitge
  • Hospital de Cruces
  • Hospital Universitario de Burgos
  • Hospital Universitario Reina Sofía
  • Hospital Ramón y Cajal
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario Central de Asturias
  • Hospital Son Espases
  • Hospital Marqués de Valdecilla
  • Hospital Universitario Virgen Macarena
  • Hospital Universitario y Politécnico La Fe
  • Hospital Royo Villanova

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Other

Arm Label

Fosfomycin sodium intravenous

Meropenem intravenous

Ceftriaxone intravenous

Arm Description

4g every 6 hours iv (60 min infusion)

1g every 8 hours (15-30 min infusion)

1g every 24h (2-4 min)

Outcomes

Primary Outcome Measures

Clinical and microbiological cure rate
Clinical Cure: Complete resolution of infection symptoms (bacteremia and/or urinary tract infection-UTI-), present at the day on which blood culture was drawn. Microbiological cure: Negative blood culture at day 5-7 after end of treatment. Besides this, if UTI was confirmed with a positive urine culture with the same microorganism than the blood culture, this culture should become negative.

Secondary Outcome Measures

Early clinical response
The infection was completely resolved after 5-7 days of complete treatment
Mortality
Death for any reason.
Length of hospital stay
It is defined as the time from admission to hospital discharge
Safety of intravenous fosfomycin in this indication
Gathering any related adverse event from the informed consent form signature to the end of follow-up.
Recurrences (relapse and reinfection) rate
Relapse: new symptoms of UTI in patient with previously considered as clinical or microbiological cured in the visit of day 5-7 plus positive urine or blood cultures with the same microorganism isolated than the initial culture. Re-infection: same definition but with different strain in the culture results.
Fosfomycin steady-state plasma concentration
Therapeutic drug monitoring of fosfomycin, basic pharmacokinetic parameters will be determined.
Microbiota impact of study treatment bacilli
Study treatment impact in the gut colonization of MDRGNB (Multi drug resistant Gram negative bacilli)
Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem
Frequency of strains that develop resistance and detection of resistance mechanisms in fosfomycin treatment arm.
Early microbiological response
Cultures are negative
Safety of intravenous antibiotic administration in this indication
Gathering any related adverse event from the informed consent form signature to the end of follow-up.

Full Information

First Posted
May 13, 2014
Last Updated
August 2, 2019
Sponsor
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Collaborators
Spanish Network for Research in Infectious Diseases
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1. Study Identification

Unique Protocol Identification Number
NCT02142751
Brief Title
Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli
Acronym
FOREST
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

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Completed
Study Start Date
July 2014 (Actual)
Primary Completion Date
December 2018 (Actual)
Study Completion Date
March 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Collaborators
Spanish Network for Research in Infectious Diseases

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
161 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fosfomycin sodium intravenous
Arm Type
Experimental
Arm Description
4g every 6 hours iv (60 min infusion)
Arm Title
Meropenem intravenous
Arm Type
Active Comparator
Arm Description
1g every 8 hours (15-30 min infusion)
Arm Title
Ceftriaxone intravenous
Arm Type
Other
Arm Description
1g every 24h (2-4 min)
Intervention Type
Drug
Intervention Name(s)
Fosfomycin sodium intravenous
Other Intervention Name(s)
Generic name: Fosfomycin, Pharmaceutical form: solution for infusion, ATC code: J01J3
Intervention Description
4g every 6 hours iv (60 min infusion)
Intervention Type
Drug
Intervention Name(s)
Meropenem intravenous
Other Intervention Name(s)
Generic name: Meropenem, Pharmaceutical form: solution for infusion, ATC code: J01D5
Intervention Description
1g every 8 hours (15-30 min infusion) It depends on strain sensitivity: Strain with resistance to cephalosporins
Intervention Type
Drug
Intervention Name(s)
Ceftriaxone intravenous
Other Intervention Name(s)
generic name: ceftriaxone, Pharmaceutical form: solution for infusion, ATC code:J01DA
Intervention Description
1g every 24 hours iv (2-4 min infusion) It depends on strain sensitivity: Strain with resistance to quinolone but sensitivity to cephalosporins
Primary Outcome Measure Information:
Title
Clinical and microbiological cure rate
Description
Clinical Cure: Complete resolution of infection symptoms (bacteremia and/or urinary tract infection-UTI-), present at the day on which blood culture was drawn. Microbiological cure: Negative blood culture at day 5-7 after end of treatment. Besides this, if UTI was confirmed with a positive urine culture with the same microorganism than the blood culture, this culture should become negative.
Time Frame
Day 5-7 after end of treatment (test of cure)
Secondary Outcome Measure Information:
Title
Early clinical response
Description
The infection was completely resolved after 5-7 days of complete treatment
Time Frame
After 5 -7 days of complete treatment (from the first day of study drugs administration)
Title
Mortality
Description
Death for any reason.
Time Frame
At day 30 of follow-up
Title
Length of hospital stay
Description
It is defined as the time from admission to hospital discharge
Time Frame
At day 30 of follow-up
Title
Safety of intravenous fosfomycin in this indication
Description
Gathering any related adverse event from the informed consent form signature to the end of follow-up.
Time Frame
To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Title
Recurrences (relapse and reinfection) rate
Description
Relapse: new symptoms of UTI in patient with previously considered as clinical or microbiological cured in the visit of day 5-7 plus positive urine or blood cultures with the same microorganism isolated than the initial culture. Re-infection: same definition but with different strain in the culture results.
Time Frame
To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Title
Fosfomycin steady-state plasma concentration
Description
Therapeutic drug monitoring of fosfomycin, basic pharmacokinetic parameters will be determined.
Time Frame
At 3 days after treatment started
Title
Microbiota impact of study treatment bacilli
Description
Study treatment impact in the gut colonization of MDRGNB (Multi drug resistant Gram negative bacilli)
Time Frame
Screening, day 5-7, day 12
Title
Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem
Description
Frequency of strains that develop resistance and detection of resistance mechanisms in fosfomycin treatment arm.
Time Frame
participants will be followed for the duration of fosfomycin, an expected average of 14 days
Title
Early microbiological response
Description
Cultures are negative
Time Frame
within the first 5 days after treatment started
Title
Safety of intravenous antibiotic administration in this indication
Description
Gathering any related adverse event from the informed consent form signature to the end of follow-up.
Time Frame
To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
JESUS RODRIGUEZ-BAÑO, MD, PhD
Organizational Affiliation
Spanish Network for Research in Infectious Diseases
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Mutua de Terrassa
City
Terrassa
State/Province
Barcelona
ZIP/Postal Code
08221
Country
Spain
Facility Name
Hospital Universitario de Gran Canaria Dr. Negrín
City
Las Palmas De Gran Canaria
State/Province
Gran Canarias
ZIP/Postal Code
35010
Country
Spain
Facility Name
Hospital Arnau de Vilanova
City
Vilanova
State/Province
Lleida
Country
Spain
Facility Name
Hospital Clínico Universitario Virgen de la Arrixaca
City
El Palmar
State/Province
Murcia
ZIP/Postal Code
30120
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
La Laguna
State/Province
Tenerife
ZIP/Postal Code
38320
Country
Spain
Facility Name
Hospital Marina Baixa
City
Alicante
ZIP/Postal Code
03010
Country
Spain
Facility Name
Hospital General Universitario de Alicante
City
Alicante
Country
Spain
Facility Name
Hospital Parc Salud Mar
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Facility Name
Hospital de la Santa Creu i San Pau
City
Barcelona
ZIP/Postal Code
08025
Country
Spain
Facility Name
Hospital Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Universitario de Bellvitge
City
Barcelona
Country
Spain
Facility Name
Hospital de Cruces
City
Bilbao
Country
Spain
Facility Name
Hospital Universitario de Burgos
City
Burgos
ZIP/Postal Code
09006
Country
Spain
Facility Name
Hospital Universitario Reina Sofía
City
Córdoba
Country
Spain
Facility Name
Hospital Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Hospital Universitario Central de Asturias
City
Oviedo
ZIP/Postal Code
33006
Country
Spain
Facility Name
Hospital Son Espases
City
Palma de Mallorca
ZIP/Postal Code
07010
Country
Spain
Facility Name
Hospital Marqués de Valdecilla
City
Santander
ZIP/Postal Code
39008
Country
Spain
Facility Name
Hospital Universitario Virgen Macarena
City
Sevilla
ZIP/Postal Code
41009
Country
Spain
Facility Name
Hospital Universitario y Politécnico La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Hospital Royo Villanova
City
Zaragoza
ZIP/Postal Code
50009
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35024838
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.
Results Reference
derived
PubMed Identifier
25829373
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.
Results Reference
derived

Learn more about this trial

Fosfomycin Versus Meropenem or Ceftriaxone in Bacteriemic Infections Caused by Multidrug Resistance in E.Coli

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