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

NCT02142751 | Completed Phase 3 DMC

• 1 other identifier: FOREST
• Study Type: interventional
• Target: 161
• Locations: 1 country
• Sites: 22

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.

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 5-7 after end of treatment (test of cure)

Secondary Outcomes (10)

• Early clinical response

  After 5 -7 days of complete treatment (from the first day of study drugs administration)

• Mortality

  At day 30 of follow-up

• Length of hospital stay

  At day 30 of follow-up

• Safety of intravenous fosfomycin in this indication

  To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)

• Recurrences (relapse and reinfection) rate

  To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)

Study Arms (3)

Fosfomycin sodium intravenous

EXPERIMENTAL

4g every 6 hours iv (60 min infusion)

Drug: Fosfomycin sodium intravenous

Meropenem intravenous

ACTIVE COMPARATOR

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

Drug: Meropenem intravenous

Ceftriaxone intravenous

OTHER

1g every 24h (2-4 min)

Drug: Ceftriaxone intravenous

Interventions

Fosfomycin sodium intravenous DRUG

4g every 6 hours iv (60 min infusion)

Also known as: Generic name: Fosfomycin, Pharmaceutical form: solution for infusion, ATC code: J01J3

Fosfomycin sodium intravenous

Meropenem intravenous DRUG

1g every 8 hours (15-30 min infusion) It depends on strain sensitivity: Strain with resistance to cephalosporins

Also known as: Generic name: Meropenem, Pharmaceutical form: solution for infusion, ATC code: J01D5

Meropenem intravenous

Ceftriaxone intravenous DRUG

1g every 24 hours iv (2-4 min infusion) It depends on strain sensitivity: Strain with resistance to quinolone but sensitivity to cephalosporins

Also known as: generic name: ceftriaxone, Pharmaceutical form: solution for infusion, ATC code:J01DA

Ceftriaxone intravenous

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fundación Pública Andaluza para la gestión de la Investigación en Sevilla: lead
• Spanish Network for Research in Infectious Diseases: collaborator

Study Sites (22)

Hospital Mutua de Terrassa

Terrassa, Barcelona, 08221, Spain

Location

Hospital Universitario de Gran Canaria Dr. Negrín

Las Palmas de Gran Canaria, Gran Canarias, 35010, Spain

Location

Hospital Arnau de Vilanova

Vilanova, Lleida, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

El Palmar, Murcia, 30120, Spain

Location

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Tenerife, 38320, Spain

Location

Hospital Marina Baixa

Alicante, 03010, Spain

Location

Hospital General Universitario de Alicante

Alicante, Spain

Location

Hospital Parc Salud Mar

Barcelona, 08003, Spain

Location

Hospital de la Santa Creu i San Pau

Barcelona, 08025, Spain

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario de Bellvitge

Barcelona, Spain

Location

Hospital de Cruces

Bilbao, Spain

Location

Hospital Universitario de Burgos

Burgos, 09006, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, 33006, Spain

Location

Hospital Son Espases

Palma de Mallorca, 07010, Spain

Location

Hospital Marqués de Valdecilla

Santander, 39008, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, 46026, Spain

Location

Hospital Royo Villanova

Zaragoza, 50009, Spain

Location

Related Publications (2)

• 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.

  PMID: 35024838 DERIVED

• 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.

  PMID: 25829373 DERIVED

Related Links

• Spanish Network Research in Infectious Diseases (Red Española de Investigación en Patología Infecciosa \[REIPI\])

MeSH Terms

Conditions

Escherichia coli Infections; Bacteremia; Urinary Tract Infections; Sepsis; Recurrence

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Disease Attributes

Study Officials

• JESUS RODRIGUEZ-BAÑO, MD, PhD

  Spanish Network for Research in Infectious Diseases

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2014
• First Posted: May 20, 2014
• Study Start: July 1, 2014
• Primary Completion: December 1, 2018
• Study Completion: March 1, 2019
• Last Updated: August 6, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

ES (22)