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

Infection Due to ESBL Escherichia Coli Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02142751
• Other study ID #: FOREST
• Status: Completed
• Phase: Phase 3
• Start date: July 2014
• Est. completion date: March 2019

Study information

• Verified date: August 2019
• Source: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 161
• Est. completion date: March 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Infection Due to ESBL Escherichia Coli

Intervention

Drug:
• Fosfomycin sodium intravenous
4g every 6 hours iv (60 min infusion)
• Meropenem intravenous
1g every 8 hours (15-30 min infusion) It depends on strain sensitivity: Strain with resistance to cephalosporins
• Ceftriaxone intravenous
1g every 24 hours iv (2-4 min infusion) It depends on strain sensitivity: Strain with resistance to quinolone but sensitivity to cephalosporins

Locations

Country	Name	City	State
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Marina Baixa	Alicante
Spain	Hospital de la Santa Creu i San Pau	Barcelona
Spain	Hospital Parc Salud Mar	Barcelona
Spain	Hospital Universitario de Bellvitge	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital de Cruces	Bilbao
Spain	Hospital Universitario de Burgos	Burgos
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	Hospital Universitario de Canarias	La Laguna	Tenerife
Spain	Hospital Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria	Gran Canarias
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Son Espases	Palma de Mallorca
Spain	Hospital Marqués de Valdecilla	Santander
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Mutua de Terrassa	Terrassa	Barcelona
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Arnau de Vilanova	Vilanova	Lleida
Spain	Hospital Royo Villanova	Zaragoza

Sponsors (2)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla	Spanish Network for Research in Infectious Diseases

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Early clinical response	The infection was completely resolved after 5-7 days of complete treatment	After 5 -7 days of complete treatment (from the first day of study drugs administration)
Secondary	Mortality	Death for any reason.	At day 30 of follow-up
Secondary	Length of hospital stay	It is defined as the time from admission to hospital discharge	At day 30 of follow-up
Secondary	Safety of intravenous fosfomycin in this indication	Gathering any related adverse event from the informed consent form signature to the end of follow-up.	To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Secondary	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.	To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)
Secondary	Fosfomycin steady-state plasma concentration	Therapeutic drug monitoring of fosfomycin, basic pharmacokinetic parameters will be determined.	At 3 days after treatment started
Secondary	Microbiota impact of study treatment bacilli	Study treatment impact in the gut colonization of MDRGNB (Multi drug resistant Gram negative bacilli)	Screening, day 5-7, day 12
Secondary	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.	participants will be followed for the duration of fosfomycin, an expected average of 14 days
Secondary	Early microbiological response	Cultures are negative	within the first 5 days after treatment started
Secondary	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.	To the last visit, at 60 plus-minus 10 days (from the first day of study drugs administration)

External Links

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