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

Condition(s) targeted: Infection Due to Multidrug-resistant Escherichia Coli

Intervention: Fosfomycin sodium intravenous (Drug); Meropenem intravenous (Drug); Ceftriaxone intravenous (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Official(s) and/or principal investigator(s):
JESUS RODRIGUEZ-BAÑO, MD, PhD, Study Chair, Affiliation: Spanish Network for Research in Infectious Diseases

Overall contact:
Clara M. Rosso Fernández, MD, PhD, Phone: +34955013414, Email: claram.rosso.sspa@juntadeandalucia.es

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.

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Clinical and microbiological cure rate

Secondary outcome:

Early clinical response

Mortality

Length of hospital stay

Safety of intravenous fosfomycin in this indication

Recurrences (relapse and reinfection) rate

Fosfomycin steady-state plasma concentration

Microbiota impact of study treatment bacilli

Emergence of resistant clinical isolates of Escherichia coli to fosfomycin and meropenem

Early microbiological response

Safety of intravenous antibiotic administration in this indication

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Clara M. Rosso Fernández, MD, PhD, Phone: +34955013414, Email: claram.rosso.sspa@juntadeandalucia.es

Hospital General Universitario de Alicante, Alicante, Spain; Recruiting
Vicente Voix Martínez, MD, Principal Investigator

Hospital Marina Baixa, Alicante 03010, Spain; Recruiting
Concepción Amador Prous, MDPhD, Principal Investigator

Hospital de la Santa Creu i San Pau, Barcelona 08025, Spain; Recruiting
Virginia Pomar Solchaga, MDPhD, Principal Investigator

Hospital Parc Salud Mar, Barcelona 08003, Spain; Recruiting
María Luisa Sorli Redó, MDPhD, Principal Investigator

Hospital Universitario de Bellvitge, Barcelona, Spain; Recruiting
Evelyn Shaw Perujo, MDPhD, Principal Investigator

Hospital Vall d'Hebron, Barcelona 08035, Spain; Recruiting
Carlos Pigrau Serrallach, MDPhD, Principal Investigator

Hospital de Cruces, Bilbao, Spain; Recruiting
Elena Bereciartua, MD.PhD, Email: ELENA.BERECIARTUABASTARRICA@osakidetza.net
Miguel Montejo, MD.PhD, Principal Investigator
Elena ELENA.BERECIARTUABASTARRICA@osakidetza.net, MD, PhD, Principal Investigator

Hospital Universitario de Burgos, Burgos 09006, Spain; Recruiting
Carlos Dueñas Gutiérrez, MDPhD, Principal Investigator

Hospital Universitario Reina Sofía, Córdoba, Spain; Recruiting
Clara Natera, MD, PhD, Email: clrntr@gmail.com
Clara Natera, MD, PhD, Principal Investigator

Hospital Ramón y Cajal, Madrid 28034, Spain; Recruiting
Vicente Pintado García, MDPhD, Principal Investigator

Hospital Universitario 12 de Octubre, Madrid 28041, Spain; Recruiting
José Tiago Sequeira López da Silva, MDPhD, Principal Investigator

Hospital Universitario Central de Asturias, Oviedo 33006, Spain; Recruiting
Ana María Fleites Gutiérrez, MDPhD, Principal Investigator

Hospital Son Espases, Palma de Mallorca 07010, Spain; Recruiting
Nuria Borrel Solé, MDPhD, Principal Investigator

Hospital Marqués de Valdecilla, Santander 39008, Spain; Recruiting
Luis Martínez Martínez, MDPhD, Principal Investigator

Hospital Universitario Virgen Macarena, Sevilla 41009, Spain; Recruiting
Jesús Sojo Dorado, MD, Phone: +34 955009024, Email: jesodo@hotmail.com
Adoración Valiente
Jesús Sojo Dorado, MD, Sub-Investigator
Zaira R Palacios Baena, MD, Sub-Investigator
Vicente Merino Bohorquez, Sub-Investigator
Adoración Valiente, MD, Sub-Investigator

Hospital Universitario y Politécnico La Fe, Valencia 46026, Spain; Recruiting
Miguel Salavert Lletí, MDPhD, Principal Investigator

Hospital Royo Villanova, Zaragoza 50009, Spain; Recruiting
Rosa María Martínez Alvarez, MDPhD, Principal Investigator

Hospital Mutua de Terrassa, Terrassa, Barcelona 08221, Spain; Recruiting
Ester Calbo, MDPhD, Principal Investigator

Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canarias, Gran Canarias 35010, Spain; Not yet recruiting
Miguel Angel Cárdenas Santana, MDPhD, Principal Investigator

Hospital Arnau de Vilanova, Vilanova, Lleida, Spain; Recruiting
Alfredo Jover, MDPhD, Principal Investigator

Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia 30120, Spain; Recruiting
Alicia Hernández Torres, MDPhD, Principal Investigator

Hospital Universitario de Canarias, La Laguna, Tenerife 38320, Spain; Recruiting
María Lecuona Fernández, MDPhD, Principal Investigator

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

Starting date: July 2014
Last updated: August 11, 2015