Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial

Clara Rosso-Fernández, Jesús Sojo-Dorado, Angel Barriga, Lucía Lavín-Alconero, Zaira Palacios, Inmaculada López-Hernández, Vicente Merino, Manuel Camean, Alvaro Pascual, Jesús Rodríguez-Baño, FOREST Study Group, J R-B, Natera Kindelán, Salavert Lletí, Merino de Lucas, Amador Prous, Hernández Torres, Shaw Perujo, Pomar, Calvo Sebastián, Sorli Redó, Pigrau Serrallach, Barcenilla Gaite, Sequeira Lopes da Silva, Pintado García, Martínez Martínez, Fleites Gutierrez, Bereciartua Bastarrica, Dueñas Gutiérrez, Martínez Álvarez, Borrell Solé, Cárdenas Santana, Lecuona Fernández, Clara Rosso-Fernández, Jesús Sojo-Dorado, Angel Barriga, Lucía Lavín-Alconero, Zaira Palacios, Inmaculada López-Hernández, Vicente Merino, Manuel Camean, Alvaro Pascual, Jesús Rodríguez-Baño, FOREST Study Group, J R-B, Natera Kindelán, Salavert Lletí, Merino de Lucas, Amador Prous, Hernández Torres, Shaw Perujo, Pomar, Calvo Sebastián, Sorli Redó, Pigrau Serrallach, Barcenilla Gaite, Sequeira Lopes da Silva, Pintado García, Martínez Martínez, Fleites Gutierrez, Bereciartua Bastarrica, Dueñas Gutiérrez, Martínez Álvarez, Borrell Solé, Cárdenas Santana, Lecuona Fernández

Abstract

Introduction: Finding therapeutic alternatives to carbapenems in infections caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is imperative. Although fosfomycin was discovered more than 40 years ago, it was not investigated in accordance with current standards and so is not used in clinical practice except in desperate situations. It is one of the so-called neglected antibiotics of high potential interest for the future.

Methods and analysis: The main objective of this project is to demonstrate the clinical non-inferiority of intravenous fosfomycin with regard to meropenem for treating bacteraemic urinary tract infections (UTI) caused by ESBL-EC. This is a 'real practice' multicentre, open-label, phase III randomised controlled trial, designed to compare the clinical and microbiological efficacy, and safety of intravenous fosfomycin (4 g/6 h) and meropenem (1 g/8 h) as targeted therapy for this infection; a change to oral therapy is permitted after 5 days in both arms, in accordance with predetermined options. The study design follows the latest recommendations for designing trials investigating new options for multidrug-resistant bacteria. Secondary objectives include the study of fosfomycin concentrations in plasma and the impact of both drugs on intestinal colonisation by multidrug-resistant Gram-negative bacilli.

Ethics and dissemination: Ethical approval was obtained from the Andalusian Coordinating Institutional Review Board (IRB) for Biomedical Research (Referral Ethics Committee), which obtained approval from the local ethics committees at all participating sites in Spain (22 sites). Data will be presented at international conferences and published in peer-reviewed journals.

Discussion: This project is proposed as an initial step in the investigation of an orphan antimicrobial of low cost with high potential as a therapeutic alternative in common infections such as UTI in selected patients. These results may have a major impact on the use of antibiotics and the development of new projects with this drug, whether as monotherapy or combination therapy.

Trial registration number: NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.

Keywords: BACTERIOLOGY; GENITOURINARY MEDICINE.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
FOREST study flow chart (PK, pharmacokinetics; UTI, urinary tract infection; ESBL-E. coli, extended-spectrum β-lactamase-producing Escherichia coli).
Figure 2
Figure 2
Schedule of visits and assessments (ALT, alanine transaminase; AST, aspartate aminotransferase; UTI, urinary tract infection).

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