title: 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.
abstract: BACKGROUND
  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
  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.
  
  
  BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.
authors.affiliation: Unidad de ensayos clínicos, Hospital Universitario Virgen del Rocío, Seville, Spain Farmacología Clínica, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Rosso-Fernández
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Seville, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Sojo-Dorado
authors.affiliation: Unidad de ensayos clínicos, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barriga
authors.affiliation: Unidad de ensayos clínicos, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Lavín-Alconero
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Seville, Spain Unidad Clínica de Medicina Interna, Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Zaira
authors.initials: Z
authors.lastname: Palacios
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Seville, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: López-Hernández
authors.affiliation: Unidad de Farmacia, Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Merino
authors.affiliation: Unidad de Farmacia, Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Camean
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Seville, Spain Departamento de Microbiología, Universidad de Sevilla, Seville, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío, Seville, Spain Departamento de Medicina, Universidad de Sevilla, Seville, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Rodríguez-Baño
mesh_terms: D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002985:Clinical Protocols; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005578:Fosfomycin / Q000097:blood / Q000627:therapeutic use*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D007422:Intestines / Q000382:microbiology; D000077731:Meropenem; D012107:Research Design; D013845:Thienamycins / Q000627:therapeutic use*; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D005578:Fosfomycin; D001618:beta-Lactamases; D000077731:Meropenem
keywords: BACTERIOLOGY; GENITOURINARY MEDICINE
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