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

Abstract

IntroductionFinding 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 analysisThe 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 disseminationEthical 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.DiscussionThis 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 numberNCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.

Fosfomycin

“…In addition, several of them were conducted years or even decades ago, and their findings may not apply to the resistance profiles of contemporary isolates or the complexity and severity of diseases and infections that patients face nowadays. Data from RCTs are still not available, but RCTs evaluating the comparative efficacy of fosfomycin and meropenem for bacteremic UTIs and fosfomycin in addition to daptomycin for MRSA bacteremia are under way (238,239). Similarly, fosfomycin is being evaluated in combination with other antibiotics for MDR or XDR infections (NCT01297894, NCT02142751, and NCT00871104).…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…It primarily undergoes renal elimination and is indicated for treatment of uncomplicated urinary tract infection (UTI) caused by Escherichia coli and Enterococcus faecalis (2,6). Although an oral preparation approved for urinary tract infections is the only fosfomycin product available in the United States, the intravenous formulation has been used outside the United States for treatment of severe systemic infections (7). Fosfomycin doses of 3 g orally have been well established to treat UTIs, and bloodstream infections have been treated with fosfomycin at 50 mg/kg of body weight three to four times daily in combination with a ␤-lactam agent (4,8,9).…”

Pharmacodynamics of Fosfomycin: Insights into Clinical Use for Antimicrobial Resistance

“…The repurposing of old antimicrobials with activity against drug-resistant Enterobacteriaceae is an important strategy to address the ever-present threat of antimicrobial resistance. However, due to the scarcity of information of the clinical value of these old drugs in well-designed studies, new clinical research trials are under way in order to reevaluate the efficacy of these older drugs against the current gold standard treatments (6).…”