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

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.

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