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