RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI
RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI
The purpose of this study is to determine whether a new antibiotic, Cefiderocol which works
 against a wide variety of gram negative bacteria, is equally effective as the antibiotics
 that are currently used as current standard of care.
Infections with antibiotic resistant bacteria cause a significant burden of disease
 worldwide. Bloodstream infections may arise from a variety of sources, are commonly
 encountered in clinical practice, and are associated with significant morbidity and
 mortality. Antibiotics that have activity against a broad spectrum of pathogens are commonly
 suggested in treatment guidelines to adequately cover bloodstream infections. Increasing
 rates of resistance to antibiotics commonly used for bloodstream infection are problematic
 and may lead to initial empiric therapy not having activity against the pathogen isolated. In
 patients with bloodstream infections and sepsis, delay until the receipt of effective therapy
 is associated with an increase in mortality .

 Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of
 extended spectrum beta lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and
 other mechanisms of resistance are identified in common hospital and healthcare associated
 pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii.
 Uncommonly, Gram-negative organisms such as Klebsiella pneumoniae and, in tropical areas such
 as south-east Asia and northern Australia, Burkholderia pseudomallei can cause severe
 community-acquired pneumonia resulting in bloodstream infection.

 Cefiderocol (previously S-649266) is a novel siderophore cephalosporin antibiotic with a
 catechol moiety on the 3-position side chain. The catechol side chain enables ferric iron ion
 binding, and the resulting complex of cefiderocol and iron ions is actively transported into
 bacteria via ferric iron transporter systems with subsequent destruction of cell wall
 synthesis. Cefiderocol has been shown to be potent in vitro against a broad range of
 Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and
 multi-drug resistant (MDR) P. aeruginosa and A. baumannii . This activity is considered to be
 due to not only efficient uptake via the active siderophore systems but also the high
 stability of cefiderocol against carbapenemase hydrolysis. Limited in vitro data suggests
 cefiderocol may have activity against B. pseudomallei .

 Recent clinical data has shown cefiderocol to be effective in the setting of complicated
 urinary tract infections , including patients with concomitant bacteremia. A study examining
 the use of cefiderocol in the setting of infections caused by carbapenem-resistant organisms
 is currently underway, as is a study of cefiderocol for hospital acquired pneumonia
 (ClinicalTrials.gov NCT02714595 & NCT03032380). Given the broad spectrum of activity against
 Gram-negative organisms, including those with resistant phenotypes, cefiderocol may be an
 ideal agent for empiric use in the setting of bloodstream infections acquired in the hospital
 or healthcare setting but as yet no clinical trial has examined this
Inclusion Criteria:

 -  Bloodstream infection with a Gram-negative organism from at least one blood culture
 draw. Bacterial identification to species level will be performed using standard
 laboratory methods (e.g. MALDI-TOF) and susceptibility testing (e.g. Vitek2).

 -  The blood stream infection fulfils the criteria as a hospital acquired or healthcare
 associated infection as per the following definitions

 -  1a Hospital acquired - Blood stream infection occurring greater than 48 hours after
 hospital admission, assessed as symptoms or signs of infection not present at time of
 hospital admission

 -  1b Healthcare associated - Blood stream infection present at admission to hospital or
 within 48 hours of admission in patients that fulfil ANY of following criteria

 -  2a Patient has an intravascular catheter/line that is the source of infection

 -  2b Attended a hospital or haemodialysis clinic or received intravenous chemotherapy in
 the previous 30 days

 -  2c were hospitalized in an acute care hospital for two or more days in the previous 90
 days

 -  2d resided in a nursing home or long-term care facility

 -  2e received intravenous antibiotic therapy at home, wound care or specialized nursing
 care through a healthcare agency, family or friends; or had self-administered
 intravenous antibiotic medical therapy in the 30 days before the infection

 -  1c OR patient meets the diagnosis of community acquired pneumonia where the
 Gram-negative organism isolated is considered or proven to be the causative agent of
 the pneumonia.

 -  No more than 36 hours has elapsed since the positive blood culture collection.

 -  Patient is aged 18 years and over (21 in Singapore)

 -  The patient or approved proxy is able to provide informed consent.

 Exclusion Criteria:

 -  Refractory shock or comorbid condition such that patient not expected to survive more
 than 7 days

 -  Patient with history of moderate to severe hypersensitivity reaction to a
 cephalosporin

 -  Patient with Gram-positive bacteraemia including a significant Gram-positive pathogen
 (a Gram-positive skin contaminant in one set of blood cultures may not regarded as
 significant).

 -  Where the bloodstream infection is thought to be related to a vascular catheter and
 the catheter is unable to be removed.

 -  Treatment is not with the intent to cure the infection (that is, palliative care is an
 exclusion).

 -  Known pregnancy or breast-feeding.

 -  Patient is receiving peritoneal dialysis