RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI (GAMECHANGER)

  • STATUS
    Recruiting
  • days left to enroll
    55
  • participants needed
    439
  • sponsor
    The University of Queensland
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Updated on 16 June 2022
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Summary

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.

Description

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

Details
Condition Bloodstream Infections
Treatment Best Available Therapy, Cefiderocol
Clinical Study IdentifierNCT03869437
SponsorThe University of Queensland
Last Modified on16 June 2022

Eligibility

 Yes No Not Sure

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
a 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
b Healthcare associated - Blood stream infection present at admission to hospital or within 48 hours of admission in patients that fulfil ANY of following criteria
a Patient has an intravascular catheter/line that is the source of infection
b Attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the previous 30 days
c were hospitalized in an acute care hospital for two or more days in the previous 90 days
d resided in a nursing home or long-term care facility
e 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
c 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
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