A Phase 2 interventional study of Cefiderocol and Best Available Therapy in Bloodstream Infections, sponsored by The University of Queensland. Completed at 19 sites in 6 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-02-13.
Sponsored by The University of Queensland · Phase 2, Interventional, and Treatment
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.
6,686 studies on the registry are indexed under Infections; 807 are open to participants now.
This study's enrollment of 513 is above the median of 120 across 4,199 interventional studies indexed under Infections.
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The blood stream infection fulfils the criteria as a hospital acquired or healthcare associated infection as per the following definitions:
i. Participant has an intravascular catheter/line that is the source of infection ii. Attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the previous 30 days iii. were hospitalized in an acute care hospital for two or more days in the previous 90 days iv. resided in a nursing home or long-term care facility v. 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
Exclusion Criteria:
Participants will receive Cefiderocol 2 grams administered intravenously over 3 hours, every 8 hours for a minium of 5 days and a maximun of 14 days.
Drug: Cefiderocol
BAT will be chosen by the investigator and intravenously administered per country-specific guidelines.
Other: Best Available Therapy
2 grams intravenously administered over 3 hours every 8 hours for a period of 5 to 14 days (dosage adjustment is necessary based on renal function).
Also known as: S-649266
Standard of care was determined by the investigator
Mortality at 14 days
To compare the 14-day mortality from day of randomisation of each regimen (cefiderocol versus standard of care therapy). If the primary objective meets the criteria for non-inferiority (with a margin of 10% for the difference in proportions), superiority will be examined.
Time frame: 14 days post date of randomisation
Mortality post blood stream infection of each regimen at longer time points
If a date of death is recorded on or before our calculation of Day 14, the participant will be classed as dead, otherwise considered to be alive. Similar for Day 30. Where possible this rule will also be applied for Day 90 vital status. If the Day 90 follow-up actually occurred on day 85 to 89 and the participant was alive we will assume the participant was alive at day 90.
Time frame: 30 and 90 days, from day of randomisation or "day 1"
Clinical and microbiological failure at day 14
Defined as composite of: 1. Death 2. Still in hospital and clinical failure, as defined by 1. If baseline SOFA ≥3, D(day)14 SOFA not improved by ≥30% 2. If baseline SOFA \<3, D14 SOFA worse 3. Microbiological failure (GNB Growth in blood of same species as index GNB from days 3-14) The SOFA score we will calculate is a slight modification of the original SOFA score. It will be used for ICU and non-ICU participants. The sole modification is that the respiratory component will be scored as in the modified SOFA: * 0 (if SaO2/FiO2 \>400) * 1 (if SaO2/FiO2 315-400) * 2 (if SaO2/FiO2 235-314) * 3 (if SaO2/FiO2 150-234) * 4 (if SaO2/FiO2 \<150)
Time frame: Day 14, from day of randomisation or "day 1"
Microbiological failure days 3 to 90 post randomisation
Defined as growth in blood cultures of the same GNB as the index blood culture(s), from day 3 up to day 90.
Time frame: Day 3 through to day 90
Colonisation or infection with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Gram-negative bacilli or Candida bloodstream infection.
Defined as the presence of MRSA, VRE or carbapenem-resistant Gram-negative bacilli (of a different species from primary BSI organism) on culture +/- molecular test of clinical samples or screening swabs, or Candida species grown in blood cultures from day 3 up to day 90.
Time frame: Day 3 through to day 90
Clostridioides difficile infection days 3 to 90 post randomisation.
Defined as presence of a compatible clinical illness with a positive laboratory stool test for C. difficile (as per local diagnostic protocol / method).
Time frame: Day 3 through to day 90
Improvement in functional status at day 30 post randomisation compared to baseline.
Functional status will be measured according to a score ranging from 0 (dead) to 7 (out of hospital, healthy, able to complete daily actvities). This score is based on the Functional Bloodstream Infection Score (FBIS) \[McNamara et al. Clin Microbiol Infect. 2020 Feb;26(2):257.e1-257\].
Time frame: Day 30, from day of randomisation or "day 1"
Time to hospital discharge.
Defined as to the day of first discharge alive (e.g. Day 2 is the day after randomisation). However, if a participant dies in the 3 days following first hospital discharge, we will consider that participant as not having a discharge alive.
Time frame: From day of randomisation or "day 1" through to day 90
Treatment emergent SAEs (Serious Adverse Events)
Defined as a serious adverse event possibly, probably or definitely related to the randomised drug treatment.
Time frame: From day of randomisation or "day 1" through to 5 days post end of study treatment.
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