Journal Club: Cefiderocol or best available therapy in carbapenem-resistant gram-negative infections (CREDIBLE-CR)

Andrew Purdy, Pharm.D.

September 15, 2021

BACKGROUND- THE STUDY QUESTION

Background • Multi-drug resistant pathogens, especially carbapenem-resistant gram-negative bacteria, have become more prevalent and
of more concern to public health due to the limited treatment options available for them.
• Cefiderocol is a novel siderophore cephalosporin that works by binding to free iron and using this to be actively transported
across the bacterial cell membrane and into the periplasm via iron transport channels, and acts by inhibiting PBP
• It has shown in-vitro activity against more than 97% of isolates non-susceptible to carbapenems, including metallo-beta-
lactamase producing enterobacterales, Stenotrophomonas maltophilia, Acinetobacter baumannii, and Pseudomonas
aeruginosa.
• Cefiderocol is currently FDA-approved for treatment of complicated urinary tract infections as well as hospital and
ventilator acquired pneumonia, but clinically is reserved for multidrug resistant pathogens.
Previous trials • Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated
urinary tract infections caused by gram-negative uropathogens (APEKS-cUTI): a phase 2, randomized, double-blind, non-
inferiority trial. Lancet Infect Dis 2018;18(12):1319-1328. DOI: 10.1016/S1473-3099(18)30554-1.
• Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the
treatment of gram-negative nosocomial pneumonia (APEKS-NP): a randomized, double-blind, phase 3, non-inferiority trail.
Lancet Infect Dis 2021;21(2):213-225. DOI: 10.1016/S1473-3099(20)30731-3.
Why this study? • There is no in-vivo data showing the efficacy of cefiderocol in the treatment of carbapenem-resistant infections, the specific
infection types that it is reserved for.
• A pathogen-focused study in the patient population that cefiderocol would clinically be used for was required for approval
of the drug by the European Medicines Agency.
GENERAL STUDY OVERVIEW
Title/Citation • Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of
serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomized, open-label,
multicenter, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis 2021;21(2):226-240. DOI: 10.1016/S1473-
3099(20)30796-9.
Funding • Funded by Shionogi and Company
• Sponsor supplied the cefiderocol and participated in study design, protocol development, data analysis and interpretation,
and report writing.
Null hypothesis • Descriptive study – no hypothesis developed or tested.
Trial design • Randomized, open-label, multicenter, pathogen-focused, descriptive, phase 3 trial
Objectives • Assess clinical cure of infection and microbiological eradication in cefiderocol versus best available treatment in nosocomial
pneumonia, bacteremia, or complicated urinary tract infections caused by carbapenem-resistant gram-negative bacteria.
Enrollment • Patients were enrolled from September 2016 to April 2019 at 95 different hospitals across 16 countries in North America,
South America, Europe, and Asia.

Inclusion criteria 1. Adult male or female, age ≥ 18 years old

2. Diagnosis of nosocomial pneumonia (HAP, VAP, or HCAP), a bloodstream infection or sepsis (primary source outside of
pneumonia or complicated UTI), or complicated urinary tract infection (cUTI).
3. Evidence of carbapenem-resistant gram-negative infection, defined as one of the following:
• Treatment failure on empiric antibiotics with a carbapenem-resistant gram-negative pathogen confirmed by culture
• Rapid diagnostics confirming a carbapenem-resistant pathogen
• Pathogen where local antibiogram shows >90% rate of non-susceptibility to carbapenems
• Pathogen confirmed to be Stenotrophomonas maltophilia
• Patient confirmed to be colonized with carbapenem-resistant gram-negative pathogen within 72 hours of
randomization and later developed an infection at this site
Exclusion • Potentially effective antibiotics given for current carbapenem-resistant infection within 72 hours of randomization
criteria • More than three systemic gram-negative antibiotics given as best available therapy
• Acute Physiology and Chronic Health Evaluation (APACHE) II score > 30
• Refractory septic shock (not responding to fluid resuscitation)
• Concomitant inhaled gram-negative antibiotics for nosocomial pneumonia patients
Interventions Eligible patients were randomly assigned in a 2:1 ratio
• Cefiderocol arm: Cefiderocol 2g q8h, infused over 3 hours – 2g q6h for patients with CrCl>120 (n=101)
• One additional antibiotic (excluding polymyxins, cephalosporins, and carbapenems) allowed to be added for
pneumonia, sepsis, or bacteremia patients
• Best available therapy arm: Up to three systemic antibiotics, determined by investigator based on individual patient
assessment, prespecified before randomization, and dosed according to country’s labeling (n=51)
Stratified by infection type, APACHE II scores, and geographical region
Treatment duration of 7-14 days (5 days minimum for cUTIs): could be extended to 21 days at investigator discretion
De-escalation of adjunctive agent in cefiderocol group and in combination best available therapy group was allowed at day 3-4
Escalation was not allowed
Monitoring • Assessed at early assessment (day 3-4), end of treatment, test of cure (7±2 days after end of treatment), and follow-up
(14±3 days after end of treatment): treatment effect, safety, SOFA scores, clinical signs and symptoms of infection.
Endpoints Primary endpoints
• Nosocomial pneumonia, sepsis, bacteremia: proportion of patients reaching clinical cure at test of cure
• Complicated UTIs: microbiological eradication at test of cure
Secondary Endpoints
• Clinical and microbiological outcomes at end of treatment, test of cure, and follow-up
• All-cause mortality at days 14 and 28 for each diagnosis
• Composite of survival and no change in antibiotic treatment due to drug-related toxicity or lack of therapeutic benefit
at test of cure
Safety Endpoints
• Treatment-emergent adverse events and clinical laboratory safety tests
Statistical Descriptive Study: no hypothesis testing
analysis • 95% confidence intervals
• Primary endpoint: Carbapenem-resistant microbiological intention-to-treat (ITT) population – confirmed carbapenem-
resistant gram-negative pathogen and receiving at least one dose of study drug
• Other endpoints: ITT population and carbapenem-resistant microbiological ITT population
Statistical Tests
• Clopper-Pearson method for primary and secondary endpoints and Cochran-Mantel-Haenszel method for composite
survival endpoint
• Kaplan-Meier analysis for probability of survival, and the Miettinen-Nurminem method for all-cause mortality
Subgroup Analyses
• Age, sex, race, clinical diagnosis, baseline carbapenem-resistant pathogen, APACHE II score, and region

Baseline • 152 eligible patients were randomized from September 2016 to April 2019
characteristics • 80 and 38 patients in carbapenem-resistant microbiological ITT population
• Baseline characteristics are presented in Table 1: generally similar among patients
Primary • Clinical cure: nosocomial pneumonia
outcome o Cefiderocol group: 50% (20/40 patients) vs Best available therapy group: 53% (10/19 patients)
• Clinical cure: bacteremia or sepsis
o Cefiderocol group: 43% (10/23 patients) vs Best available therapy group: 43% (6/14 patients)
• Microbiological Eradication: complicated UTI
o Cefiderocol group: 53% (9/17 patients) vs Best available therapy group: 20% (1/5 patients)
Secondary • All-cause mortality at the end of study
outcome o Cefiderocol group: 34% (34/101 patients) vs Best available therapy group: 18% (9/49 patients)
o *Acinetobacter species: 50% (21/42 patients) versus 18% (3/17 patients)
o Klebsiella pneumoniae: 21% (6/28 patients) versus 27% (4/15 patients)
o Pseudomonas aeruginosa: 18% (2/11 patients) versus 18% (2/11 patients)
• Safety
o TEAEs: 91% (21/101) versus 96% (47/49) - Drug-related TEAEs: 15% (15/101) versus 22% (11/49)
AUTHORS’ CONCLUSIONS
• “The patient population in this study represents a real clinical scenario with a high unmet need, and the study findings provide evidence of
the efficacy and safety of cefiderocol for physicians treating such patients.”
STUDY CRITIQUE & DISCUSSIONS
Patient • Real world study looking at carbapenem-resistant organisms only – more reflective of actual cefiderocol use
population/ • Descriptive study without hypothesis testing – makes it more challenging to draw conclusions from the study
Design • Stratification according to infection type and organism – allows for sub-analysis
Intervention • Follow up time of assessment of cure was appropriate (7 days after completion of treatment)
• Non-standardized and poorly-defined control group – made it difficult to assess what ceficerocol was being compared to
Endpoints • Non-standardized primary endpoint – no overall primary endpoint assessments can be made
• All-cause mortality assessment could be clinically relevant
Statistics • Carbapenem-resistant microbiological Intention to treat – ensured clinically relevant primary endpoint population
LEADER’S CONCLUSIONS
• Results of this study indicated similar rates of clinical and microbiological cures with cefiderocol compared to best available therapy in
carbapenem-resistant infections, yet increased mortality with cefiderocol, particularly in carbapenem-resistant Acinetobacter species
infections. However, the non-standardized and descriptive design of this trial, along with small sample size and lack of defined control
group makes it challenging to draw strong conclusions from this study. Cefiderocol remains one of the few antibiotics to retain activity
against some of the most resistant gram-negative infections, including metallo-beta-lactamase producers, multidrug resistant
Acinetobacter baumannii and pseudomonas aeruginosa, and stenotrophomonas maltophilia. Given the scarcity of options, along other
clinical and in-vitro data, cefiderocol remains a last-line options for multidrug resistant gram-negative infections. However, further data is
needed in a more standardized manner to assess its safety and efficacy versus other last-line options like polymyxin B, colistin, tigecycline,
and eravacycline.