Retrospective Cefiderocol Chart Review Studies—PERSEUS and PROVE1-4

NEW REAL-WORLD EVIDENCE

PERSEUS study1,2:

Real-world evidence is intended to complement data from randomized clinical trials. Observational retrospective analyses are not intended for direct comparison with clinical trials.

A retrospective, multicenter, observational, medical chart review study in patients (N=261) with Gram-negative bacterial infections in Spain (2018-2022)1

Study design1

  • Included patients with documented Gram-negative bacterial infection (GNBI); with known infection site and species, and had received cefiderocol continuously for at least 72 hours for the first time (with known start and stop dates, cefiderocol dose, and duration) and documented treatment outcome and discharge status
  • Patients were excluded for incomplete data, enrollment in cefiderocol clinical trials, if infected with Acinetobacter spp, enrollment into a clinical study of another investigational product, or had a coinfection with confirmed cefiderocol-resistant Gram-negative bacteria in the prior 28 days of initiation of cefiderocol treatment for the current infection
  • Patients included in the study received cefiderocol only when other treatment options were unavailable due to resistance or other factors as it was administered under a compassionate use/early access program
  • Data are shown for 163 patients with urinary tract (n=38) and respiratory tract (n=125) infections out of the overall population (N=261) of patients
  • Study objective: assess clinical outcomes in patients treated for at least 72 hours and up to Day 28
    • Clinical cure: cessation of cefiderocol treatment due to resolution of clinical signs and symptoms of the infection
    • All-cause mortality (ACM), or survival, at Day 28 from the start of cefiderocol treatment
  • Limitations of PERSEUS include the noncomparative, retrospective, observational nature of the study. Results should be considered descriptive. Additionally, some subgroups had a small number of patients. Expanded access program limits the ability to extrapolate data to routine clinical practice. Susceptibility information was based on reports in the medical charts without confirmatory testing by a central lab. Cefiderocol susceptibility was not routinely available at the time of this study
Select patient demographics2
RESPIRATORY TRACT
(n=125)		 URINARY TRACT
(n=38)
Age (years), median (IQR) 60 (46-66) 66.5 (55-75)
ICU, % (n) 89.6% (112) 18.4% (7)
Renal replacement therapy (RRT), % (n) 36.0% (45) 7.9 (3)
Creatinine clearance <60 mL/min, % (n)a 20.5% (16/78) 51.7% (15/29)
Immunosuppressed, % (n)b 22.4% (28) 42.1% (16)
Secondary bacteremia, % (n) 20.8% (26) 10.5% (4)
Polymicrobial infection, % (n)c 24.0% (30) 13.2% (5)
Prior antibioticsd N=100 N=33
Number of prior courses of antibiotic treatments, median (IQR) 3 (2.0-4.0) 2 (1.0-3.0)
1, % (n) 20.0% (20) 45.5% (15)
2, % (n) 27.0% (27) 27.3% (9)
≥3, % (n) 53.0% (53) 27.3% (9)
None, % (n) 16.8% (21) 13.2% (5)
Unknown, % (n) 4.0 0.0
Duration of prior antibiotic treatment (days), median (IQR) 6.7 (4.0-10.4) 4 (3.0-7.0)
Cefiderocol as first-line therapy, % (n) 16.8% (21) 13.2% (5)
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IQR=interquartile range.

a
Excluding patients on RRT; denominator excludes missing data.2
b
Transplant recipient, immunosuppressive treatment (eg, high-dose corticosteroids, calcineurin inhibitors, anti-CD20, IL-1 inhibitors, and IL-6 inhibitors).2
c
Primary pathogen in polymicrobial infections, for which cefiderocol was requested, was confirmed by the treating physician.2
d
Prior antibiotics were given to a total of 219 patients; data are shown for 212 patients with a full data set; information is missing for 7 patients.2

Fetroja continued to demonstrate real-world efficacy, including in patients with challenging infections with a high degree of resistance to established BL/BLI combinations1

Outcomes in patients with urinary tract infections2

Clinical outcomes in patients with urinary tract infections for PERSUS are: 94.7% (36/38) overall clinical response at EOT and 96.4% (27/28) for P aeruginosa. On day 28 ACM, the cinical response was 15.8% (6/38) overall and 14.3% (4/28) for P aeruginosa.
Resistance profile2:
>90% of patients had an infection resistant to both ceftazidime/avibactam and ceftolozane/tazobactam

Outcomes in patients with respiratory tract infections2

Clinical outcomes in patients with respiratory tract infections for PERSUS are: 76.0% (95/125) overall clinical response at EOT and 79.0% (27/28) for P aeruginosa. On day 28 ACM, the cinical response was 27.2% (34/125) overall and 22.2% (18/81) for P aeruginosa.
Resistance profile2:
>70% of patients had an infection resistant to both ceftazidime/avibactam and ceftolozane/tazobactam

Adverse drug reactions in all screened patients2

Adverse drug reactions in all screened patients2
OVERALL
(N=314)a
Any, n (%) 7 (2.2)
Discontinuation due to ADR, n (%)b 3 (1.0)
Serious ADR, n (%) 3 (1.0)
Discontinuation due to serious ADR, n (%)b 3 (1.0)
Death due to serious ADR, n (%)c 1 (0.3)
a
Number of screened patients.1
b
One patient discontinued due to septic rash (patient was withdrawn from the primary analysis population because of cefiderocol treatment <72 hours); 1 patient discontinued due to mild leukopenia; and 1 patient discontinued due to fatal toxic epidermal necrolysis.1
c
One event of fatal toxic epidermal necrolysis.1

US interim analysis of patients treated between November 2020 and March 20233

PROVE study3,4:

Real-world evidence is intended to complement data from randomized clinical trials. Observational retrospective analyses are not intended for direct comparison with clinical trials.

Study design3

  • PROVE is an ongoing, multicenter, retrospective chart review study of existing medical records from patients receiving first-time cefiderocol treatment for a GNBI
  • Study endpoints included clinical response at the end of cefiderocol treatment; in-hospital ACM; and safety (ie, adverse drug reactions)
  • Included patients with documented GNBI; with known infection site and species, and had received first-time cefiderocol treatment lasting ≥72 hours (with known start and stop dates, starting dose, and duration) and documented treatment outcome and discharge status
  • Patients were excluded for incomplete data, enrollment in cefiderocol clinical trials, or use before commercial availability
  • Data are shown for 151 patients with urinary tract (n=15) and respiratory tract (n=136) infections out of the overall population (N=244) of patients in the US interim analysis
  • Limitations of PROVE include the noncomparative, descriptive nature of the study, use of local susceptibility testing reports, short follow-up period, small number of patients in certain subgroups, and the use of concomitant antibiotics during treatment with cefiderocol
Select patient characteristics by infection site4
RESPIRATORY TRACT
(n=136)		 URINARY TRACT
(n=15)
Age ≥65 years, % (n) 24.3% (33) 66.7% (10)
Gender, male, % (n) 58.1% (79) 60.0% (9)
Organ support while in ICU, % (n) 65.4% (89) 20.0% (3)
Mechanical ventilation 61.0% (83) 6.7% (1)
Continuous RRT 19.1% (26) 6.7% (1)
Vasopressor use 33.8% (46) 6.7% (1)
COVID-19, % (n) 14.7% (20) 0.0% (0)
Antimicrobials or antifungals used prior to cefiderocol, % (n) 47.1% (64) 40.0% (6)
Monomicrobial infections, % (n) 70.6% (96) 73.3% (11)
Polymicrobial infections, % (n) 29.4% (40) 26.7% (4)
Reason for starting cefiderocol, % (n)
Empiric for suspected CR Gram-negative bacterial infection 10.3% (14) 13.3% (2)
Documented infection 75.0% (102) 73.3% (11)
Salvage treatment due to prior antibiotics failed or not treated 14.7% (20) 13.3% (2)
Time from positive culture to first cefiderocol dose, days (median, Q1-Q3) 5 (3-7) 5 (3-11)
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PROVE study US interim analysis:
Real-world evidence supports efficacy data across clinical trials3

Outcomes in patients with urinary tract infections3

Outcomes in patients with urinary tract infections: 93.3% (14/15) overall clinical response at EOT and 6.7% (1/15) overall 30-day ACM.

Outcomes in patients with respiratory tract infections3

Outcomes in patients with respiratory tract infections: 71.3% (97/136) overall clinical response at EOT and 22.8% (31/136) overall 30-day ACM.
Clinical response at EOT is defined as patients with resolution or improvement of signs/symptoms at the EOT as reported by the physician and who were alive at EOT, regardless of whether they had a relapse/reinfection with the same species after EOT.3
  • In the overall population (N=244), 2% (n=5) of patients experienced 6 adverse drug reactions (1 diarrhea [suspected Clostridioides difficile but never confirmed], 1 diarrhea that could have been from cefiderocol or daptomycin, 1 increased liver function test, 1 rash, and 1 urticarial rash), including 1 patient who experienced a serious adverse drug reaction (interstitial nephritis, acute kidney injury)3,4
  • Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP

Real-world evidence supports Fetroja as an option for patients with Gram-negative bacterial infections and limited treatment options3