Fetcroja®’s structure and novel mode of cell entry1,2 both contribute to broad spectrum aerobic Gram-negative antimicrobial coverage including carbapenem-resistant pathogens, as has been demonstrated via extensive in vitro testing of cefiderocol.3–6

Fetcroja® has been studied to-date in limited clinical settings,1,3 demonstrating a similar tolerability profile to other cephalosporins and non-inferiority efficacy compared with best available treatments.3,7,8

ANTIMICROBIAL COVERAGE

In vitro testing of cefiderocol against over 30,000 clinical isolates of aerobic Gram-negative bacteria in multi-national surveillance studies have shown high rates of susceptibility, even against isolates with extreme drug resistance, resistance to carbapenems and other last-line antibiotics.3–5 These include pathogens identified by the World Health Organization as “critical priority” due to their carbapenem-resistance: Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii.3,9

The in vitro activity of cefiderocol against aerobic Gram-negative strains is consistently equivalent or more extensive to that of comparators, including colistin.3–5

 
PERCENTAGE OF SUSCEPTIBLE STRAINS*
 
Cefiderocol
Ceftazidime-avibactam
Ceftolozane-tazobactam
Ciprofloxacin
Colistin**
All Gram-negative
(30,459)
          
Enterobacterales
(20,949)
          
Non-fermenters
(9,510)†
          
CarbNS Enterobacterales
(578)‡
          
ESCR Enterobacterales
(2,547)§
          
CarbNS non-fermenters
(4,331)†‡
          
CarbNS P. aeruginosa
(1,154)‡
          
CarbNS A. baumannii
(1,891)‡
          
S. maltophilia
(1,173)
          
   >80% susceptible
   50-80% susceptible
   <50% susceptible

Data adapted from Fetcroja® CHMP assessment report,3 with categories from Thalhammer 2018.5

*Percentage susceptibility was calculated according to the EUCAST interpretative clinical breakpoint criteria.10 Where clinical breakpoints were not available for cefiderocol, PD-PK breakpoints have been applied.

†Non-fermenters include P. aeruginosa, Burkholderia spp., S. maltophilia and Acinetobacter spp.

‡CarbNS strain was defined as meropenem MIC ≥4 mg/L.

§ESCR Enterobacteriaceae strain was defined as cefepime MIC ≥8 mg/L for Enterobacteriaceae.

**Serratia spp., Proteeae and Burkholderia spp. were excluded because they are intrinsically resistant to colistin.

HOW DOES THIS SUPPORT THE NICE RECOMMENDATION FOR USE OF FETCROJA® IN ENGLAND?

Cefiderocol is recommended, within its marketing authorisation, as an option for treating severe drug-resistant infections caused by Gram-negative bacteria.11

If results of susceptibility and/or mechanisms of resistance testing are not yet available, cefiderocol may be offered, but only if the infection:11

  • Needs urgent treatment, and
  • Is expected to be susceptible to cefiderocol and not to other suitable antibiotics*

Clinicians should follow advice from specialists in microbiology or infectious disease and offer cefiderocol only if there are no suitable alternative treatment options.11*

Prescribers should follow the recommendations on new antimicrobials in the NICE guideline on antimicrobial stewardship.11

READ THE FULL GUIDANCE

*As well as considering susceptibility, judgements about whether an alternative treatment is suitable may take account of concerns about its toxicity, availability or interactions with other drugs, and its spectrum of activity.11

TOLERABILITY

Fetcroja® has a tolerability profile comparable to other cephalosporins. In clinical trials performed to date, Fetcroja® exhibited a similar adverse event profile to imipenem-cilastatin and high-dose extended-infusion meropenem.7,8

The most common adverse reactions associated with Fetcroja® are diarrhoea (8.2%), vomiting (3.6%), nausea (3.3%) and cough (2%).1

A higher all-cause mortality rate was observed in patients treated with cefiderocol as compared to best available therapy in a randomised, open-label trial in critically-ill patients with infections known or suspected to be due to carbapenem-resistant Gram-negative bacteria.1 The cause of the increase in mortality has not been established.1,3

It should be noted that patients in this descriptive, open-label trial were severely ill – in conventional phase 3 clinical trials, many comorbidities, immunosuppression and short life expectancy are exclusion criteria, which was not the case here.12

SAFETY PROFILE

The most common adverse reactions identified during clinical trials in patients receiving Fetcroja (cefiderocol) were diarrhoea (8.2%), vomiting (3.6%), nausea (3.3%) and cough (2%).1

System organ class
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Unknown
Infections and infestation
Candidiasis including oral candidiasis, vulvovaginal candidiasis,
candiduria and candida infection, 
Clostridioides difficile colitis including pseudomembranous colitis and Clostridioides difficile infection
    
Blood and lymphatic system disorders
    
Neutropenia
Immune system disorders
  
Hypersensitivity including skin reactions and Pruritus
  
Respiratory, thoracic and mediastinal disorders
Cough
    
Gastrointestinal disorders
Diarrhoea, nausea, vomiting
    
Skin and subcutaneous tissue disorders
Rash including rash macular, rash maculo-papular, rash erythematous and drug eruption
    
General disorders and administration site conditions
Infusion site reaction including infusion site pain, injection site pain, infusion site erythema and injection site phlebitis
    
Investigations
Alanine aminotransferase  increased, Gamma-glutamyltransferase  increased, Aspartate aminotransferase  increased, hepatic function abnormal including liver function test increased, hepatic enzyme increased, transaminases increased and liver function test abnormal, blood creatinine increased
Blood urea increased
  

Source: Fetcroja®(cefiderocol) Summary of Product Characteristics.

FETCROJA CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the following excipients:1

  • Sucrose
  • Sodium chloride
  • Sodium hydroxide (pH adjustment)

Hypersensitivity to any cephalosporin antibacterial medicinal product.1

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).1

CLINICAL DATA

To date, Fetcroja® has been studied in only limited patient trials.1,3 Marketing authorisation was based on in vitro and in vivo data, and results from three clinical studies.3 Click on the associated links to find out more about the individual trials.

APEKS-cUTI – phase 2, randomised, double-blind study of Fetcroja® vs. imipenem/cilastatin in complicated urinary tract infections caused by Gram-negative pathogens.3,7

https://clinicaltrials.gov/ct2/show/study/NCT02321800

https://www.ncbi.nlm.nih.gov/pubmed/30509675

APEKS-NP – phase 3, randomised, double-blind, parallel-group study of Fetcroja® compared with high-dose extended-infusion meropenem in patients with nosocomial pneumonia including hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, and healthcare-associated bacterial pneumonia caused by Gram-negative pathogens.3,8

https://clinicaltrials.gov/ct2/show/study/NCT03032380

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810733

CREDIBLE-CR – multicentre, open-label, randomised active-controlled study of Fetcroja® compared with ‘best available therapy’ in patients in hospitalised patients with evidence of carbapenem-resistant infections, including patients with hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP), or bloodstream infections (BSI) or sepsis, or cUTI caused by CR Gram-negative bacteria.3,12

A higher all-cause mortality rate was observed in patients treated with cefiderocol as compared to best available therapy (BAT) in a randomised, open-label trial in critically-ill patients with infections known or suspected to be due to carbapenem-resistant Gram-negative bacteria.1

The higher day 28 all-cause mortality rate with cefiderocol occurred in patients treated for nosocomial pneumonia, bacteraemia and/or sepsis [25/101 (24.8%) vs. 9/49 (18.4%) with BAT; treatment difference 6.4%, 95% CI (-8.6, 19.2)].1

All-cause mortality remained higher in patients treated with cefiderocol through end-of-study [34/101 (33.7%) vs. 9/49 (18.4%) with BAT; treatment difference 15.3%, 95% CI (-0.2, 28.6)].1

The cause of the increase in mortality has not been established. In the cefiderocol group there was an association between mortality and infection with Acinetobacter spp., which accounted for the majority of infections due to non-fermenters. In contrast, mortality was not higher in cefiderocol vs. BAT patients with infections due to other non-fermenters.1

It should be noted that the patients in this descriptive study were severely ill – in conventional phase 3 clinical trials, many comorbidities, immunosuppression, and short life expectancy are exclusion criteria, which was not the case here.12

https://clinicaltrials.gov/ct2/show/study/NCT02714595

SENTRY DATA

Fetcroja® is highly effective against extensively drug-resistant (XDR), Gram-negative isolates (in vitro data).13,14

In 2020, a European in vitro surveillance study was conducted, to assess the potency of Fetcroja® against non-glucose fermenting (NGF) bacteria.13,14 NGF organisms are a group of Gram-negative bacteria that are often intrinsically XDR, which makes the infections that they cause difficult to treat.15

SENTRY is an antimicrobial surveillance program that receives clinical isolates from around the world to monitor the antimicrobial resistance patterns of bacterial pathogens. The activity of Fetcroja® and comparator β-lactam/β-lactamase inhibitors was investigated against 1574 European NGF isolates collected from 18 European countries.13,14

Fetcroja® was found to be highly active against a broad range of European NGF isolates, and was the most effective antibiotic against P. aeruginosa, A. baumannii-calcoaceticus complex (ABC) and S. maltophilia isolates. Critically, it retains this activity against a panel of resistant isolates, including XDR strains, for which the treatments are limited.13,14

References:

  1. Fetcroja® (cefiderocol) Summary of Product Characteristics.
  2. Zhanel GG, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79:271–289.
  3. Fetcroja® (cefiderocol) CHMP opinion https://www.ema.europa.eu/en/medicines/human/EPAR/fetcroja#assessment-history-section. Accessed August 2023.
  4. Hackel MA, et al. In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant Gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 Study). Antimicrob Agents Chemother. 2017;61:e00093-17.
  5. Thalhammer F. Behandlung multiresistenter Enterobakterien. JATROS Infektiologie & Gastroenterologie-Hepatologie 01/2018,10-12.
  6. Aoki T, et al. Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship. Eur J Med Chem. 2018;155:847–868.
  7. Portsmouth S, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18:1319–1328.
  8. Wunderink RG, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21:213–225.
  9. Tacconelli E, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:318–327.
  10. Breakpoints for cefiderocol from EUCAST. Addendum to EUCAST breakpoint tables v. 10.0, May 2020. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Addenda/Cefiderocol_addendum_20200501.pdf. Accessed August 2023.
  11. NICE. Cefiderocol for treating severe drug-resistant gram-negative bacterial infections, August 2022. Available at: https://www.nice.org.uk/about/what-we-do/life-sciences/scientific-advice/models-for-the-evaluation-and-purchase-of-antimicrobials/cefiderocol. Accessed August 2023.
  12. Bassetti M, 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 randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21:226–240.
  13.  Shortridge D, et al. Presentation #01563, 31st European Congress of Clinical Microbiology & Infectious Diseases, 9–12 July 2021.
  14. Shortridge D, et al. Poster #01606, 31st European Congress of Clinical Microbiology & Infectious Diseases, 9–12 July 2021.
  15. Gniadek TJ, et al. Carbapenem-Resistant Non-Glucose-Fermenting Gram-Negative Bacilli: the Missing Piece to the Puzzle. J Clin Microbiol. 2016;54(7):1700−1710.
PP-UK-FDC-0868 | August 2023