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Cefiderocol: Does a new drug bring new successes?

Reviewed by Hannah Imlay, MD, MS, University of Utah

Two recent trials have refined the role of cefiderocol in clinical practice and shaped IDSA recommendations for treatment of resistant Gram-negative infections.

The first, APEKS-NP, is an RCT comparing cefiderocol with extended infusion meropenem for treatment of Gram-negative nosocomial pneumonia. Adult patients were included if they had nosocomial pneumonia suspected to be due to a Gram-negative pathogen. They were assigned to cefiderocol vs meropenem infusions x 7-14 days with a primary endpoint of all-cause mortality at day 14 in the mITT population.  A total of 300 patients (148 cefiderocol, 152 meropenem) were enrolled with 70% in the ICU at time of randomization. Gram-negative pathogen was confirmed in 86%, with the most common organisms as K. pneumoniae (32%), P. aeruginosa (16%), A. baumannii (16%), and E. coli (14%). All-cause mortality at day 14 was 12.4% with cefiderocol vs 11.6% with meropenem, which met the criteria for non-inferiority. AEs were similar between treatment groups. These data are similar to the previous APEKS-cUTI study and demonstrate non-inferiority of cefiderocol to carbapenem therapy in this patient population.

The second study, CREDIBLE-CR, is an open-label RCT that examined a patient population with serious infections caused by carbapenem-resistant organisms, treated with cefiderocol vs best alternative therapy (BAT). This trial was done descriptively, so there were no inferential hypothesis tests done to determine significance. Patients were included if they were hospitalized with nosocomial pneumonia, bloodstream infections/sepsis, or complicated UTI (cUTI) and evidence of a carbapenem-resistant Gram neg pathogen. Patients were randomized 2:1 to cefiderocol or BAT for 7-14 days, stratified by APACHE II score. The primary endpoint for pneumonia/BSI/sepsis patients was clinical cure at 7 days after treatment. For patients with cUTI, the primary endpoint was microbiological eradication on repeat urine culture.

A total of 152 patients (101 cefiderocol, 51 BAT) were enrolled in the trial. In 118 patients in the carbapenem-R population, the most frequent pathogens were A. baumanii, K. pneumoniae, and P. aeruginosa. Most patients in the cefiderocol group received monotherapy (83%) vs only 29% of patients in the BAT group. The majority (66%) of patients in the BAT group received colistin-based treatment.

Overall, clinical cure was achieved in 50% (20/40) cefiderocol vs 53% (10/19) BAT patients with pneumonia; 43% (10/23) cefiderocol vs 43% (6/14) BAT patients with BSI/sepsis; and 53% (9/17) cefiderocol vs 20% (1/5) BAT patients with cUTI. Most notably, a higher 28-day mortality was seen in the cefiderocol group (34% vs 18%), primarily in the patient subset with Acinetobacter infections and those with bloodstream infection or pneumonia. The observed higher mortality among patients treated with cefiderocol directly influenced recent IDSA guidelines that do not recommend use of cefiderocol for treatment of infections outside the urinary tract caused by CRE, although it is acknowledged that cefiderocol may have a role in metallo-β-lactamase-producing CRE infections. 

In general, the low rates of clinical success in this patient population highlight the unmet need for effective therapies. In addition, it was notable that cefiderocol did not perform better than a colistin-based regimen for all types of infection except perhaps the cUTI group. While cefiderocol expands our treatment options for difficult to treat resistant organisms, more effective treatments are clearly still needed.

References:

  1. Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, Lodise TP, Naas T, Niki Y, Paterson DL, Portsmouth S, Torre-Cisneros J, Toyoizumi K, Wunderink RG, Nagata TD. 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 Feb;21(2):226-240. doi: 10.1016/S1473-3099(20)30796-9. Epub 2020 Oct 12. PMID: 33058795.
  2. Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye KS, Kollef M, Menon A, Pogue JM, Shorr AF, Timsit JF, Zeitlinger M, Nagata TD. 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 Feb;21(2):213-225. doi: 10.1016/S1473-3099(20)30731-3. Epub 2020 Oct 12. PMID: 33058798 
  3. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2020 Oct 27: ciaa1478. doi: 10.1093/cid/ciaa1478. Epub ahead of print. PMID: 33106864. 
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