What outcomes data are available for cefiderocol in the treatment of serious, resistant infections?

Introduction

Antibiotic resistance is a significant problem in the United States. The Centers for Disease Control and Prevention (CDC) estimates that over 2.8 million antibiotic-resistant infections occur each year, resulting in 35,000 deaths.1 Multidrug-resistant Gram negative pathogens are recognized as particularly important threats to public health; these multidrug-resistant organisms include carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Treatment options for these resistant infections are limited, and often associated with significant toxicity.2,3 Although some newer, less toxic antibiotics have become available to treat resistant organisms, they are ineffective against certain types of beta-lactamases. Therefore, additional antibiotic options are still needed to treat multidrug-resistant organisms.

Cefiderocol is a first-in-class siderophore cephalosporin antibiotic with potent in vitro activity against a number of multidrug-resistant Gram negative bacteria, including P aeruginosa, A baumannii, and CRE.3,4 On November 14, 2019, cefiderocol was approved by the U.S. Food and Drug Administration for the treatment of complicated urinary tract infections in adults who have limited or no alternative treatment options.5 It gained an additional indication for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) in September 2020.6

Cefiderocol is unique in terms of its structure and mechanism of action. It is a cephalosporin antibiotic conjugated with a catechol moiety.2 Like other cephalosporins, cefiderocol can penetrate the outer membrane of the bacterial cell wall via passive diffusion through porin channels; however, its chemical structure also allows it to cross the outer membrane using the siderophore-iron complex pathway, which in turn leads to higher drug concentrations in the periplasmic space.4 The catechol moiety of cefiderocol mimics siderophores, which are iron-chelating molecules secreted by bacteria.2 These molecules capture iron and deliver it to bacterial cells for use in various enzymatic reactions.2,4 Cefiderocol forms a complex with iron and utilizes the bacterial ferric iron transport system to cross the outer membrane of the bacterial cell wall.2 Once inside the periplasmic space, cefiderocol dissociates from iron and binds to penicillin-binding proteins, thereby inhibiting peptidoglycan synthesis and causing bacterial cell lysis.3 Cefiderocol’s chemical structure confers stability against a variety of ESBLs, as well as serine-type and metallo-type carbapenemases.2,3 Thus, it offers a broad spectrum of coverage for a variety of drug-resistant Gram negative bacteria.3

Summary of evidence for cefiderocol

Several clinical trials have been conducted to examine the efficacy and safety of cefiderocol in serious Gram negative infections (Table 1).7-9 In a phase 2 trial of patients with complicated urinary tract infections, cefiderocol was non-inferior to imipenem-cilastatin in terms of clinical and microbiological response.9 This finding was consistent among the subset of patients in the trial with ESBL-producing Gram negative pathogens. The phase 3 APEKS-NP trial examined the efficacy of cefiderocol in critically-ill patients with nosocomial pneumonia and found that cefiderocol was non-inferior to meropenem in terms of 14-day all-cause mortality.8 However, a third trial, CREDIBLE-CR, reported mortality findings that seem to conflict with those of the APEKS-NP trial.7 In this randomized open label study, cefiderocol was compared to best available therapy (most frequently colistin) in patients hospitalized with carbapenem-resistant Gram negative pathogens. Patients in this trial could have nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Although clinical cure rates were similar for cefiderocol and best available therapy, all-cause mortality rates were increased in the cefiderocol group; this finding was primarily driven by an increased mortality rate among patients with Acinetobacter nosocomial pneumonia or bloodstream infection/sepsis. Based on the data from CREDIBLE-CR, a warning for increased all-cause mortality in patients with carbapenem-resistant Gram negative bacterial infections has been added to the prescribing information for cefiderocol.10

The differing mortality findings in CREDIBLE-CR and APEKS-NP may be due in part to differences in the patient populations that were enrolled, as well as differences in the comparator therapies used. In the CREDIBLE-CR study, Acinetobacter infections were present in approximately 46% of the study population, and all patients in the trial had carbapenem-resistant pathogens.7 Patients with known carbapenem-resistant pathogens at randomization were excluded from the APEKS-NP trial, but 19% of patients in the study population were found to have carbapenem-resistant pathogens after randomization.8 In the subset of APEKS-NP patients with carbapenem-resistant infections (n=56), 14-day and 28-day mortality rates did not differ between cefiderocol and meropenem (20% versus 19% and 27% versus 31%, respectively). Among the 16% of patients with Acinetobacter baumannii infection at baseline, 14-day all-cause mortality rates were also similar for cefiderocol versus meropenem (19% [5/26] versus 22% [6/27] for cefiderocol and meropenem respectively). It is not possible to draw any firm conclusions based on these small subsets of patients, but the fact that cefiderocol’s outcomes were similar to those of meropenem may indicate that it is similarly suboptimal for the treatment of carbapenem-resistant infections.11 The authors of the CREDIBLE-CR trial suggest that their mortality data may have been influenced by confounding factors, because Acinetobacter-infected patients in the cefiderocol group had higher rates of intensive care unit (ICU) admission and higher rates of septic shock at baseline than the Acinetobacter-infected patients in the best available therapy group.7 However, until more data are available, it may be prudent to reserve cefiderocol as a salvage option in the case of carbapenem-resistant Acinetobacter infections.11

Table 1. Overview of randomized controlled trials for cefiderocol in serious infections.7-9
Study design and durationSubjectsInterventionsResultsConclusions
Bassetti 20207

CREDIBLE-CR

Phase 3, MC, OL, pathogen-focused descriptive RCT

Follow-up for 28 days after end of treatment		N=150 adult patients hospitalized with nosocomial pneumonia (HAP, VAP, or HCAP), bloodstream infection or sepsis, or complicated urinary tract infection and evidence of a carbapenem-resistant Gram negative pathogen

Median age: 69 years (cefiderocol), 62 years (best available therapy)

Nosocomial pneumonia was the most common (45%), followed by bloodstream infection or sepsis (31%)		Cefiderocol 2 g IV over 3 hours, every 8 hours (n=101)

Best available therapy with a maximum of 3 drugs (n=49; 66% received colistin-based therapy)

Treatment duration of 7 to 14 days (could be extended up to 21 days at investigator discretion; median treatment durations for pneumonia and bloodstream infections or sepsis were 11 days and 13 days for cefiderocol and best available therapy respectively; median treatment durations for complicated urinary tract infections were 10.5 days and 6.5 days for cefiderocol and best available therapy, respectively)

Patients with pneumonia or bloodstream infection or sepsis could receive 1 adjunctive antibiotic in addition to cefiderocol (not a polymyxin, cephalosporin or carbapenem); 83% received cefiderocol monotherapy

Primary endpoint was analyzed in the carbapenem-resistant microbiological ITT population (N=118; cefiderocol n=80 and best available therapy n=38)		Primary:
Nosocomial pneumonia: Clinical cure at test of cure visit (7 days after end of treatment): 50% (20/40; 95% CI, 33.8 to 66.2) vs 53% (10/19; 95% CI, 28.9 to 75.6) with cefiderocol vs best available therapy

Bloodstream infection or sepsis
Clinical cure at test of cure visit (7 days after end of treatment): 43% (10/23; 95% CI, 23.2 to 65.5) vs 43% (6/14; 95% CI, 17.7 to 71.1) with cefiderocol vs best available therapy

Complicated urinary tract infection: Microbiological eradication at test of cure visit (7 days after end of treatment): 53% (9/17; 95% CI, 27.8 to 77.0) vs 20% (1/5; 95% CI, 0.5 to 71.6) with cefiderocol vs best available therapy

Secondary:
Complicated urinary tract infection
Clinical cure at test of cure visit (7 days after end of treatment): 71% (12/17; 95% CI, 44.0 to 89.7) vs 60% (3/5; 95% CI, 14.7 to 94.7) for cefiderocol vs best available therapy

Survival without the need to change antibiotic: 63% (50/80) with cefiderocol vs 61% (23/38) with best available therapy (difference, 1.1%; 95% CI, -17.7 to 20.0)

All-cause mortality at day 14 and day 28 was higher with cefiderocol vs best available therapy (19% vs 12% at day 14 and 25% vs 18% at day 28); mortality rates among patients with pneumonia or bloodstream infection or sepsis were numerically greater with cefiderocol, but mortality rates among patients with complicated urinary tract infections were numerically lower with cefiderocol
Among patients with Acinetobacter infections, mortality rates were 50% (21/42) with cefiderocol and 18% (3/17) with best available therapy

Safety:
AE rates were similar between groups (91% and 96% for cefiderocol vs best available therapy); drug-related AE rates were 15% and 22%, respectively

The most common AEs were diarrhea (19% vs 12%), pyrexia (14% vs 12%), septic shock (13% vs 14%), and vomiting (13% vs 14%), all cefiderocol vs best available therapy, respectively

Serious AEs occurred in 50% and 47% of cefiderocol and best available therapy groups, respectively; drug-related serious AE rates were 1% and 10%, respectively

Liver-related AEs were more common with cefiderocol (30% vs 14%)

Mortality rates were 34% and 18% for cefiderocol and best available therapy, respectively at the end of the study; however, additional deaths were spontaneously reported after the end of study timepoint, bringing the rates to 36% and 29%,  respectively		Clinical and microbiological outcomes were generally similar for cefiderocol and best available therapy. Patients receiving cefiderocol had a higher all-cause mortality rate than patients receiving best available therapy; this was particularly true for patients with pneumonia or bloodstream infection or sepsis and infection with an Acinetobacter species. However, this finding may have been the result of confounding factors. Acinetobacter-infected patients in the cefiderocol group were more likely to have had shock or be admitted to the ICU at baseline compared to Acinetobacter-infected patients in the best available therapy group.
Wunderink 20208

APEKS-NP

Phase 3, MC, DB, NI, RCT

Follow-up for 28 days after end of treatment
N=292 adults admitted to the hospital with acute bacterial pneumonia (HAP, VAP, or HCAP) suspected to be due to Gram negative bacteria

Mean age: 64.6 years (cefiderocol), 65.4 years (meropenem)

Most patients had VAP (42%) or HAP (41%); 70% were in the ICU at randomization and 60% required mechanical ventilation		Cefiderocol 2 g IV over 3 hours, given every 8 hours (n=145)

Meropenem 2 g IV over 3 hours, given every 8 hours (n=147)

Treatment duration of 7 to 14 days (could be extended up to 21 days at investigator discretion; mean duration, 10 days)

All patients additionally received at least 5 days of linezolid to ensure Gram-positive coverage		Primary:
All-cause mortality at day 14: 12.4% with cefiderocol and 11.6% with meropenem (difference, 0.8%; 95% CI, -6.6 to 8.2; p=0.002; NI margin, -12.5%)

Secondary:
Clinical cure at test of cure visit (7 days after end of treatment): 65% and 67% for cefiderocol and meropenem respectively (difference, -2.0%; 95% CI, -12.5 to 8.5)

Microbiological eradication at test of cure visit: 48% in each group

All-cause mortality at day 28: 21.0% and 20.5% with cefiderocol and meropenem respectively (difference, 0.5%; 95% CI, -8.7 to 9.8)

In patients with ESBL-producing pathogens, all-cause mortality was similar between groups at days 14 and 28

Safety:
AE rates were similar between cefiderocol (88%) and meropenem (86%), with the most common AEs being urinary tract infection (16% vs. 11%) and hypokalemia (11% vs. 15%)

Treatment-emergent serious AEs occurred in 36% and 30% of the cefiderocol and meropenem groups respectively, but drug-related serious AEs were low in both groups (2% and 3%, respectively)		Cefiderocol was non-inferior to high-dose, extended infusion meropenem for all-cause mortality in critically-ill patients with nosocomial pneumonia.
Portsmouth 20189

Phase 2, MC, DB, NI, RCT

Follow-up for 14 days after end of treatment
N=371 adults admitted to the hospital with a complicated urinary tract infection with or without pyelonephritis or acute uncomplicated pyelonephritis

Mean age: 62.3 years (cefiderocol), 61.3 years (imipenem-cilastatin)		Cefiderocol 2 g IV over 1 hour, given every 8 hours (n=252)

Imipenem-cilastatin 1 g IV over 1 hour, given every 8 hours (n=119)

Recommended treatment duration of 7 to 14 days (median duration, 9 days)		Primary:
Composite clinical and microbiological response at test of cure visit (7 days after end of treatment): 73% with cefiderocol vs 55% with imipenem-cilastatin (difference, 18.58%; 95% CI, 8.23 to 28.92; p=0.0004; NI margin, ‑15%)

Secondary:
Clinical response at test of cure visit: 90% vs. 87% for cefiderocol and imipenem respectively (difference, 2.39%; 95% CI, -4.66 to 9.44)

Microbiological response at test of cure visit: 73% vs. 56% for cefiderocol and imipenem-cilastatin, respectively (difference, 17.25%; 95% CI, 6.92 to 27.58)

Among patients with ESBL-producing Gram negative uropathogens, composite response rates at test of cure were 62.9% (44/70) and 47.2% (17/36) for cefiderocol and imipenem-cilastatin, respectively (difference, 16.66%; 95% CI, -3.08 to 36.40)

Safety:
AEs occurred in 41% of cefiderocol-treated patients and 51% of imipenem-cilastatin-treated patients; serious AEs occurred in 5% and 8% respectively

The most common AEs in each group were diarrhea and constipation		Cefiderocol was non-inferior to imipenem-cilastatin for the treatment of complicated urinary tract infections.
Abbreviations: AEs=adverse events; CI=confidence interval; DB=double-blind; ESBL=extended-spectrum beta-lactamase; HAP=hospital-acquired pneumonia; HCAP=health-care-associated pneumonia; ICU=intensive care unit; ITT=intent-to-treat; IV=intravenous; MC=multicenter; NI=noninferiority; OL=open label; RCT=randomized controlled trial; VAP=ventilator-associated pneumonia.

Safety of cefiderocol

Cefiderocol can cause hypersensitivity reactions, and it is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibiotics.10 It also carries warnings for Clostridium difficile infection and possible central nervous system adverse reactions (eg, seizures). In clinical trials, cefiderocol was generally well-tolerated, with a toxicity profile similar to that of other cephalosporins.3 In trials for complicated urinary tract infection, the most common adverse effects were diarrhea, infusion site reaction, constipation, rash, candidiasis, cough, elevations in liver enzymes, headache, hypokalemia, nausea, and vomiting.10 In trials for pneumonia, the most common adverse effects were elevations in liver enzymes, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation.

Dosing and administration

Cefiderocol is an intravenous antibiotic, administered at a dose of 2 g every 8 hours.10 Cefiderocol must be reconstituted and diluted in normal saline or 5% dextrose prior to administration, and doses are typically infused over 3 hours. Dose adjustments are required for patients with creatinine clearance (CrCl) <60 mL/min or ≥120 mL/min. Patients with CrCl ≥120 mL/min should receive 2 g every 6 hours. For CrCl 30 to 59 mL/min, the dose is 1.5 g every 8 hours, and for CrCl 15 to 29 mL/min, the dose is 1 g every 8 hours. Patients with CrCl <15 mL/min, with or without intermittent hemodialysis, should receive a dose of 0.75 g every 12 hours. Patients on hemodialysis should receive their doses immediately after dialysis completion. Separate dosing recommendations are available for patients on continuous renal replacement therapy. The recommended dose will vary depending on the effluent flow rate.

Conclusion and ongoing trials

Cefiderocol is a novel antibiotic option for serious, resistant Gram negative pathogens. In clinical trials, cefiderocol was non-inferior to carbapenems for the treatment of complicated urinary tract infections and nosocomial pneumonias, including those caused by ESBL-producing organisms.8,9 However, data from the CREDIBLE-CR study suggest that it may be associated with increased mortality when used to treat carbapenem-resistant pneumonia and bloodstream infections, particularly those associated with Acinetobacter species.7 In light of these findings, some recommend that cefiderocol be reserved for salvage therapy, except in the case of drug-resistant urinary tract infections and infections with ESBL-producing Enterobacteriaceae.11 In the setting of severe carbapenem-resistant Gram negative infections (including pneumonia and bloodstream infections), there are insufficient data to recommend cefiderocol over other agents, such as ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, tigecycline, aminoglycosides, and colistin.2 Additional data are needed to determine the true place in therapy for cefiderocol. An ongoing study aims to compare cefiderocol to best available therapy for the treatment of Gram negative bloodstream infections (GAMECHANGER; NCT03869437).12

References

  1. Antibiotic resistance threats in the United States, 2019. Centers for Disease Control and Prevention. Published December 2019. Accessed November 22, 2020. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
  2. El-Lababidi RM, Rizk JG. Cefiderocol: a siderophore cephalosporin. Ann Pharmacother. 2020;54(12):1215-1231. doi:10.1177/1060028020929988
  3. Wu JY, Srinivas P, Pogue JM. Cefiderocol: a novel agent for the management of multidrug-resistant gram-negative organisms. Infect Dis Ther. 2020;9(1):17-40. doi:10.1007/s40121-020-00286-6
  4. Abdul-Mutakabbir JC, Alosaimy S, Morrisette T, Kebriaei R, Rybak MJ. Cefiderocol: a novel siderophore cephalosporin against multidrug-resistant gram-negative pathogens. Pharmacotherapy. 2020. doi:10.1002/phar.2476
  5. FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance. U.S. Food and Drug Administration. Published November 14, 2019. Accessed November 22, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-efforts
  6. Shionogi announces FDA approval of FETROJA® (cefiderocol) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Shionogi Inc. Published September 28, 2020. Accessed November 22, 2020. https://www.shionogi.com/us/en/news/2020/9/shionogi-announces-fda-approval-of-fetroja-cefiderocol-for-the-treatment-of-hospital-acquired-bacterial-pneumonia-and-ventilator-associated-bacterial-pneumonia.html
  7. 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 randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2020. doi:10.1016/s1473-3099(20)30796-9
  8. 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 randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2020. doi:10.1016/s1473-3099(20)30731-3
  9. 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: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/s1473-3099(18)30554-1
  10. Fetroja. Package insert. Florham Park, NJ: Shionogi Inc.; 2020.
  11. Heil EL, Tamma PD. Cefiderocol: the Trojan horse has arrived but will Troy fall? Lancet Infect Dis. 2020. doi:10.1016/s1473-3099(20)30828-8
  12. RCT cefiderocol vs BAT for treatment of gram negative BSI (GAMECHANGER). ClinicalTrials.gov. Published March 11, 2019. Updated November 25, 2019. Accessed November 23, 2020. https://clinicaltrials.gov/ct2/show/NCT03869437?term=cefiderocol&draw=2&rank=3

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2020

The information presented is current as of November 12, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.