By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a new antibacterial for complicated urinary tract infections (cUTI) caused by multidrug-resistant, Gram-negative bacteria. Cefiderocol is a siderophore (iron carrier) cephalosporin with bactericidal activity against Gram-negative aerobic bacteria and no relevant activity against Gram-positive or anaerobic bacteria.1 The FDA has granted a Qualified Infectious Disease Product designation and priority review. The drug is distributed as Fetroja.

INDICATIONS

Cefiderocol should be prescribed to treat cUTI, including pyelonephritis, in adults ≥ 18 years of age with limited or no alternative treatment options. Infections in these patients are caused by susceptible Gram-negative microorganisms.1 Susceptible Gram-negative microorganisms include Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

DOSAGE

The recommended dose is 2 g administered by IV infusion (over three hours) every eight hours.1 Dose adjustments are required in patients with creatinine clearance less than 60 mL/min or ≥ 120 mL/min.

POTENTIAL ADVANTAGES

Cefiderocol possesses high stability against all classes of carbapenemases, including both serine-carbapenemases and metallo-beta-lactamases.2,3 In addition, its iron-binding ability facilitates transport of the drug into the periplasmic space of the bacteria.2

POTENTIAL DISADVANTAGES

A numerical increase (24.8% vs. 18.4%) in 28-day, all-cause mortality was observed in a study (n = 150) with cefiderocol compared to best available therapy (mainly colistin-containing regimens) in critically ill subjects with carbapenem-resistant, Gram-negative infection. These subjects had either hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), healthcare-associated bacterial pneumonia (HCABP), cUTI, bloodstream infections (BSI), or sepsis. Although the cause of increase in mortality has not been established, deaths generally were the result of worsening or complication of infection (including Acinetobacter baumannii, Stenotrophomonas maltophilia, and P. aeruginosa) or underlying comorbidities.1

COMMENTS

The approval of cefiderocol was based on limited clinical and safety data.1 The authors of a phase II, randomized, double-blind, noninferiority trial compared cefiderocol to imipenem/cilastatin for the treatment of cUTI.1,5 Subjects were randomized at a 2:1 ratio to cefiderocol (2 g every eight hours) or imipenem/cilastatin (1 g/1 g every eight hours) for seven to 14 days. The primary efficacy endpoint was a composite of clinical response and microbiological response at the test of cure (TOC) assessment at seven (± 2) days after end of antibiotic treatment. TOC results were 72.6% for cefiderocol and 54.6% for imipenem.

Clinical responses were comparative (89.7% vs. 87.4%), but microbiologic response favored cefiderocol (73% vs. 56.3%). Noninferiority was demonstrated for the composite outcome. A post-hoc analysis indicated superiority of cefiderocol over imipenem.5 Both agents appear to be well-tolerated. Diarrhea (6% vs. 4%) and Clostridioides difficile colitis (3% vs. 0.3%) were numerically higher for imipenem/cilastatin.5

CLINICAL IMPLICATIONS

The World Health Organization defines Priority 1 pathogens as those that require new antimicrobials. These included carbapenem-resistant A. baumannii, carbapenem-resistant P. aeruginosa, and carbapenem-resistant, third-generation, cephalosporin-resistant Enterobacteriaceae.6 Newly introduced antimicrobials, including beta-lactam/beta-lactamase inhibitors (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam), are effective against many carbapenemases, but not against metallo-beta-lactamases. Cefiderocol provides another option, with its ability to penetrate the bacteria via a “Trojan horse” approach, its stability against many Enterobacteriaceae carbapenemases, and its activity against P. aeruginosa and A. baumannii.2,7

The approval of cefiderocol was based on limited clinical data, and the numerically higher mortality rate in phase III trials needs further investigation. The authors of a recently completed study (300 enrolled) compared all-cause mortality at day 14 in participants with HABP, VABP, or HCABP who received cefiderocol + linezolid or meropenem + linezolid.8 Results are pending. Cefiderocol is expected to be available in early 2020.

REFERENCES

  1. Shionogi Inc. FETROJA (cefiderocol) approved by the FDA for treatment of complicated urinary tract infections (cUTI) in adult patients with limited or no alternative treatment options, Nov. 14, 2019. Available at: http://bit.ly/343Qot1. Accessed Dec. 9, 2019.
  2. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative Bacilli. Drugs 2019;79:271-289.
  3. Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important Gram-negative bacteria. Clin Infect Dis 2019;69(Suppl 7):S544-S551.
  4. ClinicalTrials.gov. Study of S-649266 or best available therapy for the treatment of severe infections caused by carbapenem-resistant Gram-negative pathogens (CREDIBLE - CR). Available at: http://bit.ly/350r1cZ. Accessed Dec. 9, 2019.
  5. 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;18:1319-1328.
  6. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at: http://bit.ly/36hTbAj. Accessed Dec. 9, 2019.
  7. Doi Y. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin Infect Dis 2019;69:S565-S575.
  8. ClinicalTrials.gov. Clinical study of S-649266 for the treatment of nosocomial pneumonia caused by Gram-negative pathogens (APEKS-NP). Available at: http://bit.ly/2RKLaAb. Accessed Dec. 9, 2019.