January 22, 2020
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Cefiderocol: A novel siderophore cephalosporin for MDR gram-negative infections

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Multidrug-resistant (MDR) gram-negative bacteria continue to present an important threat to public health, and a long-stagnating antibiotic pipeline prompted the launch of the “10 x ’20” initiative by the Infectious Diseases Society of America in 2010. The IDSA called for FDA approval of 10 new systemic antibiotics by the year 2020. This goal has now been met and exceeded, largely through the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act, which permitted fast track and priority review, followed by an additional 5 years of patent exclusivity upon approval, for novel antimicrobials.

Among the newest agents to have been approved following priority review is cefiderocol, marketed as Fetroja (Shionogi).

Leah Molloy
Leah Molloy

Mechanism and spectrum

Cefiderocol is a siderophore cephalosporin antibiotic with structural similarities to both cefepime and ceftazidime but with an added catechol moiety. This group provides both added stability against beta-lactamase enzymes and binds to ferric iron, thus being recognized by bacteria as a siderophore. This allows cefiderocol to bypass typical mechanisms of antibiotic resistance: degradation by beta-lactamase enzymes; reduced exposure secondary to common cell membrane alterations, including a reduced presence of influx porins; and increased expression of efflux pumps. Activity against gram-positive bacteria is limited.

Beta-lactamase production is a significant driver of antibiotic resistance across several gram-negative pathogens, particularly Enterobacteriaceae. Recently developed novel beta-lactamase inhibitors like avibactam, vaborbactam and relebactam have improved the ability to treat infections caused by bacteria harboring extended-spectrum beta-lactamases, most notably Klebsiella pneumoniae carbapenemase (KPC), that were previously untreatable with beta-lactam antibiotics. Compared with ceftazidime/avibactam, cefiderocol offers similar stability against KPC enzymes and additionally is much less affected by the class D oxacillinase enzymes common in MDR Acinetobacter baumannii (see Tables 1 and 2). Cefiderocol also exhibits improved activity against class B metallo-beta-lactamases, including the uniquely highly resistant New Delhi metallo-beta-lactamase — an enzyme that has remained unaffected by novel beta-lactamase inhibitors.

Cell membrane alterations are common and important mediators of antibiotic resistance among Pseudomonas aeruginosa. Cefiderocol is unaffected by these mechanisms owing to its unique method of bacterial cell entry. Instead of relying on passive diffusion through membrane porins like most antibiotics, cefiderocol is taken up by bacterial active iron transport systems. Of the new beta-lactam/beta-lactamase inhibitor products developed in the last several years, ceftolozane/tazobactam is also noted to be minimally affected by typical cell membrane changes seen in P. aeruginosa, and cefiderocol maintains potency (MIC50 = 0.25 mg/L; MIC90 = 4 mg/L) even against ceftolozane/tazobactam-resistant P. aeruginosa.

Pharm Consult Tables

Pharmacokinetics and dosage

Cefiderocol has pharmacokinetics similar to cefepime (see Table 3), with a relatively short half-life, moderate protein binding and primarily urinary excretion. The recommended dose of cefiderocol is identical to cefepime in patients with normal renal function — 2 g every 8 hours but with a standard infusion time of 3 hours. Like most beta-lactams, cefiderocol requires dose adjustment for impaired renal function. Additionally, more frequent administration of 2 g every 6 hours is recommended for patients with creatinine clearance of 120 mL/min or greater.

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FDA approval and clinical studies

Cefiderocol was granted FDA approval on Nov. 14, 2019, for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, based on a phase 2 multicenter double-blind trial that randomly assigned 452 patients to receive 7 to 14 days of cefiderocol or imipenem/cilastatin for cUTI. Among those included in the primary efficacy analysis, more patients treated with cefiderocol (183/252; 73%) than those treated with imipenem/cilastatin (65/119; 55%) achieved the composite primary microbiologic and clinical endpoint, with an adjusted treatment difference of 18.58% (95% CI, 8.23-28.92).

Additional studies have evaluated the clinical utility of cefiderocol in other disease states. The APEKS-NP trial found similar 14-day all-cause mortality among adults randomly assigned to receive either cefiderocol (18/145; 12.4%) or meropenem (17/146; 11.6%) for the treatment of nosocomial pneumonia. However, a higher all-cause mortality rate was observed among hospitalized patients with carbapenem-resistant infections treated with cefiderocol (19/101; 18.8% at day 14 and 25/101; 24.8% at day 28) than those who received the best available treatment (6/49; 12.2% at day 14 and 9/49; 18.4% at day 28) in the CREDIBLE-CR study. This finding is included as a warning in the package insert. The mortality difference was most pronounced among patients treated for nosocomial pneumonia, and the cause for this imbalance has not been identified.

Additional adverse effects noted in the package insert are comparable to other beta-lactam antibiotics: hypersensitivity, Clostridioides difficile-associated diarrhea, and central nervous system toxicities, including seizures. While awaiting more real-world experience with this newly approved agent, cefiderocol is a significant addition to a growing list of novel antimicrobials poised to improve the care of patients infected with MDR gram-negatives.

Disclosure: Molloy reports no relevant financial disclosures.