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Novel Cephalosporin Agent Shows Promise for Complicated UTIs

A recent press release from the developer, Shionogi Inc, details the results of their clinical trial comparing their phase III agent cefiderocol (S-649266) to imipenem/cilastatin in complicated urinary tract infections (cUTIs). The study, APEK-cUTI (NCT02321800), enrolled 452 patients hospitalized with cUTIs, including pyelonephritis, across multiple sites internationally. Patients were randomized 2:1 to either IV cefiderocol 2 grams every eight hours or IV imipenem/cilastatin 1 gram every eight hours, adjusting for renal function, for a total duration of seven to 14 days. The primary efficacy endpoint was a combination of both clinical cure and microbiological eradication at the test of cure visit occurring approximately seven days after treatment. Cefiderocol proved not only to be non-inferior, but superior to imipenem/cilastatin at the test of cure visit, with a weighted difference in primary outcome of 18.58% (95% confidence interval 8.23% to 28.92%).
Cefiderocol is among a few agents in the antibiotic pipeline with a novel mechanism of action that allows for activity against a wide variety of drug-resistant Gram-negative organisms. This novel cephalosporin is a siderophore, binding to ferric iron, travelling through the bacterial outer membrane through iron transporters, concentrating in the periplasmic space, and inhibiting cell wall synthesis. This was elucidated in a 2016 Antimicrobial Agents and Chemotherapy (AAC) article where cefiderocol was tested against Pseudomonas aeruginosa (P. aeruginosa) ATCC 27853 and P. aeruginosa PAO1. This agent also has high stability against hydrolysis by extended-spectrum beta-lactamases and carbapenemase-producing organisms, including New Delhi metallo-beta-lactamase (NDM).
This news came one day prior to the Centers for Disease Control and Prevention (CDC) report of a woman in Nevada succumbing to carbapenem-resistant Enterobacteriaceae (CRE) infection that was resistant to all 26 antibiotics currently available in the United States. The patient, who was admitted in August for sepsis secondary to a right hip seroma, had a history of multiple hospitalizations in India related to osteomyelitis of the right hip and femur. The isolated organism was a Klebsiella pneumoniae which the CDC confirmed was NDM-producing. The isolate was also tested for the presence of the MCR-1gene, which is responsible for colistin resistant and gained significant attention in the United States this summer after the publication of a case report in AAC. This isolate was negative for MCR-1. Importantly, the MIC to fosfomycin indicated potential clinical utility (MIC of 16 mcg/mL by E-test) but IV fosfomycin is not commercially available in the United States.
Shionogi Inc. also pointed out in their press release that the trial was designed to include “… patients that are more difficult to treat” according to their Chief Medical Officer Dr. Tsutae Den Nagata. Details on the patient population enrolled in the study are not currently available but exclusion criteria are minimal, excluding confirmed Gram-positive UTI, fungal UTI, asymptomatic bacteriuria, and/or receipt of hemodialysis. Additionally, previous work from the company has focused on determining the pharmacokinetics of cefiderocol in patients with renal impairment.
Cefiderocol qualifies for priority review and eligibility for fast-track approval at the FDA. There is also an ongoing trial focused on carbapenemase-producing organisms, CREDIBLE-CR (NCT02714595), with a goal of enrolling 150 patients internationally. More information on this drug is sure to be forthcoming as more information comes to light.
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