Cefiderocol noninferior to high-dose meropenem in phase 3 trial for nosocomial pneumonia
WASHINGTON — Cefiderocol, a novel siderophore cephalosporin, was noninferior to high-dose meropenem for the primary endpoint of all-cause mortality 14 days after treatment was started in patients with nosocomial pneumonia caused by gram-negative pathogens, according to results of a randomized phase 3 trial called APEKS-NP.
“Data from APEKS-NP provide meaningful evidence that cefiderocol has the potential to be an effective treatment option for severely ill hospitalized patients with pneumonia,” Tsutae “Den” Nagata, MD, PhD, FFPM, chief medical officer at Shionogi, said in a press release.
According to Shionogi, which is developing the antibiotic, cefiderocol has a novel mechanism for penetrating the outer cell membrane of gram-negative pathogens, including multidrug-resistant strains, and it has a unique ability to evade carbapenem resistance.
“Cefiderocol overcomes all three major mechanisms of beta-lactam resistance, including porin channel loss, beta-lactamases and efflux pumps,” Yuko Matsunaga, MD, PhD, MPH, medical director at Shionogi, said during a presentation at IDWeek.
In the trial, 300 hospitalized patients with pneumonia caused by gram-negative pathogens — including hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP) and health care-associated pneumonia — were randomly assigned in a 1:1 ratio to receive 2 g of IV cefiderocol or 2 g of IV meropenem over a 3-hour period every 8 hours, for 7 to 14 days.
Linezolid was additionally administered for at least 5 days in both arms of the APEKS-NP trial to provide coverage for MRSA, and for gram-positive bacteria in the cefiderocol group.
To give a sense of how ill the patients were, Matsunaga mentioned that 60% were ventilated and approximately 70% of patients were in ICU at baseline.
Results from APEKS-NP showed that at day 14, the rate of all-cause mortality in the modified intent-to-treat population was 12.4% for cefiderocol and 11.6% for high-dose meropenem, respectively (difference = 0.8; 95% CI, –6.6 to 8.2), falling within the noninferiority margin.
Day 28 all-cause mortality — a secondary outcome — was 21% in the cefiderocol arm compared with 20.5% in the meropenem arm (difference = 0.5; 95% CI, –8.7 to 9.8).
Cefiderocol also achieved secondary endpoints of clinical and microbiological outcomes at test of cure (TOC). Specifically, clinical cure at TOC was 64.8% for cefiderocol vs. 66.7% for meropenem (difference = –2; 95% CI, –12.5 to 8.5), and microbiological eradication at TOC was 47.6% for cefiderocol vs. 48% for meropenem (difference = –1.4; 95% CI, –13.5 to 10.7).
According to the researchers, there were no unexpected safety signals in the study. The incidence of treatment-emergent adverse events was comparable between treatment arms — 87.8% for cefiderocol vs. 86% for meropenem (difference = 1.8; 95% CI, –5.8 to 9.5).
“Carbapenem resistance is a growing problem in the U.S. and around the world, with increasing infections due to strains that are resistant to most or all currently available antibiotics,” Nagata said. “These phase 3 APEKS-NP data, combined with data from our phase 2 APEKS-cUTI trial in complicated urinary tract infection, underscore the potential of cefiderocol to help solve an unmet medical need for patients battling life-threatening infections caused by deadly, hard-to-treat gram-negative pathogens.”
On Oct. 16, Shionogi announced that the FDA’s Antimicrobial Drugs Advisory Committee voted 14 to two to recommend the approval of cefiderocol for the treatment of complicated UTIs, including pyelonephritis, in patients with limited or no alternative treatment options. – by John Schoen
Editor’s note: This article was updated on Oct. 17.
Wunderlink RG, et al. Abstract LB4. Presented at: IDWeek; Oct. 2-6, 2019; Washington, D.C.
Disclosures: Nagata and Matsunaga are employed by Shionogi.