Investigational antibiotic shows promise in UTIs

Results from a phase 2 randomised trial, led by pharmaceutical company Shionogi, suggest that a new investigational antibiotic is as effective as the current standard-of-care antibiotic for the treatment of complicated urinary tract infections (UTIs) caused by several multidrug-resistant Gram-negative bacteria.

Published in The Lancet Infectious Diseases, the findings indicated that patients treated with the siderophore-based drug cefiderocol had a higher and more sustained level of pathogen eradication and similar clinical outcomes to those treated with the current standard of care, imipenem-cilastatin.

Antibiotic resistance has been identified as one of the biggest threats to human health globally, with the WHO considering carbapenem-resistant, Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae as the highest priority and critical for development of new antibiotics. Previous studies have demonstrated that cefiderocol is active against all three multidrug-resistant pathogens.

Cefiderocol is novel in its approach to overcoming the three main mechanisms of antibiotic resistance used by Gram-negative bacteria: two outer membranes that make it hard for antibiotics to penetrate; porin channels, which can adapt and change to block the antibiotic entry; and efflux pumps that expel antibiotics back out of the cell and make the drugs ineffective.

“Cefiderocol acts as a Trojan horse,” explained Shionogi’s Dr Simon Portsmouth, who led the research. “The drug uses a novel mechanism of cell entry that takes advantage of the bacteria’s need for iron to survive.

“During an acute infection, one of our innate immune responses is to create an iron-poor environment. In response, bacteria increase their iron intake. Cefiderocol binds to irons and is transported through the extra outer membrane by the bacterium’s own iron-transport system. These iron channels also enable the drug to bypass the bacteria’s porin channels and gain repeat entry even if the bacterium has evolved efflux pumps.”

As part of the US FDA’s approach to fast-tracking antibiotic development, the new study randomised 448 adults who had been hospitalised with a complicated UTI or uncomplicated pyelonephritis (inflammation of the kidney dur to a bacterial infection) to receive three daily infusions of cefiderocol (300 patients) or imipenem-cilastatin (148 patients) for seven to 14 days. In total, 252 patients treated with cefiderocol and 119 with imipenem-cilastatin had a Gram-negative uropathogen and were included in the efficacy analysis. The majority of participants had Escherichia coli, Klebsiella pneumoniae or P. aeruginosa infections.

Results suggested that cefiderocol was as effective as imipenem-cilastatin in a combined evaluation of the clinical and microbiological response, with efficacy rates of 73% and 55% respectively seven days after treatment was stopped. This difference was mainly driven by the sustained antibacterial activity of cefiderocol while the clinical responses were highly similar (90% vs 87%).

Overall, cefiderocol was well tolerated with similar numbers of adverse events to that of imipenem-cilastatin (41% vs 51%). Gastrointestinal disorders were the most common adverse events in both groups (12% patients in the cefiderocol group and 18% patients in the imipenem-cilastatin group). 5% participants in the cefiderocol group and 8% in the imipenem-cilastatin group reported at least one serious adverse event, with C. difficile colitis the most common.

The authors also note that cefiderocol’s effect on carbapenem-resistant strains — which cause some of the hardest-to-treat infections in healthcare settings, and for which there is no antibiotic alternative that does not have serious side effects or other complications — could not be properly evaluated because the carbapenem drug imipenem-cilastatin was used as the active control treatment.

“Cefiderocol was found to be both safe and tolerable in a population of older patients who were very ill with complex comorbid conditions and a wide range of multidrug-resistant pathogens,” Dr Portsmouth said. “Our results support cefiderocol as a novel approach that might be used to overcome Gram-negative resistance.

“Ongoing clinical trials of pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia, and a study in patients with carbapenem-resistant infections, will provide additional important information about cefiderocol.”

Writing in a linked Comment, Dr Angela Huttner from Geneva University Hospitals discussed the importance of assessing the post-market clinical experience of the drug, noting that the FDA issued new guidance on complicated urinary tract infection endpoints in June 2018; any trial launched more than four months ago will therefore be adhering to outdated standards and requirements. There is also no guidance on measuring baseline or emerging resistance, she said, so this too will fall to post-market development.

“Cefiderocol remains on the fast track to approval,” Dr Huttner said. “This is welcome news, as long as those in post-market clinical medicine understand the deal we have made: it will fall to us to continue the drug’s clinical development while managing its appropriate use and conservation, and thus take its true measure.”

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