New drug kills antibiotic-resistant bacteria in clinical trial

Bacteria can cause a range of infections, and sometimes the best way to fight off these stubborn “bugs” is by using antibiotics.

However, many strains of bacteria can become resistant to antibiotics.

Furthermore, misuse or overuse of antibiotics has exacerbated this problem in populations across the world.

Given how serious the situation has become, the World Health Organization (WHO) have even published a priority list of antibiotic-resistant bacteria against which scientists need to come up with effective drugs.

Now, a new phase II randomized trial is bringing us one step closer to eradicating this global crisis. The trial was led by researchers from Shionogi Inc, a pharmaceutical company headquartered in Osaka, Japan.

The researchers’ results, which now appear in The Lancet Infectious Diseases, suggest that a new antibiotic is effective in treating complicated urinary tract infections (UTIs) that stubborn Gram-negative bacteria, which are resistant to a range of other antibiotics, cause.

Novel drug is effective and well-tolerated

The trial — part of the Food and Drug Administration’s (FDA) efforts to accelerate the development of more effective antibiotics — worked with 448 adult participants.

All had arrived at the hospital with a complicated UTI or diagnosed uncomplicated pyelonephritis, which is bacterial infection-induced inflammation of the kidney.

The scientists randomly assigned the participants to take either the new investigational antibiotic cefiderocol or the standard antibiotic imipenem-cilastatin three times per day for 1–2 weeks.

Three hundred people took cefiderocol and 148 took imipenem-cilastatin. Of these, 252 individuals who took cefiderocol and 119 individuals who took imipenem-cilastatin had a Gram-negative bacterium infection, so the scientists include their data in the final analysis.

Among them, the majority had infections resulting from Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa, all of which feature on WHO’s list of antibiotic-resistant bacteria as “critical-priority” targets.

The researchers saw that cefiderocol was as effective and well-tolerated as imipenem-cilastatin in treating these stubborn infections, with very high efficacy rates.

Cefiderocol and imipenem-cilastatin had a similar number of adverse events, the most common of which were gastrointestinal disorders such as diarrhea, constipation, nausea, vomiting, and abdominal pain.

How the drug attacks stubborn bacteria

The researchers explain that what differentiates cefiderocol from other potent drugs is that it is able to bypass the three main resistance “walls” that Gram-negative bacteria put up.

These are: two solid outer membranes that keep antibiotics at bay, porin channels that can adjust to block the drugs’ activity, and efflux pumps that “spit out” antibiotics should they penetrate the first two barriers.

“Cefiderocol acts as a trojan horse,” explains lead researcher Dr. Simon Portsmouth, adding, “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,” he explains, “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.”

Dr. Simon Portsmouth

The success of this new trial suggests that cefiderocol, once specialists approve it, will make an important addition to the arsenal of weapons able to tackle stubborn bacteria.

“Cefiderocol,” explains Dr. Portsmouth, “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.”

He goes on, “Our results support cefiderocol as a novel approach that might be used to overcome Gram-negative resistance.”

However, Dr. Portsmouth also advises that further research testing this antibiotic’s effectiveness in treating other types of bacteria will be crucial going forward.

As he concludes, “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.”

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