Cefiderocol active against gram-negative drug-resistant pathogens

NEW ORLEANS — A late-stage investigational drug penetrates a variety of gram-negative pathogens and could be a valuable new weapon against multidrug resistance, according to researchers.

They presented several studies at ASM Microbe on the effectiveness of cefiderocol, for which they hope to submit a new drug application in 2017.

“This is a game-changer,” Roger Echols, MD, an infectious disease specialist and drug development consultant, told Infectious Disease News. “It’s a novel method of cell entry, which is the first thing you have to overcome among gram-negative bacteria because they have these thick outer membranes.”

Echols is a consultant for Shionogi Inc., the company developing the drug.

Cefiderocol is a siderophore cephalosporin, a molecule that binds and transports iron in microbes. That is just one of the advantages to the drug, Echols explained.

“Cefiderocol takes advantage of bacteria’s need for iron,” he said. A bacterium secretes siderophores to seek out iron and bring it back to specialized iron transport channels, he said.

As a siderophore, cefiderocol binds to irons, which provide passage through the channels. The drug, therefore, acts as what Echols called a “Trojan horse.”

Passage through the iron channels allows cefiderocol to bypass the bacterium’s porin channels, which can adapt and change to deny the agent’s entry. Likewise, the iron channels can provide repeat entry even if the bacterium has efflux pumps that expel it.

The iron channels are more efficient than the efflux pumps, Echols said.

“We also think cefiderocol is not a good substrate for efflux pumps so even with efflux pump overproducers, the activity of cefiderocol is not significantly affected,” he added.

Once inside a bacterium, cefiderocol is also resistant to all classes of enzymes that work to inactivate beta-lactam antibiotics. Drug combinations including a beta lactamase inhibitor have been effective against serine beta lactamases, Echols said, but not so successful against metallo beta lactamases, which make bacteria resistant to a large variety of drugs.

“Importantly, [cefiderocol] is only active against gram-negative pathogens,” he continued. “And that has an advantage, we think, because there’s less collateral damage to the normal flora in the gastrointestinal tract, which can be disruptive and can lead to problems like Clostridium difficile and colitis. So, it’s really a targeted therapy. It’s intended for treating gram-negative infections, but it should be appropriately used to treat bugs that are resistant to carbapenems or multidrug-resistant bugs where patients have limited treatment options.”

Of four surveillance studies on cefiderocol presented at ASM Microbe, one included 7,054 gram-negative clinical isolates of 45 distinct species. The researchers determined the minimal inhibitory concentration (MIC) of cefiderocol and other drugs by treating the isolates in vitro. They found that more than 99% of the isolates had cefiderocol MICs of 4µg/mL.

For the researchers and clinicians eager to effectively fight drug-resistant infections, the studies show promise. According to the CDC, antibiotic resistance causes at least two million illnesses and 23,000 deaths each year in the United States.

WHO considers carbapenem-resistant, gram-negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae as top priority and critical for development of new drugs. Cefiderocol is active in all three pathogens, Echols said. - by Joe Green

References:

Antibiotic resistance threats in the United States, 2013. CDC. www.cdc.gov. Accessed June 2, 2017.

Tsuji M, et al. Abstract 2047. Presented at: ASM Microbe; June1-5, 2017.

Disclosure: Echols reports working as a consultant for Shionogi Inc.