Researchers at Case Western Reserve University School of Medicine in Cleveland, Ohio, have taken a significant step toward defeating antibiotic-resistant infections by combining two antibiotics that each block a different kind of drug-destroying enzyme secreted by bacteria. When combined, the antibiotics run interference for each other to fight infections. Now physicians have a new weapon to overcome one of the most pernicious infections caused by deadly bacteria endemic to hospitals, the scientists say.
Part of the challenge in treating penicillin-resistant infections lies in understanding the way bacteria inactivate penicillin antibiotics. The enzymes that do this––beta-lactamases––chop up the antibiotics, rendering them useless. One particularly troublesome group of bacterial beta-lactamases––metallo-beta-lactamases (MBLs)––is able to destroy even the newest penicillins. MBLs are often made by bacteria alongside other enzymes, including other beta-lactamases, that allow certain bacteria to destroy the entire penicillin arsenal.
Carbapenem-resistant Enterobacteriaceae (CRE) cause approximately one-third of health care-associated infections in the United States and kill nearly half of infected persons, according to a recent epidemiologic study published in Antimicrobial Agents and Chemotherapy. The researchers’ new combination antibiotic drug regimen proved effective against 81% of CRE specimens tested in a second study, published in the same journal issue.
The strategy uses two antibiotic drugs to protect each other from being neutralized by CRE’s problematic enzymes. The first half of the antibiotic combination regimen––ceftazidime/avibactam––is vulnerable to the neutralizing effect of MBLs, but the other antibiotic in the regimen––aztreonam––is not. Aztreonam, however, is vulnerable to other types of CRE enzymes, which are in turn neutralized by ceftazidime/avibactam. When combined, the two antibiotics run interference for each other and in tag-team fashion defeat the infection.
The new combination helps doctors overcome antibiotic-neutralizing MBLs, the researchers claim. With protection from the other half of the regimen, “aztreonam skirts around the metallo-beta-lactamase and hits its target––the penicillin-binding proteins,” explained lead investigator Robert A. Bonomo, MD. Bacteria with aztreonam attached to their penicillin-binding proteins can’t build effective cell walls with the drug in the way, and they quickly die. “If we understand the fundamental mechanisms by which bacteria become resistant to antibiotics, we can use what we know to help design better therapies,” Bonomo said.
He and his team demonstrated their regimen’s promise in laboratory models but were soon faced with patients who had no other treatment options. Doctors used the new regimen to treat a young kidney-transplant patient at Nationwide Children’s Hospital and an elderly woman who had just received a hip transplant at University Hospitals. Both patients had infections that verged on being fatal, and yet they survived because of the new treatment, according to the researchers. The combination approach still needs to be tested in clinical trials and to undergo additional research before it can become a commonly used treatment, they said.
Source: EurekAlert; March 9, 2017.