Since the 1940s, antibiotics have been used to treat infectious diseases. With long-term use, however, the infectious organisms have adapted to the drugs designed to destroy them, rendering the drugs much less effective.

Simply using antibiotics creates resistance. Up to 50 percent of the time antibiotics are not optimally prescribed. It is not uncommon for antibiotics to be prescribed when not needed or dosed incorrectly.

Each year in the United States, at least 2 million people become infected with bacteria that are resistant to antibiotics, and at least 23,000 people die each year as a direct result of these infections. In addition, almost 250,000 people who are hospitalized or require hospitalization get Clostridium difficile each year, an infection usually related to antibiotic use. C. difficile causes deadly diarrhea and kills at least 14,000 people each year.

But many C. difficile infections and drug-resistant infections can be prevented. Studies have estimated that in the U.S., antibiotic resistance adds $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year.

In fact, antibiotic resistance is one of the world's most critical public health problems, and scientists, clinicians and pharmaceutical companies have struggled to find new antibiotics or alternative strategies against these multidrug-resistant bacteria. Carbapenem-resistant enterobacteriaceae (CRE) causes approximately one-third of healthcare-associated infections in the U.S. and kills nearly half its victims.

Now, researchers in Cleveland have begun to defeat antibiotic-resistant infections by combining two different antibiotics, each blocking a different kind of drug-destroying enzyme secreted by bacteria. The study was led by Robert A. Bonomo, M.D., Professor of Medicine, Pharmacology, Biochemistry, Molecular Biology and Microbiology at Case Western Reserve University School of Medicine and Chief of Medical Service at the Louis Stokes Cleveland Veterans Affairs Medical Center.

In this multicenter study, researchers characterized patients with CRE bacteremia in 2013 at eight medical centers in New York and New Jersey and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps) and antimicrobial susceptibilities.

The new combination antibiotic drug regimen was effective against 81 percent of CRE specimens. The regimen 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 the metallo-beta-lactamases; whereas the other antibiotic in the regimen, aztreonam, is not. But aztreonam is vulnerable to other types of CRE enzymes, which are in turn neutralized by ceftazidime/avibactam.

When combined, the two antibiotics work together to defeat the infection.

This novel combination will help physicians overcome the antibiotic neutralizing metallo-beta-lactamases. The other half of the regimen, aztreonam, skirts around the metallo-beta-lactamase and hits its target — the penicillin-binding proteins. What happens is that bacteria with aztreonam attached to their penicillin-binding proteins can't build effective cell walls with the drug in the way, so they die.

This regimen was used to treat a kidney transplant patient at Nationwide Children's Hospital and an elderly woman who had just received a new hip. Both patients had potentially fatal infections and survived because of this cutting-edge treatment.

This combination drug approach still needs to go through clinical trials before becoming a commonly used treatment.