Report: Combo therapy outwits challenging infections

Hand holding in hospital
Hand holding in hospital

Katarzyna Bialasiewicz / iStock

A new study in Antimicrobial Agents and Chemotherapy describes a novel combination therapy that could serve as a weapon against a growing antibiotic resistance threat.

The therapy involves two compounds that, when used together, helped physicians successfully treat a 72-year-old woman who had a serious, multidrug-resistant bone infection and a young kidney-transplant patient who had a hard-to-treat case of bacteremia. The idea to use this combination came after it showed efficacy in the lab and in an animal infection model, but it started with a clinical understanding of how the individual agents' strengths could be enhanced through collaboration.

The author of the study says it provides an example of how clinical knowledge can inform medical treatment and save lives.

"Good medicine is always based on good science," corresponding author Robert Bonomo, MD, an infectious disease physician and professor of medicine at the Louis Stokes Cleveland VA Medical Center in Ohio, told CIDRAP News.

Blocking enzymes

It began with a hypothesis that Bonomo and his colleagues had about combining the compound antibiotic ceftazidime/avibactam with the antibiotic aztreonam. Ceftazidime/avibactam, which was approved in the United States in 2015, has been a valuable tool for treating certain multidrug-resistant gram-negative infections. It works by inhibiting class A and class C bacterial enzymes, such as extended-spectrum beta lactamases (ESBLs), Klebsiella pneumoniae producing carbapenemases (KPCs), and cephalosporinases, which confer resistance to beta-lactam antibiotics.

But ceftazidime/avibactam has a significant weakness: metallo-beta-lactamase enzymes, which have emerged as a significant global antibiotic resistance threat, particularly in Southeast Asia and parts of Europe. Aztreonam, on the other hand, is susceptible to the class A and C beta-lactamases but isn't broken down by metallo-beta-lactamases.

What Bonomo and his team hypothesized was that if aztreonam were added to the ceftazidime/avibactam combination therapy, the duo would help free aztreonam to work against infection-causing bacteria by protecting it from the other beta-lactamase enzymes, like offensive lineman in football blocking for a running back.

"Avibactam blocks all the enzymes, the aztreonam skirts around the metallo-beta-lactamase and hits its target—the penicillin-binding proteins," Bonomo explained.

In the lab, the hypothesis proved correct. The combination of the two drugs killed or prevented further growth in 17 of 21 carbapenem-resistant, metallo-beta-lactamase–producing Enterobacteriaceae isolates. Based on these results, Bonomo and his team got a grant from the National Institutes of Health to test the approach in a mouse thigh infection model. Again, the strategy worked. 

From the lab to the hospital

Then, Bonomo was presented with two real-world cases in which he thought the combination therapy might work. One involved a 72-year-old woman with a carbapenem-resistant, metallo-beta-lactamase–producing Enterobacter cloacae infection that had developed in the wake of hip-replacement surgery and was not responding to antibiotic treatment.

The other was a 19-year-old renal transplant recipient who had developed prolonged bacteremia caused by metallo-beta-lactamase-producing Stenotrophomonas maltophilia. That patient's case report appeared September 2016 in the same journal.

Recognizing that he might have a potential solution, Bonomo recommended the strategy to the treating physicians, and in both cases, the combination of the two drugs helped clear the infections. What started out as a hypothesis ended up defeating two difficult-to-treat infections.

"I hate to see anybody suffer from an infectious disease," Bonomo said. "It hurts me to the core, and I will do whatever I can to help save a patient's life."

Bonomo said that for now the strategy is a temporary measure, given that all the researchers have to go on is anecdotal data. Further studies, including clinical trials, will be needed before physicians can fully endorse use of the combination therapy. But he thinks the study is important because it shows how basic research on the mechanisms of antibiotic resistance can help lead to better treatment.

"If we understand the fundamental mechanisms by which bacteria become resistant to antibiotics, we can use what we know to help divine better therapies," Bonomo said.

See also:

Feb 6 Antimicrob Agents Chemother abstract

September 2016 Antimicrob Agents Chemother case report

This week's top reads

Our underwriters