Combinations of Up To 5 Antibiotics May Work Against Resistant E Coli

Drug-resistant Escherichia coli (E coli) bacteria are a growing public health threat, but investigators at the University of California, Los Angeles, say that combinations of up to 4 or 5 antibiotics may be effective at killing these harmful pathogens.

While most E coli are safe and part of healthy intestinal microflora, pathogenic forms of the bacteria cause intestinal illness. Exposure from contaminated food or water can lead to symptoms such as abdominal cramping, diarrhea, and vomiting, which can lead to life-threatening complications.

A 2018 E coli outbreak in 36 states linked to contaminated romaine lettuce was the largest E coli outbreak since 2006, leading to 210 reported cases, 96 hospitalizations, and 5 deaths. While most intestinal E. coli infections pass within a week, cases of pneumonia, meningitis, or urinary tract infections from the pathogen are typically treated with an antibiotic such as a third-generation cephalosporin. Increasingly, however, E coli are becoming resistant to antibiotics by producing extended-spectrum beta-lactamase, an enzyme rendering certain antibiotics ineffective and leading to multi-drug resistance.

Antibiotic-resistant E coli is a growing global problem, and in the United States, public health officials worry that the emergence of the mcr-1 gene in a number of pathogenic bacteria could make more superbugs resistant to even last-resort drugs such as colistin. While scientists have, in the past, discouraged combining more than 2 antibiotics to fight a resistant pathogen, a new study by UCLA investigators suggests that using as many as 5 antibiotics in tandem may be an effective strategy against resistant infections.

In the study, published on September 3, 2018 in the journal npj Systems Biology and Applications, investigators used 8 antibiotic drugs to create a total of 18,278 combinations of 2 to 5 drugs and study their interactive effects on E coli. Testing how the combinations affected bacterial growth responses, the research team found that of the combinations of 4 drugs, 1,676 performed better than they expected. Of the 5-drug combinations, 6,443 were more effective than expected. Many combinations also performed below the team’s expectations, including 2,331 4-drug combinations and 5,199 5-drug combinations.

“There is a tradition of using just 1 drug, maybe 2,” said one of the study’s senior authors Pamela Yeh, PhD, in a recent statement. The authors note that some combinations were effective because the medications target E coli in different ways, such as attacking cell walls or the bacteria’s DNA. “We’re offering an alternative that looks very promising. We shouldn’t limit ourselves to just single drugs or 2-drug combinations in our medical toolbox. We expect several of these combinations, or more will work much better than existing antibiotics.”

While the investigators say they’ve found antibiotic combinations that are effective in a laboratory setting, much more testing is required before these combinations can be considered ready for testing in humans. “With the specter of antibiotic resistance threatening to turn back health care to the pre-antibiotic era, the ability to more judiciously use combinations of existing antibiotics that singly are losing potency is welcome,” Michael Kurilla, MD, PhD, director of the Division of Clinical Innovation at the National Institutes of Health/National Center for Advancing Translational Sciences said. “This work will accelerate the testing in humans of promising antibiotic combinations for bacterial infections that we are ill-equipped to deal with today.”