Antibiotic resistance is a growing problem worldwide that threatens the effectiveness of available treatments and can lead to prolonged hospital stays and increased mortality. Researchers have long searched for ways to fix the problem. Since antibiotic use fuels resistance, reducing antibiotic use offers an attractive strategy to curb resistance.
“It makes intuitive sense,” said epidemiologist Melinda Pettigrew, Ph.D, at the Yale School of Public Health in New Haven, Conn., but there are limited data on how treatment duration affects resistance genes. The ultimate goal, she says, is to find an optimal dosage that reduces antibiotic use without compromising patient health.
But it can be done, suggests a study published this week in mBio, an open access journal of the American Society for Microbiology. Pettigrew and colleagues studied data from a randomized controlled trial of children who had been diagnosed with community-acquired pneumonia (CAP) and treated with beta-lactam antibiotics. The children participated in an NIH-funded multi-institutional study called SCOUT-CAP (NCT02891915), which found that a 5-day course of beta-lactam antibiotics was as effective as the standard 10-day course for CAP treatment. Pettigrew led the microbiome substudy of the SCOUT-CAP trial.
For their sub-study, Pettigrew and his colleagues wanted to follow the influence of the 2 treatment durations on antibiotic resistance genes and the respiratory microbiota. They performed shotgun metagenomic sequencing on DNA from throat swabs and stool samples taken from the children at 2 points – first, a few days after the diagnosis of CAP, then at the end of the trial a few weeks later.
Sequencing revealed fewer resistance genes in children who received the 5-day treatment regimen compared to those who received the 10-day regimen. Some of these genes were associated with resistance to beta-lactams, which the researchers expected.
Surprisingly, the longer antibiotic treatment also resulted in a significant increase in resistance genes associated with several other antibiotics. “You may have increased resistance to drugs other than the one you’re dealing with,” Pettigrew said. “There are all these off-target effects.” The researchers also found that the duration of treatment changed the population of commensal bacteria in different ways.
So antibiotics don’t just impact the pathogens we’re trying to treat. They can affect the microbiota as a whole.
Melinda Pettigrew, Ph.D, Epidemiologist, Yale School of Public Health
The SCOUT-CAP trial, including this substudy, followed patients for 30 days. In future studies, Pettigrew said she would like to investigate the clinical implications of longer-term antibiotic treatment.
“We know that antibiotics disrupt the microbiome and increase susceptibility to other pathogens,” she said, “but we don’t have a measure of that risk.” The study also did not measure how long the effects lasted. [the collection of resistance genes in bacteria] and the microbiome will eventually return to normal.
These types of studies could help researchers harness the microbiome to identify patients most at risk for antibiotic resistance. “If future investigations confirm these findings, these techniques could one day help the FDA determine drug safety profiles and establish optimal treatment durations.
“The microbiome is so important to health, and disruption can lead to other downstream effects, including antibiotic resistance,” Pettigrew said.