Infectious Disease

In large studies, antibiotic pairs mostly show “simultaneous resistance”

August 01, 2021

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The researchers retrospectively analyzed nearly 450,000 antimicrobial susceptibility test results from a few dozen hospitals to identify pairs of antibiotics with disjunct resistance.

Erik S. Wright

“This means that a pathogen cannot be resistant to both antibiotics of the couple at the same time,” explains Erik S. Wright, PhD, WOMAN, Assistant Professor of Biomedical Computer Science at the University of Pittsburgh. “We called this disjoint resistance because a disjoint set is a set that is mutually exclusive.”

Antibiotic pills

Most antibiotic pairs that have been used to treat common bacterial pathogens have shown resistance at the same time. Source: Adobe Stock.

According to Wright, such antibiotic pairs are expected to exist because of a phenomenon known as “collateral sensitivity,” when a pathogen adapts to a drug and can become more sensitive or resistant to other drugs.

“Research had previously shown that there was collateral sensitivity between some pairs of antibiotics in vitro,” Wright said. “The question is whether this leads to observing disjoint resistance in the clinic. If so, we could possibly use these pairs of antibiotics to avoid multiple resistance. “

Instead, their review found the opposite.

“Unfortunately, at the species level, we mostly saw co-resistance in antibiotics used to treat six common bacterial pathogens, which confirms and extends previous knowledge of co-resistance between antibiotics,” said Wright.

For the study, Wright and colleagues retrospectively analyzed 448,563 antimicrobial susceptibility test results obtained from 23 hospitals in the University of Pittsburgh Medical Center’s hospital system between January 1, 2015 and December 31, 2018. According to the study, they used a mutual information-based score to identify pairs of antibiotics with disjoint resistance.

They then applied this approach to the six most commonly isolated bacterial pathogens Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, and Proteus mirabilis, as well as to subpopulations of each that emerged from conditioning for resistance to individual antibiotics.

In total, the researchers identified 69 pairs of antibiotics with different degrees of disjoint resistance in subpopulations of the six types of bacteria. However, the study showed that disjoint resistance was rare at the species level, as only six (0.7%) out of 875 antibiotic pairs showed signs of disjoint resistance.

Instead, the study showed that 53.1% of antibiotic pairs had markers of concomitant resistance when resistance to one antibiotic is linked to resistance to another. This resistance also extended to more than two antibiotics, with the observed resistance rates to three antibiotics being higher than had been predicted based on the paired information alone.

“We showed how to find pairs of antibiotics that are most likely to successfully reduce antibiotic resistance. These are good antibiotic candidates for future clinical trials, but they also require subspecies-level classification to be used correctly, “Wright said. “Our study also showed which pairs of antibiotics had the worst concomitant resistance, and sharing these antibiotics should be avoided.”

Wright added that one possible strategy for combating antibiotic resistance is to switch between different antibiotics, and that this strategy has mostly been used by giving different antibiotics to different patients in the same hospital, either every other patient or every other month.

“These switching strategies did not manage to contain resistance, but this could be due to the wrong choice of antibiotic pairs,” he said.

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