In large study, antibiotic pairs mostly display ‘concurrent
Researchers retrospectively analyzed nearly 450,000 antimicrobial susceptibility test results from a couple dozen hospitals to identify antibiotic pairs with disjoint resistance.

Some antibiotic pairs display a property known as collateral sensitivity in which the evolution of resistance to one antibiotic increases sensitivity to the other. Alternating between collaterally sensitive antibiotics has been proposed as a sustainable solution to the problem of antibiotic resistance. Researchers aimed to identify antibiotic pairs that could be considered for treatment strategies based on alternating antibiotics.

They did a retrospective analysis of 448?563 antimicrobial susceptibility test results acquired over a 4-year period (Jan 1, 2015, to Dec 31, 2018) from 23 hospitals in the University of Pittsburgh Medical Center hospital system. They used a score based on mutual information to identify pairs of antibiotics displaying disjoint resistance, wherein resistance to one antibiotic is commonly associated with susceptibility to the other and vice versa.

They applied this approach to the six most frequently isolated bacterial pathogens (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, and Proteus mirabilis) and subpopulations of each created by conditioning on resistance to individual antibiotics. To identify higher-order antibiotic interactions, they predicted rates of multidrug resistance for triplets of antibiotics using Markov random fields and compared these to the observed rates.

Researchers identified 69 antibiotic pairs displaying varying degrees of disjoint resistance for subpopulations of the six bacterial species. However, disjoint resistance was rarely conserved at the species level, with only 6 (0·7%) of 875 antibiotic pairs showing evidence of disjoint resistance. Instead, more than half of antibiotic pairs (465 [53·1%] of 875) exhibited signatures of concurrent resistance, whereby resistance to one antibiotic is associated with resistance to another. They found concurrent resistance to extend to more than two antibiotics, with observed rates of resistance to three antibiotics being higher than predicted from pairwise information alone.

The high frequency of concurrent resistance shows that bacteria have means of counteracting multiple antibiotics at a time. The almost complete absence of disjoint resistance at the species level implies that treatment strategies based on alternating between antibiotics might require subspecies level pathogen identification and be limited to a few antibiotic pairings.