Inferring the interaction structure of resistance to antimicrobials.

The growth of antimicrobial resistance presents a significant threat to human and animal health. Of particular concern is multi-drug resistance, as this increases the chances an infection will be untreatable by any antibiotic. In order to understand multi-drug resistance, it is essential to understand the association between drug resistances. Pairwise associations characterize the connectivity between resistances and are useful in making decisions about courses of treatment, or the design of drug cocktails. Higher-order associations, interactions, which tie together groups of drugs can suggest commonalities in resistance mechanism and lead to their identification. To capture interactions, we apply log-linear models of contingency tables to analyze publically available data on the resistance of Escheresia coli isolated from chicken and turkey meat by the National Antimicrobial Resistance Monitoring System. Standard large sample and conditional exact testing approaches for assessing significance of parameters in these models breakdown due to structured patterns inherent to antimicrobial resistance. To address this, we adopt a Bayesian approach which reveals that E. coli resistance associations can be broken into two subnetworks. The first subnetwork is characterized by a hierarchy of β-lactams which is consistent across the chicken and turkey datasets. Tier one in this hierarchy is a near equivalency between amoxicillin-clavulanic acid, ceftriaxone and cefoxitin. Susceptibility to tier one then implies susceptibility to ceftiofur. The second subnetwork is characterized by more complex interactions between a variety of drug classes that vary between the chicken and turkey datasets.