How antibiotic resistance evolves in patients with acute bloodstream infections

Abstract

Antibiotic resistance can cause treatment failure when a patient with a previously antibiotic-suscpetible infection develops a resistant infection. This can occur through three distinct processes: (1) de novo evolution, where mutations in the bacterial genome confer resistance; (2) horizontal gene transfer, where bacteria acquire resistance genes through gain of mobile genetic elements; or (3) change of strain, where the patient is reinfected with a distinct antibiotic resistant strain. Understanding these frequencies can inform treatment and improve patient outcomes; however, the relative contribution of each mechanism to resistance evolution is unclear for most types of infections. Here we quantify the frequencies of resistance gain mechanisms using a dataset of paired blood samples from patients in the Mass General Brigham hospital system. We developed a bioinformatics pipeline to classify the resistance gain mechanism between two samples from whole genome sequencing data, detecting 10 instances of de novo evolution, 4 instances of horizontal gene transfer, and 5 instances of change of strain. Our findings show that, in contrast to other infections, all three resistance mechanisms contribute to within-patient antibiotic resistance evolution in bloodstream infections. We further identify reinfection from a bacterial reservoir to be a potentially prominent but overlooked mechanism of resistance gain. We anticipate our analyses to lay the groundwork for future studies investigating resistance evolution at the within-patient scale and ultimately inform treatment through the framework of evolution.