In host evolution of beta lactam resistance during active treatment for bacteremia.

Multidrug-resistant (MDR) has been declared a serious threat by the United States Centers for Disease Control and Prevention. Here, we used whole genome sequencing (WGS) to investigate recurrent bloodstream infections in a severely immunocompromised patient. The infections demonstrated unusual, progressive increases in resistance to beta lactam antibiotics in the setting of active treatment with appropriate, guideline-directed agents. WGS followed by comparative genomic analysis of isolates collected over 44 days demonstrated in host evolution of a single isolate characterized by stepwise acquisition of two genetic resistance mechanisms over the course of treatment. We found a novel deletion affecting the repressor and neighboring gene , which associated with initial cefepime treatment failure. This was followed by acquisition of a porin nonsense mutation, , associated with resistance to carbapenems. This study highlights the potential for in-host evolution of during bloodstream infections in severely immunocompromised patients despite appropriate antimicrobial therapy. In addition, it demonstrates the utility of WGS for understanding unusual resistance patterns in the clinical context.