Co-resistance necessitating use of less effective or relatively toxic reserve antibiotics (aminoglycosides, tigecycline and colistin/polymyxin B) may worsen survival. We investigated difficult-to-treat resistance (DTR) in gram-negative bloodstream infections (GNBSIs) defined by absence of susceptibility to all first-line agents (carbapenems, beta-lactams and fluoroquinolones (FQ) using a large clinical database of US hospitals. We found that survival in antimicrobial-resistant GNBSI is highly contingent on presence of active first-line option(s); DTR limits treatment options to reserve agents, including aminoglycosides, which are far from universally active. DTR remained infrequent (1%) among GNBSI, but occurred at half of the hospitals examined and across all US regions. This work has been presented at the Annual Meetings of the Infectious Diseases Society of America and Society of Critical Care Medicine.We went on to validate our findings using the Cerner Health facts repository of electronic health records. As part of the NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI), we also went on to study the landscape of emerging antibiotics to understand their real-world use and demand. We found that ceftazidime-avibactam use increased several fold replacing colistin use, however overall use was still modest. As part of an FDA-funded initiative, we determined that treatment opportunities for difficult-to-treat antibiotic resistant pathogens in US hospitals remain small, suggesting that non-revenue based strategies might be necessary to sustain antibiotic development. As part of work that is funded in part by the FDA, we conducted analyses on the relationship between minimum inhibitory concentration and outcomes for two key pathogen antibiotic combinations to determine whether existing breakpoints for those combinations set by standards development organizations warrant revision. We also conducted a study to determine the inpatient utilization of novel antibiotics against DTR pathogens as well as understand the current residual market size for other future novel antibiotics. This manuscript is under review at a journal. We believe this work will inform ongoing efforts to substantiate non revenue based strategies to sustain the antibiotic development industry. As part of the NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI), we determined that one in every five patients with bloodstream infection in US hospitals receives empiric antibiotic therapy that is discordant with in vitro susceptibilities. This practice was prevalent and similar across hospital types. Bacteremic patients who received in vitro-discordant empiric therapy displayed a higher mortality risk than recipients of concordant therapy. S. aureus and Enterobacterales and their resistance phenotypes account for the overwhelming majority of burden and impact of in vitro-discordant therapy, warranting development and wide implementation of effective rapid point-of-care diagnostics, especially those targeting these pathogens and their resistance phenotypes. We also conducted a study to compare the clinical effectiveness of trimethoprim sulfamethoxazole versus levofloxacin for Stenotrophomonas maltophilia infections and found that both performed relatively comparably, suggesting there is equipoise for a future trial comparing these agents. We also studied the prevalence of ICU-onset BSI, the distribution of pathogens and their antibiotic resistance phenotypes and determined risk factors for the acquisition of these infections. We found that ICU-onset BSI represent serious infection that display a unique pathogen and resistance profile compared to BSI that necessitates admission to the ICU. We also conducted studies that associated antibiotic minimum inhibitory concentration with clinical outcomes. In collaboration with the investigators at the Harvard Department of Population Medicine, we used larger electronic health record data from over a hundred U.S. hospitals and determined that despite the extensive use of broad-spectrum empiric antibiotic therapy for community-onset sepsis, the prevalence of antibiotic resistant pathogens warranting such therapy is small. Rapid diagnostics targeting resistance phenotypes may have a role in enhancing antibiotic stewardship in sepsis. We also identified that next generation antibiotics are being underutilized by clinicians in difficult-to-treat gram-negative infections. Wider availability of new agent susceptibility testing can improve utilization. Findings have implications for incentivizing antibiotics during the current market failure in the US. We found that Carbapenem use in the treatment of extended-spectrum cephalosporin resistant Enterobacterales infections was high in US hospitals even for non severe infections and the IDSA guidance for managing resistant gram-negative infections did not alter this trend further. This suggests there is room for improving stewardship of Carbapenems in these infections.