Real-World Application of Oral Therapy for Infective Endocarditis: A Multicenter, Retrospective, Cohort Study.

BACKGROUND: We sought to compare the outcomes of patients treated with intravenous (IV)-only vs oral transitional antimicrobial therapy for infective endocarditis (IE) after implementing a new expected practice within the Los Angeles County Department of Health Services (LAC DHS). METHODS: We conducted a multicentered, retrospective cohort study of adults with definite or possible IE treated with IV-only vs oral therapy at the 3 acute care public hospitals in the LAC DHS system between December 2018 and June 2022. The primary outcome was clinical success at 90 days, defined as being alive and without recurrence of bacteremia or treatment-emergent infectious complications. RESULTS: We identified 257 patients with IE treated with IV-only (n = 211) or oral transitional (n = 46) therapy who met study inclusion criteria. Study arms were similar for many demographics; however, the IV cohort was older, had more aortic valve involvement, were hemodialysis patients, and had central venous catheters present. In contrast, the oral cohort had a higher percentage of IE caused by methicillin-resistant Staphylococcus aureus. There was no significant difference between the groups in clinical success at 90 days or last follow-up. There was no difference in recurrence of bacteremia or readmission rates. However, patients treated with oral therapy had significantly fewer adverse events. Multivariable regression adjustments did not find significant associations between any selected variables and clinical success across treatment groups. CONCLUSIONS: These results demonstrate similar outcomes of real-world use of oral vs IV-only therapy for IE, in accord with prior randomized, controlled trials and meta-analyses.

Nf1-Mutant Tumors Undergo Transcriptome and Kinome Remodeling after Inhibition of either mTOR or MEK.

Loss of the tumor suppressor NF1 leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of NF1 loss and subsequent acquired drug resistance, we analyzed the exomes, transcriptomes, and kinomes of Nf1-mutant mouse tumor cell lines and derivatives of these lines that acquired resistance to either MEKi or mTORi. Biochemical comparisons of this unique panel of tumor cells, all of which arose in Nf1+/- mice, indicate that loss of heterozygosity of Nf1 as an initial genetic event does not confer a common biochemical signature or response to kinase inhibition. Although acquired drug resistance by Nf1-mutant tumor cells was accompanied by altered kinomes and irreversibly altered transcriptomes, functionally in multiple Nf1-mutant tumor cell lines, MEKi resistance was a stable phenotype, in contrast to mTORi resistance, which was reversible. Collectively, these findings demonstrate that Nf1-mutant tumors represent a heterogeneous group biochemically and undergo broader remodeling of kinome activity and gene expression in response to targeted kinase inhibition.