The increase of multidrug resistance among Gram-positive pathogens, particularly among staphylococci and enterococci, represents a major health care problem, since it results in significant morbidity, mortality, and health care costs. The emergence of such resistant bacterial strains highlights the need to optimize treatment approaches. In this view, novel lipoglycopeptides endowed with longterm activity allowing single-shot administration would be extremely useful and may represent an attractive therapeutic option alternative for early hospital discharge, a cost-saving and a resource-saving approach. Furthermore, long-term intravenous antibiotic therapy poses a particular challenge, specially in this ongoing pandemic situation, for treating patients classified as vulnerable or at highrisk for complications, such as PWID (persons who inject drugs) or those lacking social support, including frail elderly and/or those who are homeless or with an underlying psychiatric illness. This approach may offer improved quality of life for patients, considering benefits, such as no need for a central line for daily infusions, fast hospital discharge, and less need for laboratory monitoring.