Vancomycin-resistant Enterococcus faecium (VREfm) infections were a major public health concern. The front-line antibiotic daptomycin (DAP) had become increasingly resistant to VREfm isolates. As a result, DAP, combined with other antibiotics such as fosfomycin (FOS), has gotten more attention. Antibiotic combinations had the potential to extend the efficacy of currently available antibiotics while also delaying the emergence of a new resistance. The possibility of E. faecium HOU503, a clinical VREfm isolate that was DAP and FOS sensitive, developing resistance to a DAP-FOS combination was studied. Researchers were particularly interested in seeing if the genetic mechanisms for DAP-FOS resistance were epistatic, which could reduce the efficacy of a combinatorial approach in suppressing VREfm or delaying the establishment of resistance. They showed that separate mutations could obtain DAP-FOS resistance in proteins involved in cell wall production for FOS and membrane dynamics for DAP. However, investigators found no genetic factors with significant cross-drug epistasis, which could jeopardize the DAP-FOS combination. Mutations predominantly mediated FOS resistance in HOU503 in pyruvate kinase (pyk), which resulted in alterations in phosphoenolpyruvate (PEP) flow. Increasing PEP flux could be an easily accessible strategy for FOS resistance in many diseases. They showed that HOU503 could establish DAP resistance via several molecular pathways and adaptive tactics. Finally, the study group demonstrated that adding FOS to DAP could prolong its efficacy and slow DAP resistance in vitro.