**5. Possible downstream consequences of CS and EV on antibiotic resistance in MRSA**

The effects of EV and CS on MRSA hydrophobicity, surface charge, virulence, and resistance to killing by the innate immune system host defense antimicrobial peptides have potentially harmful implications on antistaphylococcal therapy. Vancomycin and daptomycin are the only drugs approved by the US FDA for the treatment of MRSA bacteremia and endocarditis [33]. When MRSA causes endocarditis, it is due to the patient's colonizing strain. MRSA strains that are induced to relative resistance to cationic host defense peptides, such as platelet microbicidal proteins (PMPs), are associated with a proclivity to lead to persistent bacteremia, endocarditis, and metastatic infectious foci [34]. In other words, durable changes in MRSA physiology by EV and CS may have implications on the ability of this pathogen to establish endovascular infection in cases of an otherwise transient bacteremia that is thought to occur periodically in healthy hosts but otherwise rapidly quenched by the innate immune system. Furthermore, cross‐resistance between host PMPs and cathelicidin and vancomycin and daptomycin have been well‐documented [34–36]. Thus, EV and CS may have serious implications on the proclivity of MRSA to develop heteroresistance to these drugs, even before the agents are administered to the patient.

Compounding this, resistance concern is the fact that persistent lingering of MRSA *in vivo*, as a result of resistance to host defense peptide killing, further creates a selective pressure environment conducive to further cationic peptide resistance, and hence resistance to antimicrobial therapy [37]. These extrapolative hypotheses of the effects of EV and CS have yet to be proven, but if they are, have far greater public health implications than once thought.
