Bicarbonate Resensitization of Methicillin-Resistant to β-Lactam Antibiotics

Endovascular infections caused by methicillin-resistant (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as "resistant" to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO responsive) and one resistant to such agents (NaHCO nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO reduced the expression of two key genes involved in the MRSA phenotype, and , leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO-responsive (but not in NaHCO-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO-supplemented media. These findings suggest that AST of MRSA strains in NaHCO-containing media may potentially identify infections caused by NaHCO-responsive strains that are appropriate for β-lactam therapy.