Genomic investigation and clinical correlates of the in vitro β-lactam: NaHCO₃ responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial

NaHCO₃ responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO₃. NaHCO₃ responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO₃-responsive strains with β-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal β-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO₃. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO₃ were considered “NaHCO₃-responsive” to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO₃-responsive and non-responsive strains, and that were assigned to combination treatment with a β-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO₃-responsive to cefazolin and oxacillin, respectively. The NaHCO₃-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a β-lactam, there was no association between the NaHCO₃-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro β-lactam-NaHCO₃-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam.