Genomic investigation and clinical correlates of the in vitro β-lactam: NaHCO 3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial

Abstract

ABSTRACT NaHCO 3 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 NaHCO 3 . NaHCO 3 responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO 3 -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 NaHCO 3 . Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO 3 were considered “NaHCO 3 -responsive” to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO 3 -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 NaHCO 3 -responsive to cefazolin and oxacillin, respectively. The NaHCO 3 -responsive phenotype was significantly associated with sequence type 93, SCC mec 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 NaHCO 3 -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-NaHCO 3 -responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam.