Genomic investigation and clinical correlates of the ��-lactam: NaHCO responsiveness phenotype among methicillin-resistant isolates from a randomized clinical trial.
Neta Petersiel, Stefano Giulieri, Diane S Daniel, Sook-Ha Fan, Selvi C Ersoy, Joshua S Davis, Arnold S Bayer, Benjamin P Howden, Steven Y C Tong, CAMERA2 study group
Author Information
Neta Petersiel: Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. ORCID
Stefano Giulieri: Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. ORCID
Diane S Daniel: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Sook-Ha Fan: The Lundquist Institute for Biomedical Innovation, Torrance, California, USA.
Selvi C Ersoy: The Lundquist Institute for Biomedical Innovation, Torrance, California, USA. ORCID
Joshua S Davis: Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia. ORCID
Arnold S Bayer: The Lundquist Institute for Biomedical Innovation, Torrance, California, USA.
Benjamin P Howden: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Steven Y C Tong: Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. ORCID
NaHCO responsiveness is a novel phenotype where some methicillin-resistant (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO. NaHCO responsiveness correlated with treatment response to ��-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO-responsive strains with ��-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant ) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ��-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. Isolates exhibiting ���4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO were considered "NaHCO-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO-responsive and non-responsive strains, and that were assigned to combination treatment with a ��-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO-responsive to cefazolin and oxacillin, respectively. The NaHCO-responsive phenotype was significantly associated with sequence type 93, SCC type IVa, and alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ��-lactam, there was no association between the NaHCO-responsive phenotype and persistent bacteremia (cefazolin, = 0.82; oxacillin, = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an ��-lactam-NaHCO-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ��-lactam.
