Work

Ability of Bicarbonate Supplementation To Sensitize Selected Methicillin-Resistant Staphylococcus aureus Strains to β-Lactam Antibiotics in an Ex Vivo Simulated Endocardial Vegetation Model

Year: 2019

Type: article

Abstract: ABSTRACT Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate ( NaHCO 3 ) significantly increases β-lactam susceptibility of selected MRSA strains (“NaHCO 3 -responsive”). This “sensitization” phenomenon translated to enhanced β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO 3 -mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations ( SEVs ), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro “NaHCO 3 -responsive” or “NaHCO 3 -nonresponsive” phenotypes. Cefazolin ( CFZ ) and oxacillin ( OXA ) were evaluated in CAMHB±NaHCO 3 . Intra-SEV MRSA killing was determined over 72 hr exposure. In both NaHCO 3 -responsive strains, supplementation with 25 mM or 44 mM NaHCO 3 significantly reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤ 4 mg/L) resulting in bactericidal activity (≥ 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro -defined NaHCO 3 -nonresponsive MRSA strains showed significant sensitization in the SEV model to either β-lactam. At both NaHCO 3 concentrations, the fractional time-above-MIC was >50% for both CFZ and OXA in the NaHCO 3 -responsive MRSA. Also, in RPMI+10% LB media (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO 3 ), both CFZ and OXA exhibited enhanced bactericidal activity against each NaHCO 3 -responsive strain in the SEV model. Neither CFZ nor OXA exposures selected for high-level β-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO 3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO 3 -supplemented media in vitro .

Source: Antimicrobial Agents and Chemotherapy

DOI: 10.1128/aac.02072-19

Authors: Warren E. Rose, Ana M. Bienvenida, Yan Q. Xiong, Henry F. Chambers, Arnold S. Bayer, Selvi C. Ersoy