Abstract
Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) increases β-lactam susceptibility of selected methicillin-resistant Staphylococcus aureus (MRSA) strains ("NaHCO3 responsive"). This "sensitization" phenomenon translated to enhanced β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-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 NaHCO3-responsive or NaHCO3-nonresponsive phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB with or without NaHCO3 Intra-SEV MRSA killing was determined over 72-h exposures. In both "responsive" strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤4 mg/liter) and resulted in bactericidal activity (≥3-log killing) in the model for both OXA and CFZ. In contrast, neither in vitro-defined nonresponsive MRSA strain showed significant sensitization in the SEV model to either β-lactam. At both NaHCO3 concentrations, the fractional time above MIC was >50% for both CFZ and OXA in the responsive MRSA strains. Also, in media containing RPMI plus 10% Luria-Bertani broth (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against NaHCO3-responsive strains in the SEV model. Neither CFZ nor OXA exposures selected for emergence of high-level β-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.
Highlights
Staphylococcus aureus is an important human pathogen that is associated with both community- and nosocomial-associated infections
The β-lactam class of antibiotics remains the treatment of choice for a broad range of susceptible pathogens due to their potent and rapid mechanism(s) of action, as well as their relatively low rates of adverse side effects and toxicities
The current study extends our previous work on the ability of NaHCO3 supplementation of standard methicillin-resistantStaphylococcus aureus (MRSA) in vitro media to identify a sub-set of MRSA strains that may, exhibit β-lactam susceptibility [14, 22, 23]
Summary
Staphylococcus aureus is an important human pathogen that is associated with both community- and nosocomial-associated infections. Supplementation of standard media with bicarbonate (NaHCO3), a ubiquitous buffer in humans, has become the subject of several such studies [13, 14] These reports have demonstrated the ability of NaHCO3 to alter the susceptibility of selected MRSA strains in vitro to β-lactams. These investigations have focused on two conventional, prototype β-lactams not recommended for use against MRSA, OXA and cefazolin (CFZ) [14]. These in vitro phenotypes accurately predicted the ability of these same β-lactams to clear MRSA from multiple target tissues in a rabbit model of MRSA infective endocarditis (i.e., cardiac vegetations, kidneys and spleen) [14]. We hypothesized that ‘bicarbonate responsiveness’ in MRSA in this model would mirror similar findings in the rabbit endocarditis model, and that host-mimicking media within SEVs would help identify novel pharmacodynamic optimization strategies for prototypical β-lactams against such NaHCO3-responsive MRSA strains
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