A population-based cohort study to establish clinical characteristics and outcomes of patients experiencing methicillin-sensitive Staphylococcus aureus bacteremia as a function of the cefazolin high inoculum effect.

BackgroundStaphylococcus aureus bacteremia is a leading cause of morbidity and mortality. Several phenotypes (e.g. methicillin-resistance) influence patient outcomes. The high inoculum effect (HIE) is characterized by reduced susceptibility to beta-lactam antibiotics, most notably cefazolin, at high inoculums in-vitro. MethodsA population-based cohort was used to assess all MSSA bacteremia in Calgary, Alberta, from 2012-14 and 2019 (n=1.5 million). Isolates underwent genomic sequencing and cefazolin susceptibility testing at 105 and 107 CFU/ml where the HIE was defined as a 4X-increase in minimum-inhibitory concentration (MIC) and pronounced (PIE) defined as MIC[≥]16 ug/ml at 107 CFU/ml. ResultsThe incidence of MSSA bacteremia with HIE decreased from 38.9 to 24.2% between the two time periods. Patients infected with HIE phenotype could not be differentiated based on demographics, source of bacteremia, or clinical biomarkers at presentation. Sequencing confirmed associations of HIE with blaZ A, agr3, and clonal complex 30. HIE was not associated with outcomes including clearance-time and all-cause mortality when assessed in aggregate or as a function of treatment. Relapses, however, were only documented with cefazolin. PIE was observed in 3.7% of isolates and was associated with significant increased all-cause 180-day mortality, irrespective of treatment, but not at one year. DiscussionThe HIE, but not PIE, is common in an unselected general population cohort. Neither demographics nor clinical biomarkers can be used to predict HIE. If there is a deleterious impact of this phenotype on patient outcomes, it is modest and may be masked by empiric therapy provided prior to MSSA bacteremia confirmation. Importance StatementA prospective cohort study by Miller et al. (2018) observed a significant increase in 30-day mortality in individuals experiencing methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia, with isolates exhibiting the high-inoculum effect (HIE) phenotype, when treated with the cefazolin. Our study sought to understand the epidemiology and impact of the HIE, using a population-based study design thereby mitigating the selection bias associated with other conventional cohort studies (focused on specific hospitals, at-risk groups, or clinics). We address the effects of HIE on clinical outcomes, predictive factors, and associated genomic contributors for the HIE phenotype within an unbiased population. These data are important for clinicians by highlighting if it is possible to predict HIE phenotype based on clinical and genomic factors, and to establish if cefazolin use associates with worse outcomes when MSSA causing bacteremia exhibits the HIE phenotype.