Virulence Determinants in S Aureus Bacteremia

The purpose of this study is to more thoroughly investigate the impact of bacterial genetic
characteristics on the outcome of patients with S. aureus bacteremia (SAB). The
investigators will address salient aspects of bacterial virulence using strong collaborative
relationships with authorities in bacterial genetics and genomics. The overall hypothesis of
this investigation is that distinct bacterial virulence determinants influence the severity
of S. aureus infection. The specific hypothesis is that virulence determinants associated
with clinical outcome of S. aureus infection segregate into clonal groups, identified by
Multilocus Sequence Typing (MLST), and can be localized in the genome by comparative genetic
hybridization (CGH). The investigators have established the following aims to pursue this
hypothesis. Specific Aim 1: Define the allelic diversity of S. aureus bloodstream isolates
using MSLT. Allelic profiles among the 1000 isolates will be compared using the program
BURST (Based Upon Related Sequence Type), and relatedness of lineages in the overall
collection will be defined. Specific Aim 2: Define the genomic diversity of S. aureus
bloodstream isolates using CGH. Using MLST results, a subset of 200 isolates will be
selected to undergo further study. These ~200 isolates will form a unique collection
hereafter referred to as the SAGA (S. aureus genomic analysis) collection. The genomic
diversity of the SAGA subset will be defined using CGH. Specific Aim 3: Correlate MLST and
CGH results, MLST and clinical outcome, and CGH, and clinical outcome, and make SAGA
isolates available to the scientific community. In this Specific Aim, the discriminate
ability of MLST and CGH will be compared among the SAGA subset isolates undergoing both
assays. The association between bacterial clonality and clinical outcome will be considered
among 1000 S. aureus isolates collected from adults at Duke University Medical Center who
had S. aureus infections undergoing MLST. The association between clinical outcome and the
presence or absence of virulence factors and pathogenicity islands in the S. aureus genome
will also be considered among the 200 SAGA subset isolates undergoing CGH. The products of
this study will include an increased understanding of genetic diversity in S. aureus and the
role of this genetic diversity on determining the severity of infections caused by S.
aureus. The full value of the current proposal also includes the potential future benefit to
the research community as a whole if associations between pathogen genotype and clinical
outcome, only possible to identify using such a large and clinically well-characterized
collection of isolates, can be defined. To amplify these potential downstream dividends, the
final goal of Specific Aim 3 will be to make SAGA subset isolates, corresponding MLST types,
and CGH profiles available to the scientific community through the repository maintained by
the Network for Antimicrobial Resistance in S. aureus (NARSA). The long-term objectives of
this project are to: (1) identify bacterial genes contributing to the severity of infection
in isolates from a large cohort of patients with SAB; and (2) ultimately use these genes to
identify novel interventions for the control of S. aureus pathogenesis by investigating
genes that govern the virulence of this emerging pathogen. Culture-confirmed SAB nasal
carriage isolates and/or bloodstream bacterial isolates previously collected from 1000
inpatient adults at Duke University Medical Center will be used in this study.

Inclusion Criteria:

1. Adults (>= 18 years) with culture-confirmed Staphylococcus aureus bacteremia (SAB).
Patients with SAB transferred to Duke University Medical Center are eligible if
speculation and antibiotic susceptibilities are confirmed by the Duke Clinical
Microbiology Laboratory.

2. Absolute neutrophil count of > 1000 cells/cubic millimeter at the time that the
initial positive blood culture is obtained.

3. Patient or patient's representative provides signed informed consent allowing study
participation.

Exclusion Criteria:

1. Prior enrollment of patient in this investigation (to ensure statistical independence
of observations).

2. Staphylococcus aureus bacteremia (SAB) that is not confirmed by culture and
speciation at the Duke Clinical Microbiology Laboratory.

3. Outpatient status.

4. Isolation of any pathogen other than S. aureus from bloodstream.

5. Inability of patient or patient's representative to provide written informed consent.