SAN FRANCISCO – Colonization with a methicillin-resistant Staphylococcus aureus strain carrying the gene for staphylococcal enterotoxin P was highly correlated with development of MRSA bacteremia among intensive care unit patients in a nested case-control study.
From among 8,203 adults with 11,528 intensive care unit admissions, staff collected 1,578 MRSA isolates from 492 patients – either at ICU admission or readmission, ICU discharge, or during weekly MRSA surveillance screening. Case subjects were 33 colonized patients who developed MRSA bacteremia; controls were 132 colonized patients (four controls for each case patient) who did not develop bacteremia, Dr. Michael S. Calderwood, an infectious disease specialist at Brigham and Women’s Hospital, Boston, reported at an annual scientific meeting on infectious diseases.
Dr. Michael Calderwood
Full genome sequencing of collected MRSA strains was performed for all cases and for 127 controls. In particular, the investigators evaluated the isolates for the presence of 30 MRSA genes potentially associated with virulence and invasion. After controlling for host factors, they assessed the association between these genes and the development of bacteremia, Dr. Calderwood said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
"We all know that MRSA colonization is increasing in U.S. hospitals, and that colonization with MRSA is a predictor of later infection," Dr. Calderwood said, noting that more than 80% of bacteremia cases involve an identical strain in the patient’s nares and blood.
While both host and pathogen factors play a role in MRSA infection, the two are typically looked at separately; their interaction hasn’t been assessed, he said.
"We looked at combined host-pathogen risk factors in a prospective cohort with the hope of successfully identifying genomic determinants of virulence," he said, noting that identifying risk-adjusted genomic determinant of virulence may improve the ability to predict invasive disease and suggest new targets for therapeutic intervention.
Cases and controls for the current study were identified from samples from eight ICUs, banked between Sept. 1, 2003 and April 30, 2005.
Host factors considered in this study included comorbidities, wounds or recent surgeries, device use (such as a central venous catheter or intubation), recent health care exposures, antibiotic use, and lab values. Pathogen factors included Panton-Valentine leukocidin (LukS and LukF), other leukocidins (LukD and LukE), staphylococcal enterotoxins A-U, chemotaxis inhibitory protein of S. aureus, staphylococcal complement inhibitor protein family, staphylokinase, toxic shock syndrome toxin, staphylococcal cassette chromosome mec type, accessory gene regulator locus group, single-nucleotide polymorphisms (SNPs) in gene for phenol-soluble modulins, and SNPs in gene for alpha-hemolysin.
Hazard ratios were calculated for each of these factors, and those with a P value of 0.2 or less were entered into a multivariable model.
On multivariate analysis, significant risk factors for bacteremia among colonized patients included staphylococcal enterotoxin P, known as SEP (HR, 26.7), cancer (HR, 3.1), presence of a central venous catheter (HR, 2.9), and hyperglycemia (HR, 0.9). Treatment with an anti-MRSA antibiotic had a protective effect (HR, 0.5). An interaction effect was found for SEP and treatment with an anti-MRSA antibiotic (HR, 1.5), Dr. Calderwood said.
The presence of SEP – which is carried by a bacteriophage along with other genes encoding proteins that help S. aureus evade the host’s innate immune response – has been linked previously to higher mortality in S. aureus bacteremia, and lower antibody levels of S. aureus enterotoxins have been linked to bacteremia, he said, adding that the findings have potential implications for predicting and preventing MRSA bacteremia; they suggest SEP as a possible target for immunotherapeutics or vaccine development, he said.
This study was supported by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Dr. Calderwood reported having no disclosures.