Study to Identify Risk Factors for Staph Bloodstream Complications

BUFFALO, N.Y. -- The Staphylococcus aureus bacterium is one of the most common and most important disease-causing organisms in humans.

S. aureus frequently invades the bloodstream, causing S. aureus bacteremia, or SAB, an infection that attacks the heart valves and other organs with potentially deadly consequences. Even with the best care and antibiotic therapy, the mortality rate of patients with SAB is 20-30 percent, a rate that hasn't changed in 30 years.

Because there currently is no way to rule out with 100 percent accuracy the presence of S. aureus endocarditis, or heart-valve infection, even with an echocardiogram, most patients infected with the bacteria automatically receive 4-6 weeks of antibiotic therapy.

Prolonged use of antibiotics, however, contributes to the development of antibiotic resistance and increases the overall cost of medical care. Patients also may suffer the consequences of unnecessary antibiotic administration ranging from allergy to a potentially lethal form of infectious diarrhea.

In an effort to improve this process and develop new guidelines for antibiotic use for SAB, University at Buffalo researchers are collecting bacterial isolates and clinical information from SAB-infected patients hospitalized in three area hospitals and following their charted progress through inpatient treatment, discharge and for a post-discharge period. The hospitals participating in the study are Erie County Medical Center, Buffalo General and Sisters.

UB genomic specialists will compare the collected bacteria on a gene-by-gene basis, a process called complete genomic hybridization. Then, in the first time such an analysis has been conducted, the genomic architecture of the various bacterial strains identified will be compared to the risk factors and outcomes derived from the patients.

The research is supported by a three-year $690,500 grant from the John R. Oishei Foundation of Buffalo.

"One of the principles of infectious disease," said Alan Lesse, M.D., a principal investigator on the study, "is that you aren't treating just the patient in front of you, you are treating everyone who comes afterward, because you are introducing antibiotics into the microbial ecology.

"Unfortunately, just having S. aureus in the bloodstream carries a very high mortality risk," he said. "If there is infection in a heart valve, mortality approaches 40-50 percent. It's a highly lethal complication. There's significant morbidity associated with it, too, because patients with these infections end up with prolonged hospitalizations and prolonged antibiotic administration."

Lesse is associate professor of medicine, pharmacology and toxicology, and microbiology at UB. Joseph Mylotte, M.D., professor of medicine, and Stephen Gill, Ph.D., associate professor of oral biology and a member of the Infectious Disease and Genomics Group in UB's New York State Center of Excellence in Bioinformatics and Life Sciences, also are principal investigators.

The researchers will collect SAB samples from an anticipated 900 patients who will be classified as low-, moderate- or high-risk for developing complications.

Patients who have a removable focus of infection, such as a catheter; a drainable superficial abscess; a superficial, nonremoval focus such as cellulitis; no evidence of endocarditis or deep infection; no known valvular heart disease; a negative echocardiogram, and clearance of bacteria from the bloodstream within 24-72 hours after starting antibiotics will be classified as low-risk

Patients classified as moderate-risk for SAB will have features similar to low-risk patients but without an identifiable focus of the infection.

Patients at high risk of complications will be defined as having a positive blood culture for SAB 24-72 hours after starting antibiotics or with persistent signs of infection after 72 hours, whether or not a focus has been identified.

The second part of the study, the genomic analysis, is a critical part of the research. "While a few recent studies have shown a possible association of S. aureus strains with the development of complications," Lesse said, "it is not known whether specific strains of S. aureus are more likely to cause complications than others."

Gill will classify the SAB strains into clusters based on the DNA sequence of seven key genes found in all strains, using a technique called multi-locus sequence typing (MLST). UB researchers will be able to compare local isolates with strains from all over the world, based on this electronic database of isolates, Lesse said.

The second stage of the analysis will use gene arrays, where more than 7,000 genes and intergenic regions know to be present in different strains of S. aureus will be "arrayed" or spotted on a tiny chip. The genetic content from the strains in the study can then be applied to the array and a gene-by-gene comparison can be made, creating a genomic map of the infecting bacteria.

A statistical comparison of strains know to cause complication and those without complications will identify genes that may be responsible for more serious outcomes during infection.

"The results will provide the basis for establishing model guidelines to predict whether a patient diagnosed with a particular strain of S. aureus will develop complications," said Lesse. "This data then can be used in future studies to determine whether the predictions are correct and whether patients at low risk of complications can be treated with shorter (2 weeks) versus longer (4-6 weeks) of therapy.

"Such guidelines will spare patients unnecessary medications, identify patients requiring appropriate longer treatment courses and may help slow the progress of the organism's antibiotic resistance," he said.

Lesse and Mylotte are affiliated with the UB School of Medicine and Biomedical Sciences. Gill, is on the faculty of the UB School of Dental Medicine.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. The School of Medicine and Biomedical Sciences, School of Dental Medicine, School of Nursing, School of Pharmacy and Pharmaceutical Sciences and School of Public Health and Health Professions are the five schools that constitute UB's Academic Health Center. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.