INFECTION RESEARCH

Staphylococci adhering toan explanted LVAD membrane.

Staphylococcal infection is one of the leading causes of death among long-term LVAD recipients. Of all LVAD recipients, 20–40% develop infections at some time, ranging from driveline infections to sepsis. Under the direction of Frank Lowy, MD, and in collaboration with Drs. Yoshifumi Naka, Mario Deng and Kung-Ming Jan, the infection research project includes a series of complementary laboratory, clinical, and epidemiological studies designed to understand the process by which staphylococcal infections develop in LVAD patients.

One laboratory study will examine the way in which proteins on the surface of staphylococcal bacteria adhere to the inner membranes (blood contacting surfaces) of LVADs. This study will help explain why staphylococci are able to cause these life-threatening infections. By examining the membranes of devices after their removal from patients' bodies, the team is working to define the role that different proteins play in the adhesion process. "We have looked at twelve surface proteins so far," explains Dr. Lowy. "Three of these seem to be most likely responsible for adhesion to the LVAD membranes." Having done extensive research on explanted membranes, Dr. Lowy believes that clumping factor and fibronectin binding protein are the most likely culprits. He adds, "Moreover, the binding process changes over time, and we plan to find out why."

A second laboratory study will examine the ability of staphylococcal bacteria to bind to host surfaces under different flow conditions. By identifying a) the Staph aureus surface molecules and b) components of the LVAD membrane cellular matrix that mediate adhesion, Dr. Lowy's team hopes to be able to reduce adhesion of the bacteria to the device surface membrane.

Figure 1a: Cross-section of mouse aorta with patch sutured into it. Figure 1b: Live cross-section of mouse aorta with patch. During the four-week period after implantation, endothelial cells cover the patch, mimicking the clinical situation.

In a third study, the researchers will study the ability of various staphylococcal proteins to mediate adherence to an implanted aortic LVAD patch in a mouse model of infection. They will inject protein expressed on the surface of a nonpathogenic bacterial species, and then determine if it enables the bacteria to infect the patch.

Clinically, Dr. Lowy's team will oversee a multicenter, randomized, double-blind, placebo-controlled multicenter trial of an anti-staphylococcus vaccine under development by Nabi Biopharmaceuticals. Evaluating the effect of the vaccine in reducing infection during LVAD implantation, this is the first anti-Staph aureus vaccine to have progressed this far in research. The vaccine appeared promising in an earlier study among dialysis patients.

A second multicenter, randomized, double-blind, placebocontrolled clinical trial will test a topical ointment that eliminates nasal Staph aureus. "People who carry Staph aureus in the nose have a higher risk of developing infection after LVAD implantation," explains Dr. Lowy. "Our hypothesis is that if we eradicate nasal carriage prior to implantation, we can reduce the risk of infection."

Finally, a molecular epidemiological study will survey patients' normal bacterial skin flora to try to determine if bacteria already present are causing the infection, or if patients become colonized with new bacteria in the hospital during LVAD implantation.

Says Dr. Lowy, "We hope these studies will address some of the fundamental questions about the pathogenesis of these infections, and the clinical trials will provide new approaches that are non-anti-microbial based. Since there is so much bacterial resistance (due to antibiotic use), it is better to prevent than to treat infections later."