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Sepsis — the deadly finale of many serious infections — will now face a genetically engineered last-ditch treatment: Activated Protein C.
The Food and Drug Administration (FDA) recently approved the first biologic treatment for the most serious forms of sepsis. The new treatment is a genetically engineered version of a naturally occurring human protein, which interferes with some of the body’s harmful responses to severe infection, including the formation of blood clots that can lead to organ failure and death. Eli Lilly and Co. in Indianapolis will market Activated Protein C under the brand name Xigris.
Despite treatment with intravenous antibiotics and supportive care, roughly 30% of patients who develop sepsis die. Patients with severe sepsis often experience failures of various systems in the body, including the circulatory system, as well as kidney failure, bleeding, and clotting.
How many cases of sepsis have their origins as nosocomial infections? It could be as high as one-half to two-thirds, says Richard Wenzel, MD, professor and chairman of the department of internal medicine at Virginia Commonwealth University in Richmond. As many as 900,000 cases of sepsis may occur annually, says Wenzel, a frequent lecturer on sepsis at infection control conferences. "It is a complicated issue, but imagine when you take the whole sepsis [spectrum]; in my crude estimate, there might be 400,000 of cases of sepsis, 300,000 of severe sepsis, and 200,000 of septic shock," he says. "The septic shock is the targeted area for this drug."
Xigris was approved by FDA for the treatment of adult patients with severe sepsis who have an especially high risk of dying from sepsis, as measured by a scoring system based on their general health and the severity of their illness. "Those with septic shock and two organs failing will be the kind of candidates for this drug," Wenzel says.
In a placebo-controlled, multicenter, randomized clinical trial of nearly 1,700 patients, the overall mortality rate was reduced by 6% (from 31% to 25%) during the 28-day study period of the trial.1 Treatment with the new biologic did not lower mortality rates in patients who were less severely ill. However, among patients at higher risk of dying — the group for whom Xigris is now indicated — mortality was reduced 13% (from 44% to 31%).
"It’s an important development," Wenzel says. "It’s a modest reduction in the [overall] mortality. The side effect that could become more important when you give this to thousands of people is bleeding. That is something I think is a potentially serious problem."
Because Activated Protein C interferes with blood clotting, the most serious side effect associated with the new therapy is bleeding — heightening the risk for stroke. During the period of time when the drug was infused (continuously over four days), serious bleeding episodes occurred in 2.4% of patients treated with Xigris compared to 1% of patients in the placebo group. Patients at high risk of bleeding were excluded from the trial, as were severely ill patients with pre-existing conditions not related to sepsis that made them likely to die within the study period.
Activated Protein C is contraindicated for patients who have active internal bleeding, or who are more likely to bleed because of certain medical conditions including recent strokes, head or spinal surgery, or severe head trauma. The benefits and risks of treatment will have to be carefully weighed for each individual patient, most of whom will be at risk of death regardless.
Perhaps reflecting both the up and down sides, U.S. Secretary of Health Secretary Tommy Thompson called the approval of the new biologic "a hopeful milestone."
1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human Activated Protein C for severe sepsis. N Engl J Med 2001; 344:699-709.