Wednesday, August 15, 2012

Surviving Sepsis: New Device Speeds ID of Dangerous Bacteria

Nearly two years after her teenage daughter lost all four limbs to a dangerous bloodstream infection, Patricia Kirven is stunned at how little most people know about sepsis.

“You can ask the average person on the street and they don’t know what it is,” said Kirven, mother of Whitney Mitchell, now 20. “I have a friend who says that sepsis is the killer you’ve never heard of.”

Only high-profile cases seem to attract attention, like Whitney Mitchell's disfiguring infection, or the recent death of a 12-year-old New York boy, Rory Staunton, who developed severe septic shock two days after a minor gym class cut.

That’s despite the fact that hospital stays for sepsis in the U.S. have more than doubled in recent years, accounting for about 1.6 million hospitalizations a year and requiring treatment for some 4,600 new patients every day, according to a 2011 report from the Agency for Healthcare Research and Quality. 

The infection -- also known as septicemia or bacteremia -- can be sudden, capricious and difficult to identify, masquerading as a minor injury or illness that erupts into full-blown, whole-body organ failure within hours or days.

The mortality rate is alarming -- between 20 percent and 50 percent -- and largely depends on how quickly victims are diagnosed and treated with powerful antibiotics to battle the bacteria racing through their systems. Among those who live, amputations are common after the infection leads to tissue death in the limbs. 

In Whitney Mitchell’s case, a lawsuit accuses doctors at the Medical City Dallas Hospital of not giving her appropriate antibiotics for 38 hours after she showed up in the emergency room. In Rory Staunton’s case, his parents told the New York Times that critical medical information was ignored at NYU Langone Medical Center and that the signs of sepsis were disregarded. In both cases, critics said the victims were sent home from the emergency room before returning a day or so later in life-threatening condition.

“Getting a quick answer is a matter of life and death,” said Preeti Pancholi, an assistant professor of pathology and director of clinical microbiology at The Ohio State University Medical Center.

That’s why her hospital recently joined with five others across the country to test a device approved in June by the federal Food and Drug Administration that experts believe could drastically change the way sepsis infections are detected and managed.

About the size of a small microwave oven, the Verigene Gram-positive Blood Culture Nucleic Acid Test is the first system approved by the FDA to identify quickly certain bacteria responsible for bloodstream infections -- and whether some are resistant to the top drugs used against them.

Instead of the three days required for a traditional blood culture panel, results from the Verigene test come back within three hours, identifying up to a dozen specific bacteria known to cause sepsis, including strains of Staphylococcus, Streptococcus, Enterococcus and Listeria.

Plus, the test can tell whether the germs are Methicillin-resistant Staph aureus, or MRSA, or vancomycin-resistant Enterococci, or VRE, two of the toughest pathogens around.

Ledeboer, like Pancholi, agreed to participate in a seven-month clinical trial of the device produced and manufactured by Nanosphere Inc., of Northbrook, Ill.

Two weeks ago, Ledeboer, who said he has no financial ties to the product, went live with the Verigene test.

“In those two weeks, we’re seeing that patients are in fact being treated more appropriately sooner,” he said.

The reason is this: When patients come in with signs of suspected sepsis, including fever, low blood pressure and a racing heartbeat, it can be difficult for doctors to be certain it's a bloodstream infection and not another problem. Once they do confirm sepsis, doctors need to treat the patients fast. A 2010 study in the journal Critical Care Medicine found that for every hour of delay in administering antibiotics, mortality rose by 7.6 percent.

To that end, they break out what Ledeboer calls the “big guns” of antibiotics, the broad-spectrum drugs that can treat many pathogens at once. The trouble is, many bacteria are becoming resistant to antibiotics, meaning the treatments would be either be useless against the infections -- or they’ll help create the next generation of even tougher bugs.

“What we’re seeing now is that if you present with sepsis or any Gram-negative infection in New York City, you run a 30 percent risk of a pan-resistant organism,” Ledeboer said.

That is, an infection that virtually can’t be cured.

With the Verigene test, quick results mean doctors know faster exactly which bacteria they’re up against -- and whether the bugs are already resistant to top drugs.

“That’s a big change,” said Nathan Ledeboer, medical director of the clinical microbiology and molecular diagnostics laboratories at the Medical College of Wisconsin. “We don’t have to wait three days any more to get appropriate antibiotics on board.”

“It means patients are going to get out of the hospital faster, out of the ICU faster and it increases their chances of surviving sepsis,” Ledeboer said.

The test works by mapping the genome of a particular bacterium and capturing it on a glass slide, said Bill Moffitt, president and chief executive of Nanosphere. If that bacterium is present in the blood sample, it will bind to the material on the slide. Then the test uses silver-coated gold nanoparticles to bind to the captured genetic sequence. When light is shined on the slide, if the spots light up, it means the bug is present in the sample.

In trials that compared the Verigene test to traditional cultures and then verified them at an independent laboratory, the new device had a very high rate of accuracy, at least above 95 percent said Pancholi.

FDA officials based their approval decision on a study of 1,642 patient blood samples that compared traditional methods with the Vergiene test, with accuracy ranging from 93 percent to 100 percent.

Since the FDA approval, more than 200 hospitals have expressed interest, Moffitt said. The Verigene units cost between $50,000 and $100,000 apiece. The test panels cost about $75 each.

But Moffitt and Ledeboer estimate that the tests could significantly reduce the current $20,000 cost of a single sepsis workup.

Independent infectious disease experts were quick to praise the new technology.

“This seems to be the first product from our molecular revolution,” said Dr. William Schaffner, chair of the department of preventive medicine at Vanderbilt University. Quicker detection and treatment of sepsis may be the only way to start to cut the rising mortality caused by the insidious bacteria, he added.

“It’s a very exciting development," he said.

For victims already ravaged by sepsis, such progress is bittersweet. If there had been a quicker test to identify specific bacteria, perhaps doctors would have identified the source of Whitney Mitchell's infection, said Kervin, her mother. 

"They never could tell us exactly what it was," she said. 

Reached by phone at the Dallas home she shares with her mom, Whitney Mitchell said she was hospitalized for months after her amputations in 2010. She now spends her days going to physical therapy sessions, doing exercises at home to strengthen her shortened limbs and trying as best she can to resume her life. She's got a lively online presence and a supportive community. Although she has prostheses for her arms, including one set she calls her "pretty hands," she said she's gotten good at typing using a tough nub on her residual arm. 

"I'm always on the computer," said Mitchell. "I have a callus on the tip of it because I type so much."

Bob Bergert, the lawyer representing Medical City Dallas Hospital and the medical team involved said that they have "great empathy" for Mitchell and her family, but added that she received "appropriate care based on the facts and resources available to the healthcare providers."

Still, at age 20, Whitney Mitchell faces a lifetime of prosthetics and several additional surgeries. Kervin said she wishes there had been a test, a tool, anything that would have stopped the infection that raced through her daughter's body.

“It makes me happy and sad,” Kervin said. “Sad that it wasn’t there for my daughter, but glad that it will help other families from going through the pain we’re going through.”


Saturday, August 11, 2012

Beacon Food Safety Develops Low-Cost Pathogen Testing

Highlands Ranch businessmen Bill Locatis and Steve Stroud are preparing to take a product to market that has the ability to prevent an incident like the 2011 Colorado cantaloupe scare from occurring again.

Locatis, the CEO and chairman of Beacon Food Safety, and Stroud, the company’s president, have been working with a team of scientists in Aurora on developing a cost-effective, time-saving device that will detect food-borne pathogens in minutes.

While not the first rapid pathogen test on the market, Beacon’s patented BrightSPOT will be the first “true rapid test,” Locatis explained.

“The tests that are out there require 48-72 hours of culturing, and then the eight-minute result that is produced comes from having made an investment in a $60,000-$100,000 piece of lab equipment operated in a clean room by a highly specialized operator,” Locatis said. “Our device, at $20 a pop, is designed to be used by someone with a high school education that is working in the plant; there is very low lab overhead.”

The hand-held device will allow the average plant worker or farmer to test for Salmonella, E. coli or Listeria by simply swabbing a conveyer belt, for instance, with a throwaway strip that plugs into a PDA or PC and registers the results within minutes.

“In a large meat processing plant, testing can result in holding back $15 million worth of product over 72 hours,” Locatis said. “When this happens, shelf life gets depreciated and there are huge refrigeration costs, all because there is waiting to make sure (the product) is safe, so we are a tipping point technology in that regard.”

Stroud said some plants test every 20 minutes, but instead of being constantly two-three days behind on their testing, plants will now be able to be up to speed, as results for most bacteria will be available in less than a half hour.

In addition to saving millions for the big boys, the technology is expected to aid small-time farmers who couldn’t afford to test their produce before. In the cantaloupe scare of 2011, for instance, the listeria-contaminated melon shipped out unchecked. According to Locatis, this is likely because the testing available was too expensive, would have taken a lot of time and tied up inventory. Plus, it was not required.

“Had our product been in place for Rocky Ford, that cantaloupe never would have made it to market,” Locatis said. “It would have been detected and sanitized before it ever left Rocky Ford.”

The produce industry, which self-polices and has few regulations in place, is quite a bit different from the meat industry, which has USDA and FDA oversight, he said.

“They had gotten along for a hundred years without a problem,” Stroud said. “The industry has not avoided testing in the past. In the past, technology was just not available that was cost-effective and had a certain amount of timeliness and urgency to it so that you could get product out the door.

“Any given farmer would love to be able to prove that whatever got somebody sick was not their product, so if it was affordable, which it will be, they are going to take advantage of that because it protects them.”

The company, which has already created six new science research and development jobs in Colorado, expects to create between 50-100 additional jobs in the next 16-24 months as it prepares for a 2013 product launch.

From Our Colorado News. 

AuCoin gets $600,000 to Refine New Test for Deadly Bacteria

A new rapid test to diagnose melioidosis, a difficult infection to treat – and classified as a biothreat by the Centers for Disease Control and Prevention – is being optimized and tested by University of Nevada School of Medicine researcher David AuCoin.

A $600,000 National Institute of Allergy and Infectious Diseases grant through the Small Business Technology Transfer (STTR) program recognizes the potential of AuCoin’s work and supports making the new rapid test for point-of-care diagnosis of melioidosis available to countries where the disease is endemic, and expanding.

Melioidosis, also called Whitmore's disease, is predominately an infectious disease of tropical climates, especially in Southeast Asia and northern Australia where it is widespread. The bacteria causing melioidosis are found in contaminated water and soil. It is spread to humans and animals through direct contact with the contaminated source and has a high mortality rate.

“We have a prototype of the product in Thailand and Australia now, regions that are hardest hit, to evaluate it’s effectiveness in endemic settings,” AuCoin said. “There is no validated diagnostic product for melioidosis, patient samples must now be cultured, which takes three to seven days in order to diagnose the disease. Unfortunately, melioidosis can kill you well before the diagnosis is confirmed.”

With the two-year Phase I STTR grant, AuCoin’s laboratory is collaborating with InBios International of Seattle, Wash. on development of the Active Melioidosis Detect™ (AMD) test. They both are working closely with experts in the endemic areas of Thailand and Australia who are currently evaluating the test with different sample patient types.

“Results so far are very encouraging,” AuCoin said. “We produced a monoclonal antibody to identify the Burkholderia pseudomallei bacterium, which causes melioidosis, and then introduced it into a prototype lateral flow immunoassay diagnostic, which is a dipstick test that can accept many patient sample types.”
AuCoin produced and has been working with the monoclonal antibody used in the test since 2009. The work is also funded by the Pacific Southwest Regional Center for Excellence in Biodefense and Emerging Infections. 

The STTR is a Phase I grant. The team is working to secure Phase II funding following the two years of Phase I work, which will allow another three years of product development to generate the necessary preclinical studies to submit an application to the FDA for approval to distribute the assay.

In addition to diagnosing a melioidosis infection, the lab has shown that it may be possible to treat patients with antibodies that bind to B. pseudomallei to prevent severe disease.

B. pseudomallei has been classified as a biothreat by the CDC due to its high mortality rate, low infectious dose and ability to be aerosolized. Melioidosis is difficult to treat and diagnose because B. pseudomallei is resistant to common antibiotics and symptoms are non-specific. Mortality rates reach 45 percent and 20 percent in Thailand and Australia respectively, even with antibiotic treatment.

AuCoin is a principal investigator within the Diagnostics Discovery Laboratory, which is a research group within the University of Nevada School of Medicine’s Department of Microbiology and Immunology. The lateral flow immunoassay (LFI) he is developing is a similar process as another developed in the lab on the Reno campus by professor of microbiology and immunology Tom Kozel.

Kozel’s LFI is a new point-of-care test to detect a cryptococcal antigen, and diagnose cryptococcal meningitis, a leading cause of death among AIDS patients in developing countries. The new rapid diagnostic has the potential to save hundreds of thousands of lives a year. Kozel and AuCoin are also collaborating on a diagnostic product for the early detection of inhalation anthrax and invasive aspergillosis.

“The work by Dr. AuCoin and his research group is just one more outstanding example of the ways that basic science research can lead to important clinical discoveries and improve health and health care,” Thomas Schwenk, dean of the University of Nevada School of Medicine said. “In this case, the work is likely to lead to a new technology from here in Nevada that can have a profound positive impact on the outcome of a deadly disease on a global scale.” 

Influenza H3N2v: Efficacy Varies Among Rapid Detection Tests

The ability to detect the recently circulating influenza variant H3N2v was low in some commercially available rapid detection tests, according to an analysis conducted by the Centers for Disease Control and Prevention.
"The ability to detect H3N2v virus varied substantially among the tests. This evaluation emphasizes the fact that a negative [rapid influenza detection test (RIDT)] result should not be considered as conclusive evidence of lack of infection with influenza A (H3N2)v ... Results from RIDTs, both positive and negative, always should be interpreted in the broader context of the circulating influenza strains present in the area, level of clinical suspicion, severity of illness, and risk for complications in a patient with suspected infection," the CDC said Aug. 10 in an early online release from Morbidity and Mortality Weekly Report (2012;61:1-3).
The CDC analyzed seven Food and Drug Administration–cleared rapid influenza detection tests (RIDTs) for their ability to detect H3N2v viruses, of which 153 infections were reported from four states between July 12 and Aug. 9, 2012. Each of the seven RIDTs – the BinaxNOW, Directigen, FluAlert, QuickVue, Sofia, Xpect, and Veritor – was tested with seven different H3N2 viruses, according to their respective package instructions. Positive and negative controls contained in each RIDT were run before testing the viruses in the study to verify performance of each assay lot, with the exception of FluAlert, which does not provide controls.The H3N2v viruses can be definitively identified only at qualified U.S. public health laboratories using a polymerase chain reaction–based influenza diagnostic panel that is not available as a point-of-care test for clinicians. Specimens that test positive for influenza A, H3, and pandemic influenza A markers and negative for H1 and pandemic H1 markers are called "presumptive positive for influenza A(H3N2)v virus," until confirmed as influenza A(H3N2)v, the CDC said.
Only four of the seven RIDTs (Directigen, Sofia, Veritor, and Xpect) detected all influenza A(H3N2)v viruses. BinaxNOW detected five of seven, and QuickVue detected three of seven. FluAlert detected only one of seven, the CDC said.
More data are needed on the clinical performance of all RIDTs in detecting H3N2v virus in various respiratory specimens, the CDC said.
Clinicians should minimize the occurrence of false RIDT results by strictly following the manufacturer’s instructions, collecting specimens soon after the onset of influenza-like illness – ideally within the first 72 hours – and confirming RIDT results by sending the specimen to a public health laboratory. Additional CDC guidance on interpretation of RIDTs for testing of patients with suspected H3N2v infection is available here.