Seeing red: Infrared fluorescent labels, targeted to cancerous tumor cells, provide a luminescent guide for surgeons trying to remove the lethal tissue.   Credit: Nguyen et al. PNAS, doi:10.1073/pnas.0910261107

 

The fluorescent molecule targets tumors to guide surgeons and provide pre- and post-op imaging

MIT Technology Review, March 3, 2010, by Lauren Gravitz  —  A new molecule designed to seek out and label cancer cells could help guide surgeons to hidden pockets of disease–a technology that could one day allow for more complete tumor removal and increase a patient’s chances of survival.

The molecular label, developed by researchers at the University of California at San Diego (UCSD), works in two ways. It tags cancer cells with a fluorescent marker to highlight tumors for identification and removal during surgery, and it contains a magnetic marker that can be used to evaluate the disease via magnetic resonance imaging.

In two papers published recently by The Proceedings of the National Academy of Sciences, the UCSD researchers describe a novel marker that fluoresces in the near-infrared, which has wavelengths long enough to make their way through layers of opaque human tissue and can help surgeons find buried tumor cells. In studies in mice, the researchers were able to find and remove 90 percent more residual cancer cells than was possible with visible light alone. And depending on the type of cancer, they were able to increase the animals’ long-term survival rates by as much as fivefold.

When cancerous tumors take hold, a person’s fate often rests in the surgeon’s hands–the more completely a surgeon is able to remove a tumor, the better the patient’s chances of survival. But even the best surgeons work under limiting conditions, extracting only what they can see and feel and hoping that they got it all. They send the tissue to the lab while the patient is still on the operating table and, if the lab deems that the tumor is surrounded by healthy cells, they close the patient back up. If not, they must continue cutting until lab samples come back clean.

With the new molecule, “we can not only do guided surgery, but we can show an increase in survival,” says Roger Tsien, a biochemist at UCSD and the project’s lead researcher.

A small number of researchers are working to provide cancer surgeons with a visual aid to help track down tumor cells that have separated from the main mass–those wound around nerve fibers, for instance, or tucked out of sight. But while some near-infrared methods seem promising, other approaches rely on viruses to insert a fluorescent marker (a gene-therapy like approach, with questionable safety), or don’t fluoresce strongly enough to glow through human tissue.

Tsien, who shared the 2008 Nobel Prize in chemistry for his work on green fluorescent protein, and colleagues created a two-peptide structure. One peptide acts as both a fluorescent and magnetic label, and the other keeps the molecule neutral. In the presence of tumor cells, enzymes called matrix metalloproteinases (MMPs) snip off the neutralizing peptide and allows the labeled one to enter the cell. Once there, the dual probe remains for as long as four or five days.

The new marker not only provides a visual aid during surgery, but can be used to assess the presence of a tumor both before and afterward. Radiologists could localize tumors magnetically during a pre-operative MRI scan, surgeons could then follow the infrared map to remove all traces of glowing tumor, then radiologists could perform a post-operative MRI to ensure there’s no remaining evidence of disease.

Scott Hilderbrand, a chemist at Massachusetts General Hospital’s Center for Molecular Imaging Research, is also developing targeted fluorescent probes. He notes that the individual pieces of the technique developed by Tsien’s team have been shown to work by other researchers, “but to be able to do this with one agent is one of the more major advances of this approach.”

The researchers hope they may be able to add yet another feature to their molecule. “We’d love to think that with this fluorescence we’ve gotten 100 percent of the cells, but that’s not the case,” says surgeon Quyen Nguyen, one of the papers’ first authors. She says they’re working to attach a third branch to the molecule, one that becomes toxic in the presence of bright light. “At the end of the surgery, you could shine a bright light that targets the fluorescent molecule and makes it phototoxic. That way, I can kill the residual cells,” Nguyen says.

One of the drawbacks of using MMPs, however, is that they are not expressed in all cancers, and are present in some noncancerous tissues, too, including the liver and in areas of inflammation. “The mice they tested this in have only normal tissue and cancer tissue, but the human body is not so simple” says Hisataka Kobayashi, a molecular imaging specialist at the National Cancer Institute in Bethesda, MA, and another person working on the targeting cancer with fluorescent probes.

That is why the researchers are targeting their probe for use in surgical guidance, where an experienced surgeon can distinguish between cancerous tissue and inflamed areas elsewhere in the body. Nguyen says the same team is working on using the molecule to deliver therapeutics targeted directly to cancer cells, but notes that this is going to be a bit trickier.

The researchers are looking into other potential uses for their molecule, such as lighting up arterial plaques in order to identify ones most at risk of causing a stroke or heart attack. Avelas Biosciences, a new startup based in San Diego, has licensed the probe technology in 2009 and hopes to have something ready for human testing within two to three years.

Visually-impaired Paralympian Brian McKeever, left, from Canmore, Alberta races in the 50-kilometer event at the Haywood NorAm and Olympic Trials in Canmore, Alberta.   Olympic and Paralympic skier Brian McKeever is the best-known victim of the disease, which has no treatment.

Photo by Jeff McIntosh

First-Ever Designation for Treatment Using Embryonic Stem Cells

GoogleNews.com, WORCESTER, Mass., March 03, 2010  —  Advanced Cell Technology, Inc. /quotes/comstock/11k!actc (ACTC 0.10, 0.00, -3.30%) , a biotechnology company applying cellular technology in the field of regenerative medicine, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the company’s MA09-hRPE cells for use in the treatment of Stargardt’s Macular Dystrophy (SMD). As a result, the company is eligible to receive a number of benefits, including tax credits, access to grant funding for clinical trials, accelerated FDA approval and allowance for marketing exclusivity after drug approval for a period of as long as seven years.

“We are pleased that the FDA has, for the first time, granted orphan drug status for the use of an embryonic stem cell derived therapy in treating an unmet medical need,” said Edmund Mickunas, Vice President Regulatory. “We believe that our terminally differentiated RPE cells represent a promising treatment for patients with SMD and expect to be in a position to accelerate clinical development and hopefully make RPE cellular therapy available to the majority of patients sooner.”

US orphan drug designation is granted to companies with products aimed at treatment of a rare disease or condition that affects fewer than 200,000 Americans. The National Institutes of Health (NIH) recently proposed broadening the definition of a human embryonic stem cell to include ACT’s “single blastomere technology platform” which was used to derive ACT’s MA09-hRPE cells. The Company believes that the SMD program should be eligible for federal funding once the change is published in the Federal Register.

Degenerative diseases of the retina are among the most common causes of untreatable blindness in the world, and as many as ten million people in the United States have photoreceptor degenerative disease. While most of these patients have Age-Related Macular Degeneration (AMD), a smaller number have Stargardt’s, an Orphan disease and to date an untreatable form of juvenile macular degeneration leading to blindness in a much younger group of patients than are affected by AMD. ACT’s treatment for eye disease uses stem cells to re-create a type of cell in the retina that supports the photoreceptors needed for vision. These cells, called retinal pigment epithelium (RPE), are often the first to die off in SMD and AMD, which in turn leads to loss of vision.

While there is currently no treatment for SMD, several years ago ACT and its collaborators discovered that human embryonic stem cells could be a source of RPE cells. Subsequent studies found that the cells could restore vision in animal models of macular degeneration. In a Royal College of Surgeons (RCS) rat model, implantation of RPE cells resulted in 100% improvement in visual performance over untreated controls, without any adverse effects. The cells survived for more than 220 days and sustained extensive photoreceptor rescue. Functional rescue was also achieved in the ‘Stargardt’s’ mouse with near-normal functional measurements recorded at more than 70 days.

About Advanced Cell Technology, Inc.

Advanced Cell Technology, Inc. is a biotechnology company applying cellular technology in the field of regenerative medicine. For more information, visit http://www.advancedcell.com.

Forward-Looking Statements

Statements in this news release regarding future financial and operating results, future growth in research and development programs, potential applications of our technology, opportunities for the company and any other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not statements of historical fact (including statements containing the words “will,” “believes,” “plans,” “anticipates,” “expects,” “estimates,” and similar expressions) should also be considered to be forward-looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by such forward-looking statements, including: limited operating history, need for future capital, risks inherent in the development and commercialization of potential products, protection of our intellectual property, and economic conditions generally. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in the company’s periodic reports, including the report on Form 10-QSB for the quarter ended September 30, 2009. Forward-looking statements are based on the beliefs, opinions, and expectations of the company’s management at the time they are made, and the company does not assume any obligation to update its forward-looking statements if those beliefs, opinions, expectations, or other circumstances should change. Forward-looking statements are based on the beliefs, opinions, and expectations of the company’s management at the time they are made, and the company does not assume any obligation to update its forward-looking statements if those beliefs, opinions, expectations, or other circumstances should change.

SOURCE: Advanced Cell Technology, Inc.

GoogleNews.com, March 3, 2010, CHICAGO  –  A test that looks for specific patterns of genes that are switched on may lead to a better way of diagnosing dangerous yeast infections in the blood, U.S. researchers said on Wednesday.

They said mice infected with the Candida albicans fungus have a telltale signature of genes that are active, or expressed, that is not found in the blood of healthy mice.

“This study provides the basis for development of a blood-gene expression tests in humans to detect a life-threatening infection earlier than can be done using currently available methods,” said Dr. Geoffrey Ginsburg of Duke University in North Carolina, whose study appears in the journal Science Translational Medicine.

Candida is the fourth most common bloodstream infection in the United States, yet it is often hard to distinguish from a bacterial infection. Antibiotics are useless against yeast infections, which can be treated with antifungal drugs instead.

The yeast-like fungus normally lives in the mouth and gastrointestinal tract without causing trouble, but antibiotics or other drugs can kill off competing bacteria and cause an overgrowth.

When Candida organisms enter the blood, they can be disseminated throughout the body, causing severe illness. Candida infections can kill 10-15 percent of critically ill patients within the first 24 hours of infection. If undetected for up to three days, they kill 30 percent of patients.

For the study, the team took blood samples and compared the patterns of genes that were expressed in mice infected with or without a yeast infection and in those infected with a bacterial infection.

Using this, they created a genetic pattern or signature associated with yeast infection.

“We were very pleased to learn that we could further distinguish the fungal infection from a staph infection, another bloodstream disease that shares the same set of symptoms,” Dr. Aimee Zaas of Duke who worked on the research said in a statement.

The team hopes the findings will form the basis of a gene-based blood test for hospitalized patients.

Centers for Disease Control and Prevention — For more common germs, including Staph infections like MRSA, doctors have an arsenal of antibiotics.

Tim Parker for The New York Times

Doctors have no way to treat some Gram-negative bacteria, like those that killed Amy Fix’s father, Richard Armbruster.

David Maxwell for The New York Times

Dr. Louis Rice of Case Western Reserve University says hardy Gram-negative bacteria “are becoming more and more common.”

Rising Threat of Infections Unfazed by Antibiotics

The New York Times, March 2, 2010, by Andrew Pollack — A minor-league pitcher in his younger days, Richard Armbruster kept playing baseball recreationally into his 70s, until his right hip started bothering him. Last February he went to a St. Louis hospital for what was to be a routine hip replacement.

By late March, Mr. Armbruster, then 78, was dead. After a series of postsurgical complications, the final blow was a bloodstream infection that sent him into shock and resisted treatment with antibiotics.

“Never in my wildest dreams did I think my dad would walk in for a hip replacement and be dead two months later,” said Amy Fix, one of his daughters.

Not until the day Mr. Armbruster died did a laboratory culture identify the organism that had infected him: Acinetobacter baumannii.

The germ is one of a category of bacteria that by some estimates are already killing tens of thousands of hospital patients each year. While the organisms do not receive as much attention as the one known as MRSA — for methicillin-resistant Staphylococcus aureus — some infectious-disease specialists say they could emerge as a bigger threat.

That is because there are several drugs, including some approved in the last few years, that can treat MRSA. But for a combination of business reasons and scientific challenges, the pharmaceuticals industry is pursuing very few drugs for Acinetobacter and other organisms of its type, known as Gram-negative bacteria. Meanwhile, the germs are evolving and becoming ever more immune to existing antibiotics.

“In many respects it’s far worse than MRSA,” said Dr. Louis B. Rice, an infectious-disease specialist at the Louis Stokes Cleveland V.A. Medical Center and at Case Western Reserve University. “There are strains out there, and they are becoming more and more common, that are resistant to virtually every antibiotic we have.”

The bacteria, classified as Gram-negative because of their reaction to the so-called Gram stain test, can cause severe pneumonia and infections of the urinary tract, bloodstream and other parts of the body. Their cell structure makes them more difficult to attack with antibiotics than Gram-positive organisms like MRSA.

Acinetobacter, which killed Mr. Armbruster, came to wide attention a few years ago in infections of soldiers wounded in Iraq.

Meanwhile, New York City hospitals, perhaps because of the large numbers of patients they treat, have become the global breeding ground for another drug-resistant Gram-negative germ, Klebsiella pneumoniae.

According to researchers at SUNY Downstate Medical Center, more than 20 percent of the Klebsiella infections in Brooklyn hospitals are now resistant to virtually all modern antibiotics. And those supergerms are now spreading worldwide.

Health authorities do not have good figures on how many infections and deaths in the United States are caused by Gram-negative bacteria. The Centers for Disease Control and Prevention estimates that roughly 1.7 million hospital-associated infections, from all types of bacteria combined, cause or contribute to 99,000 deaths each year.

But in Europe, where hospital surveys have been conducted, Gram-negative infections are estimated to account for two-thirds of the 25,000 deaths each year caused by some of the most troublesome hospital-acquired infections, according to a report released in September by health authorities there.

To be sure, MRSA remains the single most common source of hospital infections. And it is especially feared because it can also infect people outside the hospital. There have been serious, even deadly, infections of otherwise healthy athletes and school children.

By comparison, the drug-resistant Gram-negative germs for the most part threaten only hospitalized patients whose immune systems are weak. The germs can survive for a long time on surfaces in the hospital and enter the body through wounds, catheters and ventilators.

What is most worrisome about the Gram-negatives is not their frequency but their drug resistance.

“For Gram-positives we need better drugs; for Gram-negatives we need any drugs,” said Dr. Brad Spellberg, an infectious-disease specialist at Harbor-U.C.L.A. Medical Center in Torrance, Calif., and the author of “Rising Plague,” a book about drug-resistant pathogens. Dr. Spellberg is a consultant to some antibiotics companies and has co-founded two companies working on other anti-infective approaches. Dr. Rice of Cleveland has also been a consultant to some pharmaceutical companies.

Doctors treating resistant strains of Gram-negative bacteria are often forced to rely on two similar antibiotics developed in the 1940s — colistin and polymyxin B. These drugs were largely abandoned decades ago because they can cause kidney and nerve damage, but because they have not been used much, bacteria have not had much chance to evolve resistance to them yet.

“You don’t really have much choice,” said Dr. Azza Elemam, an infectious-disease specialist in Louisville, Ky. “If a person has a life-threatening infection, you have to take a risk of causing damage to the kidney.”

Such a tradeoff confronted Kimberly Dozier, a CBS News correspondent who developed an Acinetobacter infection after being injured by a car bomb in 2006 while on assignment in Iraq. After two weeks on colistin, Ms. Dozier’s kidneys began to fail, she recounted in her book, “Breathing the Fire.”

Rejecting one doctor’s advice to go on dialysis and seek a kidney transplant, Ms. Dozier stopped taking the antibiotic to save her kidneys. She eventually recovered from the infection.

Even that dire tradeoff might not be available to some patients. Last year doctors at St. Vincent’s Hospital in Manhattan published a paper describing two cases of “pan-resistant” Klebsiella, untreatable by even the kidney-damaging older antibiotics. One of the patients died and the other eventually recovered on her own, after the antibiotics were stopped.

“It is a rarity for a physician in the developed world to have a patient die of an overwhelming infection for which there are no therapeutic options,” the authors wrote in the journal Clinical Infectious Diseases.

In some cases, antibiotic resistance is spreading to Gram-negative bacteria that can infect people outside the hospital.

Sabiha Khan, 66, went to the emergency room of a Chicago hospital on New Year’s Day suffering from a urinary tract and kidney infection caused by E. coli resistant to the usual oral antibiotics. Instead of being sent home to take pills, Ms. Khan had to stay in the hospital 11 days to receive powerful intravenous antibiotics.

This month, the infection returned, sending her back to the hospital for an additional two weeks.

Some patient advocacy groups say hospitals need to take better steps to prevent such infections, like making sure that health care workers frequently wash their hands and that surfaces and instruments are disinfected. And antibiotics should not be overused, they say, because that contributes to the evolution of resistance.

To encourage prevention, an Atlanta couple, Armando and Victoria Nahum, started the Safe Care Campaign after their 27-year-old son, Joshua, died from a hospital-acquired infection in October 2006.

Joshua, a skydiving instructor in Colorado, had fractured his skull and thigh bone on a hard landing. During his treatment, he twice acquired MRSA and then was infected by Enterobacter aerogenes, a Gram-negative bacterium.

“The MRSA they got rid of with antibiotics,” Mr. Nahum said. “But this one they just couldn’t do anything about.”

Watch the videos, below, to learn more about drug resistant bacterial:


Have You Ever Used Piperacillin/Tazobactam for Pseudomonas aeruginosa? (Johns Hopkins School of Medicine)


MRSA: What Do We Tell Our Patients about Institutional Preca
(Johns Hopkins Hospital)


MRSA: Methicillin-resistant Staphylococcus Aureus (Univ. California
at Davis – School of Medicine)


Pediatrician Offers ‘Straight Talk’ On MRSA


FDA Alert – Warning on Colistimethate for Inhalation


FDA Alert – Bacterial Contamination of Vapotherm Devices


FDA Alert – New Safety Concerns about Zyvox


Drug Resistant TB, Malaria, MRSA, Pneumonia, etc.


Antibiotic-free animals


FDA Warning on Tendon Injuries with Fluoroquinolone Antibiotics


Black Box Warning For Certain Antibiotics

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial infection that is highly resistant to some antibiotics.

Causes

MRSA is a strain of Staphylococcus aureus (S. aureus) bacteria. S. aureus is a common type of bacteria that normally live on the skin and sometimes in the nasal passages of healthy people. MRSA refers to S. aureus strains that do not respond to some of the antibiotics used to treat staph infections.

The bacteria can cause infection when they enter the body through a cut, sore, catheter, or breathing tube. The infection can be minor and local (for example, a pimple), or more serious (involving the heart, lung, blood, or bone).

Serious staph infections are more common in people with weak immune systems. This includes patients in hospitals and long-term care facilities and those receiving kidney dialysis.

MRSA infections are grouped into two types:

  • Healthcare-associated MRSA (HA-MRSA) infections occur in people who are or have recently been in a hospital or other health-care facility. Those who have been hospitalized or had surgery within the past year are at increased risk. MRSA bacteria are responsible for a large percentage of hospital-acquired staph infections.
  • Community-associated MRSA (CA-MRSA) infections occur in otherwise healthy people who have not recently been in the hospital. The infections have occurred among athletes who share equipment or personal items (such as towels or razors) and children in daycare facilities. Members of the military and those who get tattoos are also at risk. The number of CA-MRSA cases is increasing.

Symptoms

Staph skin infections cause a red, swollen, and painful area on the skin. Other symptoms may include:

  • Drainage of pus or other fluids from the site
  • Fever
  • Skin abscess
  • Warmth around the infected area

Symptoms of a more serious staph infection may include:

Exams and Tests

Depending on your symptoms, your doctor may recommend the following tests to detect and confirm the bacteria causing the infection:

Treatment

Draining the skin sore may be the only treatment needed for a local skin MRSA infection. This can be done at the doctor’s office.

More serious MRSA infections, especially HA-MRSA infections, are becoming increasingly difficult to treat. Antibiotics that may still work include:

  • Clindamycin
  • Daptomycin
  • Doxycycline
  • Linezolid (Zyvox)
  • Minocycline
  • Tetracycline
  • Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)
  • Vancomycin (Vancocin, Vancoled)

It is important to finish all doses of antibiotics you have been given, even if you feel better before the final dose. Stopping treatment early by not finishing the full course of antibiotics can lead to further drug resistance in the bacteria, or can cause an infection that seemed to be gone to come back (relapse).

Other treatments may be needed for more serious infections. The person may be admitted to a hospital. Treatment may involve:

  • Fluids and medications given through a vein
  • Kidney dialysis (if kidney failure occurs)
  • Oxygen

Support Groups

For more information about MRSA, see the Centers for Disease Control web site: www.cdc.gov/mrsa/.

Outlook (Prognosis)

How well a person does depends on the severity of the infection and their overall health. MRSA-related pneumonia and blood infections are associated with high death rates.

Possible Complications

Serious staph infections may lead to:

Organ failure and death may result from untreated MRSA infections.

When to Contact a Medical Professional

Call your health care provider if:

  • A wound seems to get worse rather than heal
  • You have any other symptoms of staph infection

Prevention

Careful attention to personal hygiene is key to avoiding MRSA infections.

  • Wash your hands frequently, especially if visiting someone in a hospital or long-term care facility.
  • Make sure all doctors, nurses, and other health care providers wash their hands before examining you.
  • Do not share personal items such as towels or razors with another person — MRSA can be transmitted through contaminated items.
  • Cover all wounds with a clean bandage, and avoid contact with other people’s soiled bandages.
  • If you share sporting equipment, clean it first with antiseptic solution.
  • Avoid common whirlpools or saunas if another participant has an open sore.
  • Make sure that shared bathing facilities are clean.

Alternative Names

Methicillin-resistant Staphylococcus aureus; Community-acquired MRSA (CA-MRSA); Hospital-acquired MRSA (HA-MRSA)

References

Archer GL. Staphylococcal infections. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier. 2007: chap 310.

Centers for Disease Control and Prevention. Overview of community-associated MRSA. October 26, 2007. Accessed January 25, 2008

Nicolle L. Community-acquired MRSA: a practitioner’s guide. CMAJ. 2006;175:145.

Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Management of multi-drug resistant organisms in healthcare settings, 2006. US Centers for Disease Control and Prevention. Accessed January 25, 2008.

Update Date: 5/30/2009

Updated by: David C. Dugdale, III, MD, Professor of Medicine, Division of General Medicine, Department of Medicine, University of Washington School of Medicine; and Jatin M. Vyas, PhD, MD, Instructor in Medicine, Harvard Medical School, Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A colorized SEM of MRSA

Methicillin-resistant Staphylococcus aureus was discovered in 1961 in the United Kingdom. It made its first major appearance in the United States in 1981 among intravenous drug users. MRSA is often referred to in the press as a “superbug.”

In 1997, four fatal cases were reported involving children from Minnesota and North Dakota.  Over the next several years, it became clear that CA-MRSA infections were caused by strains of MRSA that differed from the older and better studied health care-associated strains.

The number of MRSA infections in the United States has been increasing significantly. A 2007 report in Emerging Infectious Diseases, a publication of the Centers for Disease Control and Prevention (CDC), estimated the number of MRSA infections in hospitals doubled nationwide, from approximately 127,000 in 1999 to 278,000 in 2005, while at the same time annual deaths increased from 11,000 to more than 17,000.  Another study led by the CDC and published in the October 17, 2007 issue of the Journal of the American Medical Association estimated that MRSA would have been responsible for 94,360 serious infections and associated with 18,650 hospital stay-related deaths in the United States in 2005.  These figures suggest that MRSA infections are responsible for more deaths in the U.S. each year than AIDS.

The Office for National Statistics reported 1,629 MRSA-related deaths in England and Wales during 2005, indicating a MRSA-related mortality rate half the rate of that in the United States for 2005, even though the figures from the British source were explained to be high because of “improved levels of reporting, possibly brought about by the continued high public profile of the disease” during the time of the 2005 United Kingdom General Election. MRSA is thought to have caused 1,652 deaths in 2006 in UK up from 51 in 1993.

It has been argued that the observed increased mortality among MRSA-infected patients may be the result of the increased underlying morbidity of these patients. Several studies, however, including one by Blot and colleagues, that have adjusted for underlying disease still found MRSA bacteremia to have a higher attributable mortality than methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.

While the statistics suggest a national epidemic growing out of control, it has been difficult to quantify the degree of morbidity and mortality attributable to MRSA. A population-based study of the incidence of MRSA infections in San Francisco during 2004-5 demonstrated that nearly 1 in 300 residents suffered from such an infection in the course of a year and that greater than 85% of these infections occurred outside of the health care setting.  A 2004 study showed that patients in the United States with S. aureus infection had, on average, three times the length of hospital stay (14.3 vs. 4.5 days), incurred three times the total cost ($48,824 vs $14,141), and experienced five times the risk of in-hospital death (11.2% vs 2.3%) than patients without this infection.  In a meta-analysis of 31 studies, Cosgrove et al.,  concluded that MRSA bacteremia is associated with increased mortality as compared with MSSA bacteremia (odds ratio = 1.93; 95% CI = 1.93±0.39).  In addition, Wyllie et al. report a death rate of 34% within 30 days among patients infected with MRSA, a rate similar to the death rate of 27% seen among MSSA-infected patients.

Clinical presentation and concerns

A ruptured MRSA abscess

S. aureus most commonly colonizes the anterior nares (the nostrils), although the respiratory tract, opened wounds, intravenous catheters, and urinary tract are also potential sites for infection. Healthy individuals may carry MRSA asymptomatically for periods ranging from a few weeks to many years. Patients with compromised immune systems are at a significantly greater risk of symptomatic secondary infection.

MRSA can be detected by swabbing the nostrils of patients and isolating the bacteria found inside. Combined with extra sanitary measures for those in contact with infected patients, screening patients admitted to hospitals has been found to be effective in minimizing the spread of MRSA in hospitals in the United States,  Denmark, Finland, and the Netherlands.

MRSA progresses substantially within 24–48 hours of initial topical symptoms. After 72 hours, MRSA can take hold in human tissues and become resistant to treatment. The initial presentation of MRSA is small red bumps that resemble pimples, spider bites, or boils that may be accompanied by fever and occasionally rashes. Within a few days the bumps become larger, more painful, and eventually open into deep, pus-filled boils.  About 75 percent of CA-MRSA infections are localized to skin and soft tissue and usually can be treated effectively. However CA-MRSA strains display enhanced virulence, spreading more rapidly and causing illness much more severe than traditional HA-MRSA infections, and they can affect vital organs and lead to widespread infection (sepsis), toxic shock syndrome and necrotizing (“flesh-eating”) pneumonia. This is thought to be due to toxins carried by CA-MRSA strains, such as PVL and PSM, though PVL was recently found to not be a factor in a study by the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH. It is not known why some healthy people develop CA-MRSA skin infections that are treatable whereas others infected with the same strain develop severe infections or die.

The most common manifestations of CA-MRSA are skin infections such as necrotizing fasciitis or pyomyositis (most commonly found in the tropics), necrotizing pneumonia, infective endocarditis (which affects the valves of the heart), or bone or joint infections.  CA-MRSA often results in abscess formation that requires incision and drainage. Before the spread of MRSA into the community, abscesses were not considered contagious because it was assumed that infection required violation of skin integrity and the introduction of staphylococci from normal skin colonization. However, newly emerging CA-MRSA is transmissible (similar, but with very important differences) from Hospital-Associated MRSA. CA-MRSA is less likely than other forms of MRSA to cause cellulitis.

Treatment

Both CA-MRSA and HA-MRSA are resistant to traditional anti-staphylococcal beta-lactam antibiotics, such as cephalexin. CA-MRSA has a greater spectrum of antimicrobial susceptibility, including to sulfa drugs (like co-trimoxazole/trimethoprim-sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin, but the drug of choice for treating CA-MRSA has not been established.  HA-MRSA is resistant even to these antibiotics and often is susceptible only to vancomycin. Newer drugs, such as linezolid (belonging to the newer oxazolidinones class), may be effective against both CA-MRSA and HA-MRSA.

Vancomycin and teicoplanin are glycopeptide antibiotics used to treat MRSA infections. Teicoplanin is a structural congener of vancomycin that has a similar activity spectrum but a longer half-life.  Because the oral absorption of vancomycin and teicoplanin is very low, these agents must be administered intravenously to control systemic infections.  Treatment of MRSA infection with vancomycin can be complicated, due to its inconvenient route of administration. Moreover, many clinicians believe that the efficacy of vancomycin against MRSA is inferior to that of anti-staphylococcal beta-lactam antibiotics against MSSA.  (Methicillin-Sensitive Staphylococcus Aureus)

[What is the antibiotic resistance phenotype of methicilin sensitive staphylococcus aureus (MSSA)?  The phenotype is the expression of the genotype and it is implied in the name- it is sensitive to methicilin vs MRSA which is methicilin resistant staphylococcus aureus.]

Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new evolutions of the MRSA bacterium have been dubbed Vancomycin intermediate-resistant Staphylococcus aureus (VISA).  Linezolid, quinupristin/dalfopristin, daptomycin, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin.

On May 18, 2006, a report in Nature identified a new antibiotic, called platensimycin, that had demonstrated successful use against MRSA.

An entirely different and promising approach is phage therapy (e.g., at the Eliava Institute in Georgia), which in mice had a reported efficacy against up to 95% of tested Staphylococcus isolates.

It has been reported that maggot therapy to clean out necrotic tissue of MRSA infection has been successful. Studies in diabetic patients reported significantly shorter treatment times than those achieved with standard treatments.

Ocean-dwelling living sponges produce compounds that may make MRSA more susceptible to antibiotics.

Image crunching: Pivot is designed to help users tease out patterns as they sort through large amounts of data. The tool can be used to filter and organize images based on accompanying textual information.
Credit: Microsoft Live Labs

 

A new tool explores large sets of data–and might help organize the Web

MIT Technology Review, March 3, 2010, by Erica Naone  —  “How do you take a big collection of things and make sense out of it?” asks Gary Flake, founder and director of Microsoft Live Labs, a division of the software giant that designs experimental Web tools. The problem is becoming more common, even for the average user, because the Web makes huge quantities of information readily available.

Flake’s lab’s answer to this question is Pivot, a tool released to the public earlier this month in conjunction with a demonstration Flake gave at the TED conference in Long Beach, CA.

Pivot presents data in the form of a collection of images accompanied by textual data. Sorting through data collated from Wikipedia, for example, means creating thumbnail images to accompany that information. The user can zoom into this collage of images to see individual pieces of data more closely, or zoom out to see items grouped according to various criteria. Though other tools can be used to organize data in various configurations, Flake hopes that Pivot’s simple and intuitive graphical interface will help insights about the data to pop out visually.

The power of Pivot, Flake says, lies in its consistent user interface, which is designed to make it easy for users to tease out the patterns in a large set of data. “You can interact with the data in a way that’s not quite browsing and not quite searching,” he says.

The technology at the core of Pivot is Microsoft’s Seadragon, software designed for manipulating large quantities of visual information. It allows commodity hardware to rapidly move through vast collections of graphics, zooming in seamlessly without having to wait for information to load, and zooming out to view hundreds or thousands of images at once. A tool as visually rich as Pivot wouldn’t have been possible even five years ago, Flake says, because most users’ computers wouldn’t have been able to process the graphics.

The team at Live Labs has made several sample collections that users can view, but the intention is for users to make their own collections. To do this, they need to convert their images to the Deep Zoom format used by Seadragon, and annotate them using a format based on the Web standard Extensible Markup Language (XML). The team has released an add-in for Microsoft Excel, called the Pivot Collection Tool, that lets users do this without requiring knowledge of XML.

Collections can be simple, consisting of a relatively small number of images with static data attached, or they can be very large, connected to a feed of changing data. Since Pivot has been released, one user has used it to view and sort through his Facebook friends, examining how they are related to each other.

Pivot can also be used to browse the Web and to view and organize Web pages. Flake says he foresees the Pivot interface being integrated with features such as search. Pivot might, he says, provide users a better way to sort through search results–instead of seeing the 10 top search results on a page, they could sort though thousands of results visually. “We are really taking a step back from the Web and trying to see it as a physical Web,” Flake says.

Pivot turned heads at TED. Roger McNamee, managing director and cofounder of the venture capital firm Elevation Partners, described the technology as “the brightest star” among a collection of impressive demos.

“Pivot’s clever user interface enables new forms of related and serendipitous search that I expect to transform the way I relate to the Web,” he says. “After several boring years, the ‘search wars’ may get interesting again.”

Martin Wattenberg, who developed the IBM data visualization program Many Eyes with his colleague Fernanda Viegas, says the Pivot team is tackling one of the big unsolved problems of dealing with modern data by building an interface that pulls together different types of media, including text and images.

Wattenberg says the goal is to provide more sophisticated mathematical techniques for sorting through data. “What is the standard deviation of a collection of images?” he says. “That question doesn’t even make sense.”

The key for all visualization tools, says Wattenberg, is to integrate them well with the rest of the Web. It would be useful to have open standards to let different software interoperate, he says, and to allow users to embed visualizations into their own Web pages. “We need to make visualization ubiquitous and seamless,” he says. “Like everything else in computing, we want to have it anytime, anywhere.”