OT but interesting - WHAT GERMS DON'T KNOW CAN'T HURT YOU
CHICAGO RESEARCHERS TEST A NOVEL STRATEGY TO FIGHT KILLER BACTERIA THAT ARE IMMUNE TO ANTIBIOTICS
By Lee Scheier, a Chicago freelance writer and a frequent contributor to the Magazine
Published November 14, 2004
When Christopher Reeve died last month of a bacterial infection, he was surrounded by doctors who were powerless to prevent the lethal microbes from overwhelming his body's defenses. The death of the quadriplegic film star, whose disease took root in the pressure sores he got from sitting in a wheelchair, drew renewed attention to the tens of thousands of hospital patients and others who each year succumb to a runaway bacteria attack.
The problem is increasingly alarming because of bacteria's well-known ability to develop resistance to even the most up-to-date antibiotics. Although many patients contract infections they didn't come into the hospital with, many also bring along germs that have been living peacefully inside them for their entire lives and which suddenly flare up. These patients often die because no drugs work against the microorganisms.
But continually inventing new antibiotics isn't the answer, says Dr. John Alverdy, a gastroenterological surgeon and researcher at the University of Chicago. Instead of trying to kill bacteria, Alverdy is developing an approach that, in effect, makes them feel safe and content inside their human host. If they don't sense a need or opportunity to attack, he reasons, they remain happy campers and no infection occurs.
"I don't want to kill bugs," asserts Alverdy, whose goal is to find drugs that blind the bacteria to signals that the person is ill and vulnerable to attack. "In essence, the bacteria become ignorant of how sick the host really is," he says.
Alverdy has long been on a mission to deal with such bacteria, but his efforts intensified in February 1998 on reading a letter to the Tribune from Jill Cunniff of Highland Park. She had written about the death of her 7-year-old son, Danny, from an infection while being treated for leukemia.
"Many children will die from the secondary infections that they will contract while they are immunosuppressed during chemotherapy," Cunniff wrote. "My 7-year old son was technically in remission [from leukemia] when he died from a fungal infection contracted in the hospital. . . ."
Alverdy was deeply moved by her account and later read it to an audience of physicians and grant coordinators at the National Institutes of Health in Bethesda, Md. "I told them that this was the human face of all the statistics we cite," he recalls. "I told them that we gave this kid all the antibiotics in the world and it didn't work, which is why we have to find alternative ways to treat these lethal infections."
He put the letter on the wall of his Chicago office in clear view of his desk and telephoned Cunniff. "He told me that my letter powerfully described the terrible problem of death from hospital-induced infections that he was working on," she says. "The doctors gave Danny amphotericin and vancomycin. The bottom line is that the antibiotics didn't help."
Eight months after his plea to NIH, Alverdy received a $1 million grant to study how pathogens turn virulent. The research led to his strategy for treating infections without antibiotics.
The seriousness of the problem can hardly be overstated. According to the Centers for Disease Control and Prevention, each year nearly 2 million patients in the U.S. get an infection while hospitalized, and about 90,000 die as a result.
"Antibiotic resistance is a ticking time bomb," says Dr. Abigail Salyers, professor of microbiology at the University of Illinois at Urbana-Champaign. She notes that not only are many bacteria and fungi becoming resistant to antibiotics, but the pharmaceutical industry has cut back or eliminated antibiotic drug discovery programs because they are not highly profitable.
According to a report of the American Society of Microbiologists, the driving force in the development of antibiotic resistance is widespread overuse of the drugs. More than 90 percent of strains of one form of bacteria, Staphylococcus aureus, have become resistant to penicillin and other antibiotics.
A similar problem exists with the most deadly pathogen of all, Pseudomonas aeruginosa, the one that's getting Alverdy's attention. It is antibiotic-resistant, extremely quick to act and metabolically diverse; that is, it can grow anyplace it finds one of the vast array of nutrients it can subsist on. It is found almost everywhere, including drinking fountains, faucets, streams, moist soil and the surface of vegetables.
"The average person is exposed to Pseudomonas aeruginosa every day," says Dr. Alan Hauser, assistant professor of microbiology and immunology at Northwestern University.
An estimated 70 percent of those infected with it die. It claims the lives of 60 percent of patients in burn units, 50 percent of AIDS patients and most of those with cystic fibrosis. Alverdy reasoned that he should start with this most wanton of killers. "If I could defeat the worst [form of bacteria], then I could apply that template of discovery to defeat many of the others," he says.
Those include germs like the ones that cause bacterial pneumonia and are now 20 percent resistant to penicillin. In some cases, says Salyers, half the bacteria of a particular species are resistant to at least one antibiotic. "What's at stake," she says, "is the possible loss of the effective use of antibiotics. This would be the first time in history that a cure was actually lost."
Alverdy argues that killer bacteria are innately benign and only turn virulent when they sense the host's tissue defenses are weakened, threatening their environment-the intestines, in the case of Pseudomonas aeruginosa.
"When the host is traumatized, bacteria like Pseudomonas aeruginosa are like rats leaving a sinking ship," says Dr. James Shapiro, professor of genetics at the U of C and an expert on bacterial behavior. "It makes sense for bacteria in a dying host to escape" by killing the host with its lethal toxins.
Based on pioneering research by Shapiro showing that bacteria are social organisms that can communicate with each other, Alverdy and his partner, Dr. Eugene Chang, professor of medicine at the University of Chicago, developed a compound that interferes with those communications.
In a recent study, they induced stress in laboratory mice and then introduced Pseudomonas aeruginosa directly into their intestines. All the mice died of the resulting infection, called gut-derived sepsis. However, when Alverdy and Chang treated the mice with their compound, a form of polyethylene glycol, the mice were completely protected. Amazingly, a virulent attack was prevented though not a single bacterium was killed.
Chang explains that the high-molecular-weight polyethylene glycol they used acts as an artificial mucus. A non-toxic polymer, it coats the bacteria and intestines and blocks the signals the microbes would otherwise send each other to mass for war and release lethal toxins. The study was recently published in the journal "Gastroenterology."
Alverdy first used the polyethylene glycol formulation on five patients who were dying of gut-derived sepsis when he worked at Chicago's Michael Reese Hospital.
"One of the patients was an 18-year-old girl who had had her appendix removed and was in the ICU," says Alverdy. "She was dying, her family was sobbing, yet there was no infection to be found anywhere. The only evidence was how sick she was. So I figured the bacteria must be in her intestines. I flushed 10 liters of polyethylene glycol through her intestines and she got better within 18 hours. So did the four other patients." All five survived.
Alverdy believes his study shows that the strategy of foiling bacterial communication holds more promise than using antibiotic drugs to fight an attack after it starts.
"Drug companies have spent billions of dollars trying to manipulate inflammation after it is initiated and have universally failed," says Alverdy. "Why not interdict before it occurs?"
Antibiotic treatment merely creates a never-ending, escalating arms race between medical researchers and bacteria, he says. And the bacteria always stay one step ahead of advances by quickly generating a genetic defense against the drugs. "Because generations of bacteria have faced multiple attempts at their elimination," he notes, "they have evolved the means to perpetually develop and refine their virulence capabilities."
Able to divide every 20 minutes, a bacterial cell could produce 5 billion progeny cells in just under 11 hours. "In the short term, we may be more clever than the bugs," says Alverdy, "but in the long term, they are more clever than we are . . . . We are just starting to understand how clever they are about changes in our biochemistry."
Shapiro agrees: "Bacteria are small, but they're not stupid," he says, noting that bacteria are very sophisticated in their information processing. "Every time a bacterium divides, tens of millions of biochemical processes have to be coordinated and controlled. The bacterial cell is the ultimate, just-in-time production facility."
This cell-to-cell communication is what allows Pseudomonas aeruginosa to make decisions about whether to assemble and secrete lethal toxins, Shapiro's research shows. "A single bacterium would not take on a host," he says. "They can sense their population density. When they sense how many of their own group are around and realize that the numbers are sufficient to kill the host, they attack."
Because the introduction of polyethylene glycol renders the bacteria unable to sense a cataclysmic change in their environment, they don't secrete the signaling molecules and don't mass for battle.
The polyethylene glycol also works by keeping the bacteria further away from the intestinal wall than usual. "Without physical contact it is rare for infection to occur," says Alverdy.
Dr. Dara Frank, professor of microbiology and molecular genetics at the Medical College of Wisconsin, is researching ways to disrupt the system that bacteria use to pump out toxins and deliver them to the cells. She says Alverdy's work is impressive, with solid data. "I think he's asking really big questions. We know that the signaling molecules are expressed in humans, particularly in cystic fibrosis patients. I think the signaling molecules are a good target to go after."
Hauser says an advantage of treatment with polyethylene glycol is that it is non-toxic and would likely be safe in a clinical trial.
"Approaches like Alverdy's have the potential to lead to interventions that could dramatically enhance our ability to prevent or treat these hospital-acquired infections," Hauser says.
On average, we have 500 to 700 species of bacteria living in or on our bodies, 3 trillion in all. A newborn baby has no "flora," a term used to describe the full array of microbes that inhabit our intestines and other structures. But around the 7th to 10th day the baby acquires all the flora it will have for the rest of its life from the environment.
The trillions of bacteria live in our intestines, sharing a kind of peaceful coexistence. But certain stresses, like surgical trauma, send signals that can cause bacteria to become virulent.
And a hospital intensive-care unit "is a strange new world for the bacteria," Alverdy says. "It's as though the bacteria is saying, 'I've been in your body for 50 years, and now I'm in an intensive care unit. They're attacking you with drugs. They won't let you eat, won't let you poop. They put the food in your veins so I have to go into your bloodstream to eat.' "
Although the bacteria have been alerted to the fact that the host is diseased and vulnerable, they have no reason to attack until the severity of the illness and the harshness of the therapies converge to create an alarming change in the bacterial environment. At that point they sense that the host has become a liability and signal each other to ascertain if there are enough of them to invade, inflame or kill the host. If the numbers are sufficient, they launch an assault.
Conversely, says Alverdy, when patients in the ICU are fed again, taken off morphine and begin to have bowel movements, the infection disappears. This, he believes, is because the bacteria sense that the host's health is improving.
Bacteria know that their survival is dependent on their host's survival, says Alverdy. "Organisms have a history of jumping to new hosts to survive, having moved, historically, from crops into cows and into man. A bacteria that kills its [sick] host has the chance that a bird will eat the carcass and ingest it, giving it a new lease on life."
Alverdy, Chang and others have formed a company in an effort to continue their research. "We have just had an offer in the millions of dollars for the licensing rights to high molecular weight [polyethylene glycol]," says Alverdy. They are awaiting approval from the FDA to begin human clinical trials. The first two populations that will undergo the trials are bone marrow transplant patients and children at risk for a type of colitis.
"If Danny [Cunniff] could have survived to get past point A and get a bone marrow transplant, he might be alive today," says his mother. "What's the point of treating cancer if the infections take you out of the treatment plan?"
She currently participates in an Internet support group with about 300 other parents. "Almost every parent in my support group who had a child [with] cancer that required an immunosuppression regimen lost that child to infections. Every kid that gets a bone marrow transplant, it's the same worry. It's the opportunistic pathogens that will kill you."
Copyright © 2004, Chicago Tribune
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