News Feature: Bug killers

Viruses that can kill bacteria were once wildly popular. Will the rising problem of antibiotic resistance bring them back? Thomas Häusler reports. When Dorota Wozniak* was a child, her foot was smashed in a car crash. It had to be partly amputated and was rebuilt using her own skin. More than 30 years after the accident, her foot is riddled with infected ulcers that won't heal. On a chilly day in early April, Wozniak sits in a small outpatient clinic in Wrocaw, a city in western Poland, waiting for relief. Next to her is Jan Kieslowski, who for more than a year had a urinary tract infection that caused him excruciating pain. "Last Christmas, I wept like a child because it hurt so much," Kieslowski says. He has taken eight different antibiotics—to no avail. In this cramped waiting room, there are five individuals, all a living indictment of modern medicine. They suffer from bacterial infections resistant to available antibiotics. But the doctors at this small clinic promise reprieve from the stubborn infections. Scientists here gave Kieslowski bacteriophages, hardy viruses that attack bacteria. After 26 days of treatment, the bacterial count in his seminal fluid came down from 1,000,000 to 10,000 per milliliter and his urine became sterile. "Also, the pain is much better," says Kieslowski. Bacteriophages infect bacterial cells, multiply up to 200-fold and then dissolve their hosts, ready to begin a new round of massacre. The phages reproduce in the body until their food—the infection—is gone. But they leave human cells unharmed. Fighting bacteria with these phages is not a new concept. Doctors treated millions of people with phages until the 1940s, but the therapy then fell into oblivion. It remained popular in some parts of the world, but has never been rigorously tested by modern standards. A few hundred miles away, in Bietigheim, Germany, the first rigorous clinical trial of phage therapy by modern standards is set to begin. Doctors at the Bietigheim Hospital are planning to test the effect of phages on infected chronic wounds—and what they find may well restore phage therapy to its former glory. Anecdotal evidence In 1919, Félix d'Herelle, one of the two discoverers of phages, began using phage therapy to treat Parisian children with bacillary dysentery. At the time, there were no real means to fight most infections, and pneumonia was the leading cause of death in the US and many other countries. From 1920 to 1940, phage therapy had its heyday. But once doctors ushered in penicillin, the method fell by the wayside in most places. In parts of the Eastern bloc, it survived for decades alongside antibiotics. After the fall of the Soviet Union, Western scientists were intrigued to note the parallel medicine behind the wall, their interest boosted by the growing problem of antibiotic resistance. Despite decades of anecdotal evidence to back phage therapy's promise, however, many infectious disease specialists remain skeptical about its benefits. "The data [from earlier studies] are weak at best," says Steven J. Projan, vice president and head of Biological Technologies at Wyeth Research. "The better done the study, the less efficacious phage therapy appears to be," Projan says. To date, phage-based drugs have not been approved by any drug regulatory agency—except those of some republics in the former Soviet Union—or even come close to that goal. The clinic in Wrocaw, which is part of the Institute of Immunology and Experimental Therapy, is the only place in the European Union where patients can officially get phage treatment. "This is a crucial step for phage therapy," says institute director Andrzej Górski. Although neither the US Food and Drug Administration (FDA) nor the European Agency for the Evaluation of Medicinal Products, its European equivalent, has approved phage therapy, Wrocaw's bioethics committee has granted the clinic a license to treat people with the 'experimental therapy.' The clinic's doctors are only allowed to use phages in cases where all else fails. But the license is an important first step toward approving the contentious therapy, says Wim Fleischmann, a German physician and phage-watcher. "This permission is fundamental." To some extent, rigorous evidence from animal experiments backs the claims about the power of phage therapy. Studies in mice have shown that phages can eliminate a variety of bacterial infections, ranging from blood poisoning to diarrhea1, 2. The Wrocaw institute also has human data from about 2,000 individuals beginning in the 1970s. The studies are not randomized or placebo-controlled, but well-documented case studies report positive outcomes in about 80% of individuals3. Still, skeptics maintain that there is not enough evidence to warrant the therapy's use in the clinic. "I think it is premature to do any of this at this time," says Ryland Young, professor of biochemistry and biophysics at Texas A&M University in College Station, Texas. "I am not convinced that the background phage knowledge is really up to the level we need before embarking." Urgent demand If they do work, phages would be a welcome answer to the growing problem of antibiotic resistance. In the UK, an estimated 39% of infections by Staphylococcus aureus in hospitals are resistant to multiple antibiotics4. In the US, this number is closer to 50%5. An estimated 90,000 US patients die each year from infections contracted in hospitals, many of them caused by multidrug-resistant bacteria6. And, in the past few years, some of these bacteria have ventured outside hospital walls and into communities in several states7. One US physician, who wishes to remain anonymous, was so overwhelmed that he began last year to use phages in hopeless cases. "We had a number of patients whose wounds would not heal," he says. In several patients, "wound-healing behavior changes with phages and it changes very positively." Spurred by the potential market, biotech companies and university researchers in the late 1990s took renewed interest in phage therapy drugs. But many commercial projects fell victim to venture capitalists' wariness. Among the abortive attempts was the only phage drug—called C33 and made by US-based Exponential Biotherapies—to have made it into FDA-approved phase 1 trials. Between 1970 and 1999, hospitals all over Poland sent the bacterial samples from their patients to scientists at the Wrocaw institute. Beata Weber-Da ogonbrowska, the head of the institute's phage lab, would check her vast collection for viruses able to infect the bacteria. This is a key step in phage therapy because each phage usually only infects some strains of a single bacterial species. Bacteria can also develop resistance to specific phages, which in turn evolve to counter this resistance. Weber-Da ogonbrowska had to search continuously for new phages to take on the evolving bacteria. "The 40 phages against E. coli we had in the 1970s have practically no activity against today's strains," she says. Weber-Da ogonbrowska still prepares the phages for the new outpatient clinic. Her source for most phages is Wrocaw's sewage system, a natural repository for the viruses. This aspect of phage therapy is another hurdle to its introduction to market—it effectively kills its potential to become a blockbuster. Along with having to find a way to patent naturally occurring phages, companies have a tough sell in a marketplace accustomed to antibiotics. About three years ago, most companies refocused their interest to phage therapies for livestock, where drug development is much cheaper. "It's taking more time than anticipated to wean the world off the standardized wide-spectrum chemical solutions in favor of the relatively service-intensive phage technology," says Asher Wilf, head of the Israeli company PhageBiotech. "The fact remains that there are still very few [phage companies] and we are all struggling." Proof of principle As phage therapy strives to gain credibility in the West, one US company has teamed up with specialists in Tbilisi, capital of Georgia in the Caucasus, to help treat infections. California-based Phage International sends people from the US, Australia and other countries to Tbilisi, which was one of the centers of phage therapy. At the same time, institutes from the former Soviet Union have tried to establish their products in the Western market. But none of these approaches has succeeded in establishing a formal proof of efficacy. The clinical studies done until World War II do not stand up to today's requirements. A whiff of quackery accompanied companies touting their phages as a panacea that could cure eczema and herpes as well as bacillary dysentery and typhoid fever. Add to that questionable studies from the Soviet era, and the skepticism about phages makes sense. The clinical trial at the Bietigheim hospital might help change all that. "This study is supposed to show the scientific community if phages work—or not," says Fleischmann, head of the hospital's department of trauma and reconstructive surgery. In the 1990s, Fleischmann played a central role in bringing back another vintage therapy: maggots. The larvae of flies are placed on wounds infected with antibiotic-resistant bacteria where they eat the bacteria and dissolve the diseased and dead flesh, but not the healthy tissue nearby. Like phages, maggots also met a lot of reservation in medical circles. But for some years, the health authorities of some countries such as Germany and the US approved maggots without applying the same stringent standards as for synthetic pharmaceuticals. "I think it would be appropriate to apply similar kinds of standards to the external usage of phages," says phage pioneer Elizabeth Kutter, professor of biophysics at Evergreen College in Olympia, Washington. After all, she notes, people are exposed to phages every day—phages are everywhere, in food and drinking water, and on our own skin. Fleischmann anticipates the same chain of events he witnessed with maggots if his trial proves the efficacy of phages. "First, people still tell you that it does not work," he says. "After that, they acknowledge that it works but stress that they've got better methods. And finally, everybody agrees that your method is an old hat and that you should not pride yourself on it." "Source":[ http://www.nature.com/nm/journal/v12/n6/full/nm0606-600.html]

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