The patients in Professor Andrzej Górski’s cramped waiting room are all a living indictment of modern medicine. They suffer from bacterial infections resistant to antibiotics. Jan Kieslowski*, for example, has an infected urinary tract for over a year. He has taken eight different antibiotics – to no avail. Next to him sits Dorota Wozniak. As 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.

 

Wozniak, Kieslowski and the other patients were sent by their doctors from all over Poland to the small outpatient clinic. It is a new part of the Institute of Immunology and Experimental Therapy (IITD) in Wroclaw, a city in western Poland about 100 miles from the borders to Germany and the Czech Republic. IITD-director Górski and his team hope to cure the stubborn bacterial infections with bacteriophage therapy. Bacteriophages are viruses that specifically attack bacteria, but not human cells. The phages administered infect bacterial cells, multiply up to 200-fold and then dissolve their hosts – ready to start a new round of massacre. The drug, in other words, produces itself in the body until its food – the infection – is gone.

 

Phage therapy has a checkered history, going back to the 1910s. One of the discoverers of phages started using them as a remedy for bacterial diseases in 1919. A very welcome idea 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. Phage therapy had its heyday from 1920 to 1940 before being pushed aside by penicillin. However, in parts of the Eastern bloc it survived 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.

 

The opening of the phage clinic in Wroclaw is thus an exciting development. It is the first place under European Union jurisdiction where patients can officially get phage treatment. “This is a crucial step for phage therapy,” says Górski. The license his clinic carries does not mean that phages are now fully approved by the European drug regulation agency EMEA. Rather, the local ethics committee has granted permission to treat people under a scheme called “experimental therapy”. IIDT doctors are only allowed to use phages in cases where all else fails. Says Wim Fleischmann, a German physician and phage-watcher: “This permission is fundamental.”

 

Górski’s patients agree. Jan Kieslowski’s urinary tract infection was so bad that, despite antibiotics, “last Christmas, I wept like a child because it hurt so much,” he says. After 26 days of phage treatment, the bacterial count in his seminal fluid came down from one million per milliliter to 10000 and his urine became sterile. “Also the pain is much better,” says Kieslowski. Another patient has had maxillary sinusitis for 4 years. Most of this time his left half of the face was swollen heavily. The culprits are multi-resistant Staphylococcus aureus, or MRSA.

 

In the UK, 39 per cent of staph infections in hospitals were multi-resistant in 2004. In the US, this number is closer to 50 per cent. An estimated 90000 US patients die annually from infections contracted in hospital, many of them caused by multi-resistant bacteria. And, in the past 4 or 5 years, doctors have been alarmed to see some MRSA strains leaving their original home – the hospitals – and conquering cities such as Los Angeles or Chicago.

 

Why then does phage therapy face such an uphill struggle? One reason is rooted in its history. None of its numerous fervent proponents has succeeded in producing formal proof of efficacy. The clinical studies done until World War II do not stand up to today’s requirements. Back then, not enough was known about phages to use them in a consistent way. That led to mixed results and angry feelings among doctors. The whiff of quackery wasn’t helped by companies touting their phages as panacea that could cure eczema and herpes as well as bacillary dysentery and typhoid fever. Add to all this studies from the Soviet era that are usually insufficient in one way ore the other and its small wonder skepticism still abounds among many infectious disease specialists.

 

 

Beata Weber-Dabrowska of the IITD and the institute’s late director Stefan Slopek were the main scientists preparing the phage drugs for treatment between 1970 and 1990. Co-operating hospitals all over Poland sent the bacterial samples from their patients and Weber checked her vast phage collection for viruses able to infect the bacteria. In phage therapy this is one of the central steps, because phages are very picky. Usually, each one infects only some strains of a single bacterial species. Plus, bacteria develop resistance to specific phages, which in turn evolve to counter this resistance. Weber had to search continuously for new phages able to take on the evolving bacteria. “The 40 phages against E. coli we had in the 70s have practically no activity against today’s strains,” says Weber. She still prepares the phages for IITD’s new outpatient clinic. Mostly, her source for fresh ones was and is Wroclaw’s sewage system.

 

This bespoke nature of phage therapy is another hurdle to its introduction to market – it effectively kills its potential to become a blockbuster. Along with the headache of how to patent naturally occurring phages companies in the sector have a rough time of it. “It’s taking more time than anticipated to wean the world off the standardized wide-spectrum chemical solutions of [antibiotics] in favor of the relatively service-intensive phage technology,” says Asher Wilf, head of the Israeli company PhageBiotech. “This may be due to underestimating the scope of the antibiotics crisis. The fact remains that there are still very few [phage companies] and we are all struggling.”

 

So around two to three years ago, most companies refocused from therapies for humans to those for livestock where drug development is much cheaper. Nontheless, some doctors and companies are trying to make phage therapy available to despairing patients anyway. One US physician was so overwhelmed that he started last year to use phages in otherwise helpless cases – although the method doesn’t have FDA approval. “We had a number of patients whose wounds would not heal,“ says the doctor who does not want to be named. “Many of them ended up losing their leg and then very shortly after that losing their life because of their major limb amputation.” In several patients, he says, “wound healing behavior [does] change with phages and it changes very positively.”

 

A US company called Phage International sends patients from the US, Australia and other countries to Georgia in the Caucasus. The capital, Tbilisi, was one of the centers of phage therapy in Soviet times and Phage International has teamed up with local specialists to provide treatment there.

 

The new phage clinic of the IITD in Wroclaw is a substantial leap in this kind of grassroots development. But as also the Polish offer carries an “experimental therapy” label safety is an issue – not least after vioxx and the recent TGN1412 trial gone awry in London. Although phage therapy proponents point out that it has been used on millions of patients without serious side effects, Górski is quick to emphasize safety as his number one priority: “We check the clinical parameters of our patients extensively before and during treatment.” If any lab tests indicate an irregularity, patients are not enrolled in the program.

 

Still, some phage researchers remain skeptical: “I think it is premature to do any of this at this time,” says Ryland Young from Texas A&M University. “I am not convinced that the background phage knowledge is really up to the level we need before embarking.” Some experts fear that this lack of knowledge will again result in inconclusive treatment results – which would be the undoing of phage therapy. “We have to set up clinical trials”, agrees Górski who is trying to secure private funds for this. In the meantime, he stresses that the intensive monitoring program of his patients allows gathering a lot of detailed data.

 

A few hundred miles away in Bietigheim, Germany, the first clinical trial of phage therapy according to modern standards could soon be underway. Wim Fleischmann from Bietigheim hospital is planning a study on chronic wounds. He estimates he will be ready in a few weeks to hand in his study protocol over to the local ethics board for approval according to German law. The phages will again come out of Beata Weber’s lab in Wroclaw.

 

“This study is supposed to show the scientific community if phages work – or not”, says Fleischmann. So many before him have tried in vain to achieve the same thing. Fleischmann could be the right man for the job. In the 1990s he 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 close by.

 

Like phages, maggots also met a lot of reservation in medical circles. But for some years, the health authorities of many countries have approved maggots without applying the same stringent standards as they to 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 from Evergreen college in Olympia, Washington. After all, she points out, we are exposed to phages every day – they live nearly everywhere, from our skin, to food and drinking water.

 

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. 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.”

 

* Names of patients are changed.

 

1 Häusler, T. “Viruses vs. Superbugs”, Macmillan, 2006, p. 221

2 Dubos, R. J. et al. (1943) ‘The multiplication of bacteriophage in vivo and its protective effects against an experimental infection with Shigella dysenteriae’, J. Exp. Med., 78: 161–8; Smith, H. W. and Huggins, M. B. (1982) ‘Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics’, J. Gen. Microbiol., 128: 307–18; Biswas, B. et al. (2002) ‘Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium’, Infect. Immun., 70: 204–10.

3 Weber-Dabrowska, B. et al. (2000) ‘Bacteriophage therapy of bacterial infections: an update of our institute’s experience’, Arch. Immunol. Ther. Exp. (Warsz) 48: 547–51.

 

 

© Thomas Häusler 2006, 2007