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Phage —advantages over ? s -resistant , Klebsiella 1996. Led by Carl Merrill, NIH Acontinue to threaten standard pneumoniae, and coli. chief of the laboratory of biochemical against bacterial , However phage therapy has not genetics, researchers developed the a new breed of may be been well received by the wider med- “serial passage” method for isolating on the horizon. Many researchers ical community. Why is, for example, long-circulating strains of phages believe that — the USA so reluctant to accept a (Proc Natl Acad Sci-USA 1996; 93: that only infect bacte- therapy that has been 3188–92). ria—are a promising deemed successful in These long-circulating phages, potential therapy for Rights were eastern Europe? produced by serial passage, were sig- bacterial disease treat- not granted to Inadequate scientific nificantly more effective than the ment. include this methodologies used by wild-type phages from which they Phage therapy boasts early scientists have were derived, in terms of curing ani- several advantages over image in contributed to the per- mals of an otherwise fatal bacter- traditional antibiotics. electronic ception of phage ther- aemia. “Long-circulating phages are “Yeast and media. Please apy as a failed important as therapeutic agents”, diarrhoea are frequent approach, explains suggests Carlton, “because the wild- side effects of antibac- refer to the Carlton. These poor type strains tend to be cleared so terial therapy because printed journal. methodologies have rapidly that they do not have time to the beneficial bacteria included “the failure to reach and kill the infecting bacteria.” of the genital tract and conduct placebo-con- Such research breakthroughs, and intestines are also trolled studies, to more recently, data from several clin- killed, disrupting the Phage attack a bacterium remove endotoxins ical trials presented at this year’s ecology and enabling from the preparations, annual meeting of the American other to grow out and and to reconfirm phage viability after Society for Microbiology, (Los cause disease”, explains Paul Gulig adding sterilising agents to the Angeles, CA, USA; May 21-25) have (University of Florida, Gainesville, preparations”, he says. Such over- won phage therapy acceptance by FL, USA). However bacteriophages sights have produced mixed and suggesting that it could tackle vari- target specific bacterial strains, thus allegedly fatal results—in fairness to ous antibiotic-resistant bacteria. For sparing patients from the side effects pioneering phage scientists, their era example, University of Florida caused by destroying natural flora. predated the discovery of phenom- researchers examined bacteriophages Another positive aspect of phages ena such as lysogeny, which helps isolated from seawater, which could is their capacity for exponential identify pure phage strains, and infect vulnificus, which can growth. Essentially, phages closely could have enhanced their research cause serious septicemia. When they follow the course of bacterial growth efforts. treated mice with iron overload and and presence, multiplying alongside The new generation of phage sci- infected them with V vulnificus, the bacteria, and dissapearing once the entists have had to overcome this bad untreated rodents died within 24h bacteria has gone. Even though bac- publicity and resolve some scientific compared with the phage treated terial resistance is a concern, unlike issues. For example, phages’ particu- mice, which recovered. antibiotics, phages can mutate in lar taste for a specific bacterial target Research will continue in the hope step with evolving bacteria. Also if increases pressure to have a precise of undoing phages therapy’s poor bacteria become resistant to one diagnosis. Rapid progressive and reputation and of perfecting natural phage, there is a natural abundance fatal infections shorten the timeframe phages to make them more potent of phage species, which could attack in which to culture and identify a and adaptive. Although phage injec- even new resistant strains. to select the suitable phage. tions or a prescription for phage pills Richard Carlton, president of Scientists have addressed these may still be a long way off, hospitals Exponential Biotherapies (Port points by combining different phages may be ready to benefit from this Washington, NY, USA), explains, into one therapy. “The down side to aid. Phages could be “one great thing about phages is that the specificity”, says Gulig, “is that used in hospitals as a prophylactic mutations that enable bacteria to all strains of a given bacterial species to decolonise immunocomprised resist antibiotics do not enable the may not be killed by every phage. patients or patients waiting for bacteria to resist the phage, and vice However, this can be compensated surgery. versa”. That’s because each form of for by using a mixture of phage that Mike DuBow (McGill University, treatment acts on a different part of collectively covers the majority, if not Montreal, Canada) suggests that the bacteria to disarm and destroy it, all, of the known strains of a disease- “phage therapy won’t be a total says Carlton. causing species”. replacement of the antibiotic arsenal Phage therapy has been deemed a Another shortcoming was that, but a supplement to it. But antibi- success in parts of eastern Europe for being foreign proteins, phages were otics remain too important, too suc- decades. In Tbilisi, Georgia, home of cleared from the body too quickly. cessful, and too necessary to the Eliava Institute of , “Many drugs have clearance prob- completely do without”. The next Microbiology, and , where lems”, says Carlton, “and that was stage, he believes, is more regulatory phages have been studied since 1934, the case with phages”. This problem than science. “What we think we researchers report that phage therapy was addressed by a collaborative know about phages has to be verified has an 80% success rate against ente- research project that involved and then deemed reproducible safe rococcus infections. In Poland, doc- Exponential Biotherapies, the and effective”, says DuBow. tors have had a 90% success rate National Institute of Health (NIH), against cases of aureus, and the National Cancer Institute in Angela Pirisi

1418 THE LANCET • Vol 356 • October 21, 2000

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