Use of Bacteriophages to Treat Bacterial Infection

USE OF BACTERIOPHAGES TO TREAT BACTERIAL INFECTION

The discovery of the lytic property of phages quickly resulted in their use as a potential bactericidal agent at the beginning of the 20th century, to combat bacteria responsible for dysentery outbreaks, first against Vibrio cholera (work of Hankin) and then Shigella shiga (work of d’ Herelle). Phages targeting bacteria causing a number of diseases such as anthrax, scarlet fever, cholera and diphtheria were quickly isolated, but with the exception of ‘cholera’ phages these did not result in useful treatments. The introduction of antibiotics in the early 1940s resulted in the end of phage therapy in the West, although it continues in the former Soviet Union, where it was used to treat a variety of bacterial infections in both the First and Second World Wars and is still used nowadays in clinical practice.

With the threat of bacterial resistance to antibiotics, there has been a renewed interest in the use of phages to control bacterial infection and product contamination and this has led to the licensing of phage products for a number of applications; the use of phages to combat Listeria monocytogenes in ready to eat meat and poultry products was authorized by the US Food and Drug Administration (FDA) in 2006 and in cheeses by the EU commission in 2009. In the UK, a phage based product to combat Pseudomonas aeruginosa in ear infection is now in phase III clinical trials. Phage preparations are also successfully employed in aquaculture, notably against Lactococcus garvieae, the cause of a serious fish disease.

There are a number of ways to prepare a phage product. ‘Natural’ phages from the environment can be selected on the basis of their activity and incorporated into a product on the basis that they are lytic and do not contain any detrimental genes encoding for example antibiotic resistance or bacterial virulence factors. Often several phages (cocktail) attacking the same species or strain are added to the product to minimize the risk of emerging bacterial resistance. Nonreplicating phages have been used with some degree of success, but in this case the lytic effect is short lived. Genetically modified phages have also been used, whereby detrimental genes can be removed and phage virulence genes added. Another advantage of using genetically modified phages is commercial where patents might be easier to file. Finally, lysogenic phages can be used following treatment to remove their lysogenic property.

Phage based products can be developed using phage components, mainly phage lytic enzymes which are employed during phage penetration and during virion excision from the host cell. Phage lytic enzymes (e.g. peptides) can be harvested and use on their own to lyse/kill bacteria.

The use of phages for surface disinfection and antisepsis or for the treatment of a bacterial infection (phage therapy) is at an early stage and further work is needed to develop appropriate phage based products, notably the effect of the different routes of administration on phage viability and effectiveness. Animal studies have shown that the route of administration is crucial for phage efficacy. Phage therapy is unlikely to supplant antibiotic therapy in the future; however, it is highly probable that commercially available phage products will increase as the advantages of phage therapy outweigh its disadvantages (Table 5.7)