Phage therapy
Encyclopedia
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
s to treat pathogenic bacterial infections. Although extensively used and developed mainly in former Soviet Union
Soviet Union
The Soviet Union , officially the Union of Soviet Socialist Republics , was a constitutionally socialist state that existed in Eurasia between 1922 and 1991....
countries circa 1920, this method of therapy is still being tested elsewhere for treatment
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of a variety of bacterial and poly-microbial biofilm
Biofilm
A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance...
infections, and has not yet been approved in countries other than Georgia
Georgia (country)
Georgia is a sovereign state in the Caucasus region of Eurasia. Located at the crossroads of Western Asia and Eastern Europe, it is bounded to the west by the Black Sea, to the north by Russia, to the southwest by Turkey, to the south by Armenia, and to the southeast by Azerbaijan. The capital of...
. Phage therapy has many potential applications in human
Human
Humans are the only living species in the Homo genus...
medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
as well as dentistry
Dentistry
Dentistry is the branch of medicine that is involved in the study, diagnosis, prevention, and treatment of diseases, disorders and conditions of the oral cavity, maxillofacial area and the adjacent and associated structures and their impact on the human body. Dentistry is widely considered...
, veterinary science, and agriculture
Agriculture
Agriculture is the cultivation of animals, plants, fungi and other life forms for food, fiber, and other products used to sustain life. Agriculture was the key implement in the rise of sedentary human civilization, whereby farming of domesticated species created food surpluses that nurtured the...
. If the target host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
of a phage therapy treatment is not an animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
the term "biocontrol
BioControl
BioControl is a peer-reviewed scientific journal published by Springer Science+Business Media covering all aspects of basic and applied research in biological control of invertebrate, vertebrate, and weed pests, and plant diseases. The journal was established in 1956 as Entomophaga and published by...
" (as in phage-mediated biocontrol of bacteria) is usually employed, rather than "phage therapy".
Bacteriophages are much more specific than antibiotics, so they can hypothetically be chosen to be indirectly harmless not only to the host organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
(human, animal, or plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
), but also to other beneficial bacteria, such as gut flora
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
, reducing the chances of opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
s. They would have a high therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, that is, phage therapy would be expected to give rise to few if any side effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s, as opposed to drugs, and would not stress the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. Because phages replicate in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, a smaller effective dose can be used. On the other hand, this specificity is also a disadvantage: a phage will only kill a bacterium if it is a match to the specific strain
Strain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a micro-organism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...
. Consequently phage mixtures are often applied to improve the chances of success, or samples can be taken and an appropriate phage identified and grown.
Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics, particularly in the Republic of Georgia
Georgia (country)
Georgia is a sovereign state in the Caucasus region of Eurasia. Located at the crossroads of Western Asia and Eastern Europe, it is bounded to the west by the Black Sea, to the north by Russia, to the southwest by Turkey, to the south by Armenia, and to the southeast by Azerbaijan. The capital of...
. They tend to be more successful than antibiotics where there is a biofilm
Biofilm
A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance...
covered by a polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
layer, which antibiotics typically cannot penetrate. In the West, no therapies are currently authorized for use on human
Human
Humans are the only living species in the Homo genus...
s, although phages for killing food poisoning bacteria (Listeria) are now in use.
History
Frederick Twort
Frederick William Twort was an English bacteriologist and was the original discoverer in 1915 of bacteriophages . He studied medicine at St Thomas's Hospital, London, was superintendent of the Brown Institute for Animals , and he was also professor of bacteriology at the University of London...
and Felix d'Hérelle
Félix d'Herelle
Félix d'Herelle was a French-Canadian microbiologist, the co-discoverer of bacteriophages and experimented with the possibility of phage therapy.-Early years:...
in 1915 and 1917, phage therapy was immediately recognized by many to be a key way forward for the eradication of bacterial infections. A Georgian, George Eliava, was making similar discoveries. He travelled to the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...
in Paris where he met d'Hérelle, and in 1923 he founded the Eliava Institute in Tbilisi
Tbilisi
Tbilisi is the capital and the largest city of Georgia, lying on the banks of the Mt'k'vari River. The name is derived from an early Georgian form T'pilisi and it was officially known as Tiflis until 1936...
, Georgia
Georgia (country)
Georgia is a sovereign state in the Caucasus region of Eurasia. Located at the crossroads of Western Asia and Eastern Europe, it is bounded to the west by the Black Sea, to the north by Russia, to the southwest by Turkey, to the south by Armenia, and to the southeast by Azerbaijan. The capital of...
, devoted to the development of phage therapy.
In neighbouring countries including Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...
, extensive research and development soon began in this field. In the USA during the 1940s commercialization of phage therapy was undertaken by the large pharmaceutical company, Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
.
Whilst knowledge was being accumulated regarding the biology of phages and how to use phage cocktails correctly, early uses of phage therapy were often unreliable. When antibiotics were discovered in 1941 and marketed widely in the USA and Europe, Western scientists mostly lost interest in further use and study of phage therapy for some time.
Isolated from Western advances in antibiotic production in the 1940s, Russian scientists continued to develop already successful phage therapy to treat the wounds of soldiers in field hospital
Field hospital
A field hospital is a large mobile medical unit that temporarily takes care of casualties on-site before they can be safely transported to more permanent hospital facilities...
s. During World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
, the Soviet Union used bacteriophages to treat many soldiers infected with various bacterial diseases e.g. dysentery and gangrene. Russian researchers continued to develop and to refine their treatments and to publish their research and results. However, due to the scientific barriers of the Cold War
Cold War
The Cold War was the continuing state from roughly 1946 to 1991 of political conflict, military tension, proxy wars, and economic competition between the Communist World—primarily the Soviet Union and its satellite states and allies—and the powers of the Western world, primarily the United States...
, this knowledge was not translated and did not proliferate across the world. A summary of these publications has been published recently in English in "A Literature Review of the Practical Application of Bacteriophage Research"
There is an extensive library and research center at the Eliava Institute in Tbilisi, Georgia. Phage therapy is today a widespread form of treatment in that region. For 80 years Georgian doctors have been treating local people, including babies and newborns, with phages.
As a result of the development of antibiotic resistance since the 1950s and an advancement of scientific knowledge, there has been renewed interest worldwide in the ability of phage therapy to eradicate bacterial infections and chronic polymicrobial biofilm, along with other strategies.
Phages have been investigated as a potential means to eliminate pathogens like Campylobacter
Campylobacter
Campylobacter is a genus of bacteria that are Gram-negative, spiral, and microaerophilic. Motile, with either unipolar or bipolar flagella, the organisms have a characteristic spiral/corkscrew appearance and are oxidase-positive. Campylobacter jejuni is now recognized as one of the main causes...
in raw food and Listeria in fresh food or to reduce food spoilage bacteria. In agricultural practice phages were used to fight pathogens like Campylobacter
Campylobacter
Campylobacter is a genus of bacteria that are Gram-negative, spiral, and microaerophilic. Motile, with either unipolar or bipolar flagella, the organisms have a characteristic spiral/corkscrew appearance and are oxidase-positive. Campylobacter jejuni is now recognized as one of the main causes...
, Escherichia
Escherichia
Escherichia is a genus of Gram-negative, non-spore forming, facultatively anaerobic, rod-shaped bacteria from the family Enterobacteriaceae. In those species which are inhabitants of the gastrointestinal tracts of warm-blooded animals, Escherichia species provide a portion of the...
and Salmonella
Salmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
in farm animals, Lactococcus
Lactococcus
Lactococcus is a genus of lactic acid bacteria that were formerly included in the genus Streptococcus Group N1. They are known as homofermentors meaning that they produce a single product, lactic acid in this case, as the major or only product of glucose fermentation...
and Vibrio
Vibrio
Vibrio is a genus of Gram-negative bacteria possessing a curved rod shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Typically found in saltwater, Vibrio are facultative anaerobes that test positive for oxidase and do not form...
pathogens in fish from aquaculture and Erwinia
Erwinia
Erwinia is a genus of Enterobacteriaceae bacteria containing mostly plant pathogenic species which was named for the first phytobacteriologist, Erwin Smith. It is a gram negative bacterium related to E. coli, Shigella, Salmonella and Yersinia. It is primarily a rod-shaped bacteria. A well-known...
and Xanthomonas
Xanthomonas
Xanthomonas is a genus of Proteobacteria, many of which cause plant diseases. Most varieties of Xanthomonas are available from the National Collection of Plant Pathogenic Bacteria in the United Kingdom and other international culture collections such as ICMP in New Zealand, CFBP in France, and...
in plants of agricultural importance. The oldest use was, however, in human medicine. Phages have been used against diarrheal diseases caused by E. coli, Shigella
Shigella
Shigella is a genus of Gram-negative, nonspore forming, non-motile, rod-shaped bacteria closely related to Escherichia coli and Salmonella. The causative agent of human shigellosis, Shigella causes disease in primates, but not in other mammals. It is only naturally found in humans and apes. During...
or Vibrio
Vibrio
Vibrio is a genus of Gram-negative bacteria possessing a curved rod shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Typically found in saltwater, Vibrio are facultative anaerobes that test positive for oxidase and do not form...
and against wound infections caused by facultative pathogens of the skin like staphylococci and streptococci. Recently the phage therapy approach has been applied to systemic and even intracellular infections and the addition of non-replicating phage and isolated phage enzymes like lysins to the antimicrobial arsenal. However, actual proof for the efficiency of these phage approaches in the field or the hospital is not available.
Some of the interest in the West can be traced back to 1994, when Soothill demonstrated (in an animal model) that the use of phages could improve the success of skin grafts by reducing the underlying Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
infection. Recent studies have provided additional support for these findings in the model system.
Although not "phage therapy" in the original sense, the use of phages as delivery mechanisms for traditional antibiotics constitutes another possible therapeutic use. The use of phages to deliver antitumor agents has also been described in preliminary in vitro experiments for cells in tissue culture.
Potential benefits
Bacteriophage treatment offers a possible alternative to conventional antibioticAntibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
treatments for bacterial infection. It is conceivable that, although bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
can develop resistance to phage, the resistance might be easier to overcome than resistance to antibiotics.
Bacteriophages are very specific, targeting only one or a few strains of bacteria. Traditional antibiotics have more wide-ranging effect, killing both harmful bacteria and useful bacteria such as those facilitating food digestion. The specificity of bacteriophages might reduce the chance that useful bacteria are killed when fighting an infection.
Some evidence shows the ability of phages to travel to a required site—including the brain, where the blood brain barrier can be crossed—and multiply in the presence of an appropriate bacterial host, to combat infections such as meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
. However the patient's immune system can, in some cases mount an immune response to the phage (2 out of 44 patients in a Polish trial).
A few research groups in the West are engineering a broader spectrum phage, and also a variety of forms of MRSA treatments, including impregnated wound dressings, preventative treatment for burn victims, phage-impregnated sutures. Enzobiotics are a new development at Rockefeller University that create enzymes from phage. These show potential for preventing secondary bacterial infections, e.g. pneumonia developing in patients suffering from flu, otitis etc. Purified recombinant phage enzymes can be used as separate antibacterial agents in their own right.
There are no non-toxic antibiotics to treat some bacteria such as multiple-resistant Klebsiella pneumoniae
Klebsiella pneumoniae
Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose fermenting, facultative anaerobic, rod shaped bacterium found in the normal flora of the mouth, skin, and intestines....
, but killing of the bacteria via intraperitoneal, intravenous or intranasal of phages in vivo has been shown to work in laboratory tests.
Collection
The simplest method of phage treatment involves collecting local samples of water likely to contain high quantities of bacteria and bacteriophages, for example effluentEffluent
Effluent is an outflowing of water or gas from a natural body of water, or from a human-made structure.Effluent is defined by the United States Environmental Protection Agency as “wastewater - treated or untreated - that flows out of a treatment plant, sewer, or industrial outfall. Generally refers...
outlets, sewage
Sewage
Sewage is water-carried waste, in solution or suspension, that is intended to be removed from a community. Also known as wastewater, it is more than 99% water and is characterized by volume or rate of flow, physical condition, chemical constituents and the bacteriological organisms that it contains...
and other sources. They can also be extracted from corpses. The samples are taken and applied to the bacteria that are to be destroyed which have been cultured on growth medium.
If the bacteria die, as usually happens, the mixture is centrifuged; the phages collect on the top of the mixture and can be drawn off.
The phage solutions are then tested to see which ones show growth suppression effects (lysogeny) or destruction (lysis) of the target bacteria. The phage showing lysis are then amplified on cultures of the target bacteria, passed through a filter to remove all but the phages, then distributed.
Treatment
Phages are "bacterium-specific" and it is therefore necessary in many cases to take a swab from the patient and culture it prior to treatment. Occasionally, isolation of therapeutic phages can require a few months to complete, but clinics generally keep supplies of phage cocktails for the most common bacterial strains in a geographical area.Phages in practice are applied orally, topically on infected wounds or spread onto surfaces, or used during surgical procedures. Injection is rarely used, avoiding any risks of trace chemical contaminants that may be present from the bacteria amplification stage,and recognizing that the immune system naturally fights against viruses introduced into the bloodstream or lymphatic system.
The direct human use of phages is likely to be very safe; suggestively, in August 2006, the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved spraying meat with phages. The approval was for ListShield (a phage preparation targeted against Listeria monocytogenes) created by Intralytix
Intralytix
Intralytix is a biotechnology company based in Baltimore, Maryland. Intralytix specializes in bacteriophage-based products used to control bacterial pathogens in environmental, food processing, and medical settings.-ListShield:...
. This was the first approval granted by the FDA and UDSA for a phage-based food additive. Although this initially raised concerns since without mandatory labeling consumers will not be aware that meat and poultry products have been treated with the spray, it confirms to the public that, for example, phages against Listeria are generally recognized as safe
Generally recognized as safe
Generally recognized as safe is an American Food and Drug Administration designation that a chemical or substance added to food is considered safe by experts, and so is exempted from the usual Federal Food, Drug, and Cosmetic Act food additive tolerance requirements.-History:On January 1, 1958,...
(GRAS status) within the worldwide scientific community and opens the way for other phages to also be recognized as having GRAS status.
Phage therapy has been attempted for the treatment of a variety of bacterial infections including: laryngitis
Laryngitis
Laryngitis is an inflammation of the larynx. It causes hoarse voice or the complete loss of the voice because of irritation to the vocal folds . Dysphonia is the medical term for a vocal disorder, of which laryngitis is one cause....
, skin infections, dysentery
Dysentery
Dysentery is an inflammatory disorder of the intestine, especially of the colon, that results in severe diarrhea containing mucus and/or blood in the faeces with fever and abdominal pain. If left untreated, dysentery can be fatal.There are differences between dysentery and normal bloody diarrhoea...
, conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...
, periodontitis, gingivitis
Gingivitis
Gingivitis is a term used to describe non-destructive periodontal disease. The most common form of gingivitis is in response to bacterial biofilms adherent to tooth surfaces, termed plaque-induced gingivitis, and is the most common form of periodontal disease...
, sinusitis
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
, urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s and intestinal infections, burns, boils, poly-microbial biofilms on chronic wounds, ulcers and infected surgical sites.
In 2007 a Phase 1/2 clinical trial was completed at the Royal National Throat, Nose and Ear Hospital
Royal National Throat, Nose and Ear Hospital
The Royal National Throat, Nose and Ear Hospital is a hospital located on the Gray's Inn Road, London in the United Kingdom. It is operated by the Royal Free Hampstead NHS Trust....
, London for Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
infections (otitis
Otitis
Otitis is a general term for inflammation or infection of the ear, in both humans and other animals.It is subdivided into the following:*Otitis externa, external otitis, or "swimmer's ear" involves the outer ear and ear canal. In external otitis, the ear hurts when touched or pulled.*Otitis media...
). Documentation of the Phase-1/Phase-2 study was published in August 2009 in the journal Clinical Otolaryngology.
Phase 1 clinical trials have now been completed in the Southwest Regional Wound Care Center, Lubbock, Texas for an approved cocktail of phages against bacteria, including P. aeruginosa, Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
and Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
(better known as E. coli). The cocktail of phages for the clinical trials was developed and supplied by Intralytix
Intralytix
Intralytix is a biotechnology company based in Baltimore, Maryland. Intralytix specializes in bacteriophage-based products used to control bacterial pathogens in environmental, food processing, and medical settings.-ListShield:...
.
Reviews of phage therapy indicate that more clinical and microbiological research is needed to meet current standards.
Distribution
Phages can usually be freeze-dried and turned into pills without materially impacting efficiency. Temperature stability up to 55 °C and shelf lives of 14 months have been shown for some types of phages in pill form.Application in liquid form is possible, stored preferably in refrigerated vials.
Oral administration works better when an antacid is included, as this increases the number of phages surviving passage through the stomach.
Topical administration often involves application to gauzes that are laid on the area to be treated.
General
The high bacterial strain specificity of phage therapy may make it necessary for clinics to make different cocktails for treatment of the same infection or disease because the bacterial components of such diseases may differ from region to region or even person to person.In addition, due to the specificity of individual phages, for a high chance of success, a mixture of phages is often applied. This means that 'banks' containing many different phages must be kept and regularly updated with new phages.
Further, bacteria can evolve different receptors either before or during treatment; this can prevent the phages from completely eradicating the bacteria.
The need for banks of phages makes regulatory testing for safety harder and more expensive. Such a process would make it difficult for large-scale production of phage therapy. Additionally, patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
issues (specifically on living organisms) may complicate distribution for pharmaceutical companies wishing to have exclusive rights over their "invention", making it unlikely that a for-profit corporation
Corporation
A corporation is created under the laws of a state as a separate legal entity that has privileges and liabilities that are distinct from those of its members. There are many different forms of corporations, most of which are used to conduct business. Early corporations were established by charter...
will invest capital in the widespread application of this technology.
As has been known for at least thirty years, mycobacteria
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
such as Mycobacterium tuberculosis have specific bacteriophages. No lytic phage has yet been discovered for Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
, which is responsible for many nosocomial diseases
Nosocomial infection
A nosocomial infection , also known as a hospital-acquired infection or HAI, is an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff...
, but some temperate phages (integrated in the genome) are known for this species, which opens encouraging avenues.
To work, the virus has to reach the site of the bacteria, and viruses do not necessarily reach the same places that antibiotics can reach.
Funding for phage therapy research and clinical trials is generally insufficient and difficult to obtain, since it is a lengthy and complex process to patent bacteriophage products. Scientists comment that 'the biggest hurdle is regulatory', whereas an official view is that individual phages would need proof individually because it would be too complicated to do as a combination, with many variables. Due to the specificity of phages, phage therapy would be most effective with a cocktail injection, which is generally rejected by the U.S. Food and Drug Administration (FDA). Researchers and observers predict that for phage therapy to be successful the FDA must change its regulatory stance on combination drug cocktails. Public awareness and education about phage therapy are generally limited to scientific or independent research rather than mainstream media.
The negative public perception of viruses may also play a role in the reluctance to embrace phage therapy.
Safety
Phage therapy is generally considered safe. As with antibiotic therapy and other methods of countering bacterial infections, endotoxinEndotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s are released by the bacteria as they are destroyed within the patient (Herxheimer reaction
Herxheimer reaction
The Herxheimer reaction resembles bacterial sepsis and can occur after initiation of antibiotic therapy or treatment of tick-borne relapsing fever. An association has been found between the release of heat-stable proteins from spirochetes and the reaction. The same can be true for candida die-off...
). This can cause symptoms of fever, or in extreme cases toxic shock (a problem also seen with antibiotics) is possible. Janakiraman Ramachandran, a former president of AstraZeneca India who 2 years ago launched GangaGen Inc., a phage-therapy start-up in Bangalore, argues that this complication can be avoided in those types of infection where this reaction is likely to occur by using genetically engineered
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
bacteriophages which have had their gene responsible for producing endolysin removed. Without this gene the host bacterium still dies but remains intact because the lysis is disabled. On the other hand this modification stops the exponential growth of phages, so one administered phage means one dead bacterial cell.
Eventually these dead cells are consumed by the normal house-cleaning duties of the phagocytes, which utilise enzymes to break the whole bacterium and its contents down into harmless proteins, polysaccharides and lipids.
Lysogenic
Lysogeny
Lysogeny, or the lysogenic cycle, is one of two methods of viral reproduction . Lysogeny is characterized by integration of the bacteriophage nucleic acid into the host bacterium's genome...
bacteriophages are not generally used therapeutically, as this group can act as a way for bacteria to exchange DNA; this can help spread antibiotic resistance or even, theoretically, make the bacteria pathogenic (see Cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
).
Effectiveness
In Russia, mixed phage preparations may have a therapeutic efficacy of 50%. This equates to the complete cure of 50 of 100 patients with terminal antibiotic-resistant infection. The rate of only 50% is likely to be due to individual choices in admixtures and ineffective diagnosis of the causative agent of infection.Cultural references
- The 1925 novel and 1926 Pulitzer prize winner ArrowsmithArrowsmith (novel)Arrowsmith is a novel by American author and playwright Sinclair Lewis that was published in 1925. It won the 1926 Pulitzer Prize for Lewis but he refused to accept it. Lewis was greatly assisted in its preparation by science writer Dr. Paul de Kruif, who received 25% of the royalties on sales, but...
used phage therapy as a plot point.