Bacteriophage or “phage” are viruses that invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and cause the bacterium to lyse. This form of biotherapy is sometimes called Phage Therapy.
This page describes the following issues:
History of Bacteriophage Therapy
The practice of phage therapy is nearly 100 years old and was discovered independently by both French and English scientists. They realized that phage had the potential to kill the bacteria that caused many infectious diseases in humans, animals, and plants.
In 1896, the British bacteriologist Ernest Hankin reported antibacterial activity (against Vibrio cholerae), which he observed in the Ganges and Jumna rivers in India. He suggested that an unidentified substance (not filterable, heat labile) was responsible for this phenomenon and for limiting the spread of cholera epidemics. Two years later, Gamaleya, the Russian bacteriologist, observed a similar phenomenon while working with Bacillus subtilis.
From 1898 to 1918, others had similar observations of what is thought to be the bacteriophage phenomenon. It was not until 1914, however, that another British bacteriologist, Frederick Twort, advanced the hypothesis by proposing that it may have been due to, among other possibilities, a virus. For various reasons, including financial difficulties, Twort did not pursue this finding.
A French-Canadian microbiologist, Felix d’Herelle, first observed in 1910 the bacteriophage phenomenon while studying microbiologic methods of controlling locusts in Mexico. In the lab, when he spread some cultures on agar, he observed round zones without growth, which he called plaques, and asserted they were caused by viral parasites. Six years later, he proposed the name “bacteriophage,” or bacterium-eater.
In 1917, d’Herelle began testing his phage in human patients. Under the clinical supervision of Professor Victor-Henri Hutinel at the Hospital des Enfants-Malades in Paris, he demonstrated the safety of his phage by ingesting them. The next day, he demonstrated their efficacy by administering them to a 12-year old boy with severe dysentery. The patient’s symptoms ceased after a single treatment, and he made a complete recovery. Dr. d’Herelle’s antidysentery phage was then administered to three additional patients, all of whom began to recover within 24 hours of treatments.
The first reported phage-based clinical trial occurred in France in 1921 by Richard Bruynoghe and Joseph Maisin. They used bacteriophages to treat staphylococcal skin disease by injection the phages into and around surgically opened lesions. The infections regressed within 24 to 48 hours. Over the next ten years, thousands of people were treated with a variety of phage preparations for other infections, including cholera and/or bubonic plague in India. There were also several hundred studies on phage therapy that followed, mostly in Eastern Europe and the former Soviet Union. Unfortunately, many of the older studies are of poor quality (compared to our current research standards) and/or they are not available in English.
In the 1930s and 40s, Dr. d’Herelle began a commercial laboratory in Paris and produced at least five phage preparations against various bacterial infections. In the United States, Eli Lilly Company produced seven therapeutic phage products for human use. However, the efficacy of phage preparations was controversial. Clinical studies were not vigorously pursued in the United States and Western Europe, and what little research there was all but ceased in the 1940s with the availability of penicillin and other commercial antibiotics. d’Herelle’s laboratory ceased production of bacteriophage, although the laboratory still operates today, under the name: L’Oreal.
In recent years, interest in phage therapy has grown, largely fueled by the increasing problem of bacterial antibiotic resistance.
Advantages of Bacteriophage Therapy
Comparison of the prophylactic and/or therapeutic use of phages and antibiotics
Bacteriophages Antibiotics Comments
Very specific (i.e., usually affect only the targeted bacterial species); therefore, dysbiosis and chances of developing secondary infections are avoided.
Antibiotics target both pathogenic microorganisms and normal microflora. This affects the microbial balance in the patient, which may lead to serious secondary infections.
High specificity may be considered to be a disadvantage of phages because the disease-causing bacterium must be identified before phage therapy can be successfully initiated. Antibiotics have a higher probability of being effective than phages when the identity of the etiologic agent has not been determined.
Replicate at the site of infection and are thus available where they are most needed.
They are metabolized and eliminated from the body and do not necessarily concentrate at the site of infection. The “exponential growth” of phages at the site of infection may require less frequent phage administration in order to achieve the optimal therapeutic effect. No serious side effects have been described. Multiple side effects, including intestinal disorders, allergies, and secondary infections (e.g., yeast infections) have been reported. A few minor side effects reported for therapeutic phages may have been due to the liberation of endotoxins from bacteria lysed in vivo by the phages. Such effects also may be observed when antibiotics are used. Phage-resistant bacteria remain susceptible to other phages having a similar target range. Resistance to antibiotics is often class-wide. Multiple antibiotics with similar mechanism of action will become ineffective once resistance develops. Because of their more broad-spectrum activity, antibiotics select for many resistant bacterial species, not just for resistant mutants of the targeted bacteria. Selecting new phages (e.g., against phage-resistant bacteria) is a relatively rapid process that can frequently be accomplished in days or weeks. Developing a new antibiotic (e.g., against antibiotic-resistant bacteria) is a time-consuming process and may take several years. Evolutionary arguments support the idea that active phages can be selected against every antibiotic-resistant or phage-resistant bacterium by the ever-ongoing process of natural selection.
Credit: Phage International
Clinical Use of Bacteriophage Therapy
Phage continue to be used therapeutically in Eastern Europe and in the former Soviet Union. The pharmacokinetics of therapeutic phage preparations is not well understood. After a single dose, phage get into the bloodstream of laboratory animals within two to four hours and into internal organs within approximately ten hours. They insert their viral DNA into the bacterial host cell to produce progeny phage. The progeny burst from the host cell, thereby killing it. Then the young phage proceed to infect more bacteria. Phage can remain in the human body for up to several days. Once the bacterial infection has been eradicated, the phage also dies, leaving no residual virus in the human host.
Phage are often species-specific, infecting only one or a few species of bacteria. They can be isolated from nature, or potentially developed in the laboratory against any bacterial infection. Phage cannot parasitize other viruses.
Phage are considered relatively safe for therapeutic use. Only a few side-effects have been reported.
In the United States and Western Europe, phage therapy is considered investigational. Regulatory authorities have not approved any specific product for any indication. Nevertheless, here is a list of clinical illnesses that have been reportedly treated by phage therapy over the past 100 years (mostly in Eastern Europe), as well as a list of the routes of administration employed.
They have been administered by the following routes:
- orally, in tablet or liquid formulations;
- locally (skin, eye, ear, nasal mucosa, etc.), in tampons, rinses, and creams;
- as aerosols or intrapleural injections;
Bacteria may develop resistance to phage, but this is not viewed as a major problem because it is much easier to develop new phage than new antibiotics. In nature, as bacteria evolve resistance, their phage parasites will co-evolve adaptation. This behavior may be duplicated in the laboratory within a few weeks. Antibiotic discovery and development, on the other hand, may take a decade or two.
Related Topics, Links and References
We direct our readers to the following sites for more information:
We are in the process of assembling a searchable database of bacteriophage therapists. Anyone with interest, knowledge or experience with bacteriophage therapy is encouraged to contact the Foundation to help assemble and/or join this referral list. Researchers recruiting subjects for clinical studies are also encouraged to post their contact information here.