According to conventional wisdom, if you let children play in the dirt, they get sick less frequently. As is often the case, science appears to back up this homespun theory. Now that many disease-inducing pathogens are developing antibacterial resistance, scientists and medical professionals are looking for answers that may literally be beneath their feet.
Bacteriophages (or “phages”) are viruses that can be found inside plants and animals and in soil, rivers, oceans and even sewers. Phages invade bacterial cells and inject their DNA into the bacterial target. Some phages can disrupt bacterial metabolism and cause the bacterium to disintegrate. The intentional application of phages to destroy bacteria is known as bacteriophage therapy.
Because phages attack bacteria and are strain-specific, they are thought to be harmless to humans. An added benefit of the strain-specific nature of phages is that they do not disrupt the natural flora that are beneficial in the body.
Bacteriophages were discovered independently by Frederick W. Twort in Great Britain (1915) and Félix d’Hérelle in France (1917). Phage use, research and development lapsed in the 1940s when antibiotics became standard treatment for bacterial infections. Interest in phage therapy has resurged in recent years: They are seen as a possible therapy against antibiotic-resistant strains of many pathogenic bacteria (Duckworth and Gulig, 2002).
The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) held a two-day public workshop in July 2017 to exchange information with the medical and scientific community about the regulatory and scientific issues associated with bacteriophage therapy. The workshop brought together government agencies, academia, industry and other stakeholders involved in research, development and regulation of bacteriophages intended for therapeutic use in humans. The goals that the FDA identified for the workshop were to:
- discuss the scientific and regulatory considerations for bacteriophage therapies
- provide a forum for the exchange of information and perspectives
- facilitate development and rigorous clinical assessment of bacteriophage therapy products.
Previously, in September 2014, the White House had released the National Strategy for Combating Antibiotic-Resistant Bacteria. The strategy’s three priorities were to:
- prevent, detect and control outbreaks of resistant pathogens recognized by the Centers for Disease Control and Prevention (CDC) as urgent or serious threats
- ensure continued availability of effective therapies for treatment of bacterial infections
- detect and control newly resistant bacteria that emerge in humans or animals.
Following the release of the 2014 national strategy, the White House issued a five-year National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB). The plan, released in March 2015, outlined interrelated goals for the federal government to address in collaboration with partners in healthcare, public health, veterinary medicine, agriculture, food safety, and academic, federal and industrial research. CARB’s goals included accelerating basic and applied research and development for new antibiotics, other therapeutics and vaccines, and improving international collaboration.
Although bacteriophages are not currently an FDA-approved therapy for humans, the FDA allows so-called compassionate use of phage therapy. At the 2017 workshop, CBER’s Scott Stibitz said that the FDA is committed to facilitating the testing of phage therapy in clinical trials. Clinical trials are currently proceeding under FDA oversight in the investigational new drug (IND) program.
CBER may authorize emergency-use expanded access for single patients within hours of the request. Recent case studies include successful phage therapy treatment against multidrug resistant (MDR) Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa).
Because phage research has been compiled for more than a century, researchers have a breadth of knowledge about phage genome sequences, lifestyle, transduction potential, host range, complementation, frequency of resistance and genetic engineering. The pharmaceutical industry, in turn, holds more than a century of antimicrobial development knowledge and experience in a range of areas, including drug discovery, pharmacokinetic/pharmacodynamic (PK/PD) modeling, toxicology, manufacturing, regulatory issues and clinical trial design.
Stibitz acknowledged that there are novel chemistry, manufacturing and controls (CMC) considerations for bacteriophage products. Bacteriophages are diverse: For most bacterial hosts, there are many phages in the environment and an “inexhaustible” supply of natural products to treat infections, Stibitz said. Yet every bacteriophage/bacterial host pair is unique, so drawing a priori conclusions about their characteristics is problematic, he said.
The specificity of bacteriophage is another consideration in phage therapy. Unlike antibiotic drugs that work in a more generalized manner, phage therapy usually requires identification of the infectious agent prior to treatment. Gene expression and replication are other specificity factors, Stibitz said.
A third consideration is immunogenicity. Mammalian hosts are likely to have an adaptive immune response to bacteriophage, which may limit the length of use or re-use of phages, Stibitz said. Few published studies address immunogenicity, so it is unclear what safety concerns may arise, he said.
Doran Fink of CBER mentioned additional safety considerations for phage therapy. Although phages are directly active only against specific target bacteria and are presumed to be inert with respect to human cells and tissues, researchers will need to determine whether certain human tissues (e.g., airways) might be sensitive to certain components of phage material, Fink said. In clinical trials, phages have been introduced intravenously and directly at the infection site. There can be potential toxic effects of product excipients or impurities (e.g., residual endotoxin) or the device/matrix used to administer the product, he said.
As is the case with other types of medical treatments, FDA licensure of phage therapy products requires demonstration of efficacy, safety, purity, potency and consistency of manufacture. These requirements, Stibitz noted, are not likely to hinder the approval of sponsors’ products.
Stibitz added that regulatory officials, scientists and product developers have shared goals and need to work together. “Communication is vital” through the phage therapy development process, Stibitz said. Through efforts such as the 2017 workshop, members of the regulatory community, industry and science show that they are interested in bridging these gaps to add phage therapy to the medical toolkit.
- Duckworth D, Gulig P. Bacteriophages: potential treatment for bacterial infections. BioDrugs. 2002; 16(1):57-62.
- The White House National Strategy for Combating Antibiotic-Resistant Bacteria, September 18, 2014. Available at: https://obamawhitehouse.archives.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
- The White House National Action Plan for Combating Antibiotic-Resistant Bacteria, March 2015. Available at: https://www.cdc.gov/drugresistance/pdf/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
Editor’s Note: This article was originally published in the Journal for Clinical Studies.
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