Phages, formally called bacteriophages — the most abundant, ubiquitous organisms in nature — are viruses that infect, replicate in, and destroy bacteria. These viruses are species-specific, and sometimes infect only certain strains within a bacterial species. Phages were discovered in 1915, and were studied as treatments for bacterial infections prior to the discovery of antibiotics in 1928. Widespread and incorrect use of antibiotics in modern medicine has led to bacteria developing mechanisms of resistance against these drugs. The Centers for Disease Control and Prevention (CDC) has defined multidrug-resistant organisms (MDROs), for epidemiologic purposes, as “microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents [antibiotics]”. (Siegel et al., 2007) Therefore, new alternative treatments for bacterial infections in humans are needed.

Several factors support phages being viable and improved treatments against multidrug-resistant (MDR) bacterial infections. Among the major advantages, phages do not infect human cells. Unlike antibiotics, these viruses attack only specific targets (bacteria) and do not harm “good” or “healthy” bacteria. Since humans are in contact with phages daily, relatively few side effects are associated with phage therapy. Because these viruses are found everywhere, phages can be isolated and developed into therapies in a much shorter time than it takes to develop an antibiotic. The use of phages in food preservation has already been found to be safe. Phages and phage cocktails (mixtures of multiple phages) have been approved by the U.S. Food and Drug Administration (FDA) to combat certain types of bacteria in the food processing industry. In addition to their antibacterial activities, phages also have strong anti-inflammatory properties that may enable them to limit inflammation caused by bacterial infections.

Along with the advantages, there are some potential limitations of phage therapy that need consideration. Mechanisms of resistance against phages have been found in bacteria. Since phages attack only specific species or strains of bacteria, the exact host bacterium must be identified when preparing a phage treatment. This may be a difficult task if phage therapies are being designed to combat highly diverse bacterial variants. Phages may potentially transfer antibiotic-resistance genes or bacterial virulence factors from one bacterium to another. The immune system may perceive phages as invaders, leading to their removal. When phages rapidly lyse bacteria, i.e., rupture the bacterial cell walls, endotoxins and super antigens may be released, triggering an inflammatory response that results in multiple organ failure. However, as Taati Moghadam et al. (2020) state: “In spite of these undesirable properties, applying phages for the treatment of resistant bacteria is still a very good alternative, because their therapeutic effects have been approved in several studies. So, it can be considered as a good treatment option for resistant infections, because it may be the only option available for rescuing patients.”

The ability of phages to effectively combat and destroy MDR bacteria in humans has already been demonstrated. In March 2016, Tom Patterson, PhD, a professor of psychiatry at the University of California San Diego (UCSD) School of Medicine, was successfully treated with intravenous (IV) phage therapy for an MDR strain of Acinetobacter baumannii. This was the first known case of a person in the U.S. being successfully treated with IV phage therapeutics. In 2019, USCD received approval from the FDA for the first U.S. clinical trial of an IV phage therapy to combat and destroy drug-resistant bacteria. This clinical trial is limited to patients who have ventricular assist devices (VADs) infected by resistant Staphylococcus aureus (S. aureus), and will assess the efficacy of phage therapy in combination with antibiotic therapy.

In the last 15 years, phage therapy has been administered to patients in France, Belgium, and Poland in cases where no existing therapeutic agents provided a cure. Currently, an approved phage based product (Stafal®) intended as a topical treatment for Staphylococcus infections is being marketed in the European Union. In the U.S., outside the one available clinical trial, phage therapy may be made available to patients under “Compassionate Use” regulations. [21 CFR § 312.310 et seq.] Under 21 CFR 312.310, patients with “serious or immediately life-threatening” conditions may receive experimental treatments if the potential benefit outweighs the potential risk to the patient and the potential risks are not unreasonable.

Despite being discovered almost a century ago, phages are not readily available treatment alternatives for patients with bacterial infections. Currently, there are no FDA approved phage treatments available, and there are no explicit regulatory guidelines for phage therapies and phage based therapeutic formulations. Naureen et al. (2020) suggest: “There are several reasons that pose regulatory barriers to the worldwide production and application of phages as alternatives to or at least as supplementary applications to antibiotics. The first and foremost is the lack of awareness and knowledge about phage therapy due to lack of supporting data obtained from clinical trials set up according to national and international ethical standards.”

A major impediment to the development of phage based therapies is the cost of development of those therapies and the unclear ability to protect intellectual property associated with such therapies. The development of new therapies typically is a multi-year process costing potentially billions of dollars. New drugs with unique chemical compositions can be patented. However, naturally occurring live organisms — like phages — have generally been denied patents. In Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), the U.S. Supreme Court held that naturally occurring DNA sequences could not be patented (but DNA manipulated in a lab could be patented). Consequently, companies seeking to develop phage based therapies would likely have to do some manipulation of phage DNA in order to patent them.

Despite the impediments to commercial development and the regulatory framework that would have to be navigated, phage based therapies remain an untapped treasure trove of treatment options for drug-resistant bacterial infections.