Traditionally, bacterial infections are met with routine antibiotics. As long as the patient follows the directions on the bottle, symptoms resolve, right? Not anymore. The emergence of antibiotic-resistant strains, or “super bugs,” has already rendered some diseases untreatable by standard prescriptions. A report from the World Health Organization in September sounded the alarm: due to rampant resistance, antibiotics are running out. Based on our previous track record in dealing with resistance, the technological cornucopia of pharmacology will pump out new, more powerful drugs. But there are no indications, that this trend will be able to continue, especially with the emergence of strains of gonorrhea, tuberculosis, and methicillin-resistant Staphylococcus aureus (MRSA) resistant to everything we throw at them. Thus, we must look for alternatives. Recently, phage therapy (PT), the use of viruses to treat infections, has caught the eye of concerned scientists, searching for the penicillin of the 21st century. Although the technology is still primitive, phage therapy may evolve into the antibiotic successor, without fear of resistance.
Antibiotic resistance emerges as a result of microevolution. The high rate of DNA mutations affords bacterial colonies massive genetic variability. Imagine it as a microbial melting pot. Occasionally, some mutations confer resistance. While antibiotic-sensitive bacteria die, resistant strains survive and propagate. Genetic mutations travel horizontally within generations as well. Bacteria exchange advantageous DNA molecules with other individuals through a process known as conjugation. Drugmakers haven’t been able to keep up. As current antibiotics continue to lose potency against evolving strains, many companies have abandoned antibiotics in favor of more profitable disease R&D. Doctors internationally are preparing for a fast-approaching crisis, wherein small infections gain treacherous lethality—the WHO went on to state: “The world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill.”
As mentioned previously, phage therapy takes advantage of viruses to eliminate and control bacterial infections. These bacteria-specific viruses, known as bacteriophages or phages for short, typically undergo the lytic cycle, which resolves in cell death of the host. Invading phages will attach to and penetrate the cell surface, injecting their viral genome—which serves to hijack organelles for the virus’ own reproduction. Necessary materials are biosynthesized and assembled into immature viruses. After maturation, the virions burst out of the host. This mass release induces cell death or lysis (hence the cycle name), obliterating the host’s biotic and pathogenic potential. In PT, cocktails of phages can be delivered to environmental and biological media such as human and animal bloodstreams, local infection sites, manure piles, corroded pipes, etc., to eradicate infectious agents and contaminators.
In principle, the technology lots of potential that scientists need to realize. However, historical phage therapy has a track record of stagnant development. The technique originated in early 20th century Tbilisi, Georgia and Eastern Europe with moderate success, but Western scientists largely dismissed Georgian findings as highly variable and unpredictable. Language and technological barriers further widened during the Cold War; science developed independently on either side of the Iron Curtain with little communication. As a result, PT progressed slowly, even stifled, eventually cast aside by Alexander Fleming’s miracle of penicillin. It’s only the recent antibiotic crisis that has brought PT back into scientific limelight. Many scientists now seek to reevaluate phage therapy in the context of modern medical technology.
With modern techniques, phage therapy has many potential benefits. If antibiotics are comparable to the widespread, devastating chemotherapy of infections, then PT is the controlled, highly specific radiotherapy equivalent. Where broad-spectrum antibiotics might deprive your body of beneficial bacteria en masse, cocktail phages tailored to pathogenic hosts leave friendlies unharmed, lowering the risk of secondary infections like yeast infections.
In addition, scientists in the Polish journal Postepy Hig Med Dosw concluded that antibiotics could be up to 400% more expensive than potential phage therapy treatment for specific infections!
MRSA, a particularly lethal strain that spreads rapidly in healthcare settings, phage therapy has recently demonstrated efficacy. In a 2011 study, Georgian scientists evaluated the lytic activity of bacteriophage Sb-1 against various isolates of S. aureus, including MRSA. Although “antibiotic resistance levels ranged from 7.2% to 99.7%,” <2% of isolates were resistant to Sb-1! In the case study, a seven-year-old with chronic colonization of S. aureus in her lungs partook in successful PT treatment. The patient received doses of Sb-1 phage cocktails via nebulizer and was monitored for a period of months. Kvachadze et al. concluded: “the amount of S. aureus drastically decreased and during a medication-free month, the level of S. aureus remained fairly low.” What’s additionally remarkable is that while strong antibiotics come with a host of adverse/side effects, this PT patient exhibited none.
These findings were corroborated by Takemura-Uchiyama et al., who similarly performed effective PT MRSA lysis in lung-derived sepsis. The study utilized the biomarker IL-6, an inflammatory protein, whose concentration positively correlates to infection severity. Mice treated with phage S13′ displayed significantly lower IL-6 levels.
Beyond MRSA, treatments for resistant and pervasive strains of C. difficile, gonorrhea, Salmonella, pneumonia, etc. become worthy targets. Newer nonhuman PT studies have previously confirmed the clinical potential against these infections. In cases like tuberculosis with about 250,000 cases per year according to the CDC, phage therapy could save thousands. Consequently, there is now significant ground to be gained against resistant threats.
But these early successes do not necessarily translate into practical effectiveness, at least not yet. Perhaps the tallest hurdle is public acceptance. It is unlikely that most would be willing to receive repeated doses of self-replicating, highly-mutative, and lytic entities. And since phages are indeed viruses, (although phage is the more specific term) laypeople may succumb to the same fears preyed on by the antivaccination movement, resulting in mass avoidance of this intervention. Thankfully, many PT candidates are genetically screened for safety; bacteriophage Sb-1 as described above possesses a genome lacking human virulence traits.
Research has picked up in the last two decades but lacks the economic incentive to accelerate progress. Biotech companies cannot exclusively commercialize or patent a naturally-occurring phage. However, with the advent of new gene editing technologies like CRISPR, designing unique, patentable phage therapy solutions becomes a possibility. One such engineered phage reduced bacterial structures crucial to colonization known as biofilms up to 99.997%!
In addition, phage selection, isolation, and purification prove considerable challenges to developing new therapeutic treatment options. Each type of infection (parameters being species, infection site, patient background, etc.) may require personalized phage cocktails, but therapy has yet to be greatly optimized. Mattila et al. proposed a novel on-demand method of phage isolation and selection for various strains of bacteria but found difficulty in isolating MRSA-targeting phages. These processes, in particular, require refinement before PT be considered for extensive clinical practice.
This doesn’t necessarily mean phage therapy is in a state of immovable infancy. Right now, scientists just need additional information before subsequent R&D endeavors and clinical trials come to prevalence. Sponsored by pharmaceutical companies and the European Commission (a division of the European Union), Phagoburn, one of the largest phage therapy trials to date, launched in 2015 and is underway to study treatment of burn wounds infected with P. aeruginosa and E. coli. Clearly, there is great scientific interest in phage therapy. If found effective in Phagoburn, PT would be further solidified as crucial to the future of global health in the post-antibiotics era. Phagoburn success may motivate R&D groups to fast-track new proposals with the goal of pumping out lucrative and curative solutions. Keep in mind that this is speculative. In the most realistic scenario, antibiotics and phage therapy coexist as infection treatments. Perhaps this may inspire new interventions, incorporating both techniques. One study has already demonstrated that phage therapy and antibiotics delivered together can potentially clear infections and reduce virulence. However, this combined treatment strategy in the context of proportional doses and in other strains and species is yet to be conclusively evaluated. A new door is opening in science—presently that opening is small, but it is widening. Current phage therapy is a long way from widespread medical applicability, but to disregard it as scientists have in the past is to waive one of the most promising anti-infectives since early antibiotics. Arriving at eventual clinical success could shift the 20th century penicillin-dominated treatment paradigm into the new virus-centered 21st. For now, only time will tell.
Editor: Maria ‘Stefi’ Ticsa