Clinical trials of the first phage-based antibacterial to be evaluated under rigorous US standards were on schedule to start as planned by the end of 2016 when this article went to press. When used in combination with antibiotics, the new treatment is expected to significantly limit the danger that resistant bacteria pose to individual patients, as well as decrease the incidence of resistance in the general population.
“The unabated rise of antimicrobial resistance is one of the greatest challenges that society faces,” Luke McNally and Sam Brown, of the University of Edinburgh and the Georgia Institute of Technology, respectively, write in the 9 September 2016 issue of Science. The scale of the problem, they say, is illustrated by the results of a recent MEGA-plate (a large dish constructed so that bacteria can evolve and spread as they would in a natural or clinical setting) experiment in which Escherichia coli became 10,000 times more resistant to trimethoprim and 100,000 times more resistant to ciprofloxacin in about 10 days. The cells accomplished this by overcoming increasing antibiotic concentrations in a step-by-step fashion.
The Centers for Disease Control and Prevention reports that at least 2 million people become infected with antibiotic-resistant bacteria in the United States each year and that an estimated 23,000 of the infected patients die as a direct result. As antibiotic-resistant pathogens continue to make even our “last resort” antibiotics obsolete, experts are looking for alterative ways to fight back.
As long as sufficient easily developed, easy-to-use, effective, and safe broad-spectrum antibiotics were readily available, bacteria-killing viruses were largely neglected. Researchers increasingly view these viruses as a promising therapeutic option.
Phage (short for bacteriophage) are viruses that replicate in bacteria, killing them in the process. It has been more than 100 years since they were first described by Frederick Twort in 1915, but phage have never achieved even a small fraction of their therapeutic potential. That seems about to change.
Here in the United States, a small group of scientists led by the Rockefeller University's Vince Fischetti is isolating phage enzymes called lysins that are used by the viruses to cleave peptidoglycan bonds from the inside of Gram-positive bacteria, lyse (destroy) the cell, and let their viral progeny out. “Adding lysins from the outside has the same lytic effect that, among other things, lets antibiotics in so they can do their jobs more efficiently,” explains Fischetti.
One such enzyme, a lysin called ContraFect-301 (CF-301), targeted against Staphylococcus aureus, has just completed its phase-one safety trial in healthy volunteers. Patient recruiting for a phase-two study evaluating efficacy in patients with S. aureus bacteremia began this past December, according to ContraFect's Paul Boni. (ContraFect is the licensing company taking lysins through the clinical trials to approval and release.)
Preclinical studies showed that CF-301 has potent and rapid lytic effects against its S. aureus targets, including the feared methicillin-resistant (MRSA) varieties. Furthermore, CF-301 disrupts the biofilms within which S. aureus might be hiding and has also proved synergistic with the standard-of-care antibiotics vancomycin and daptomycin.
Interestingly, the immune systems of animals, whether fish, corals, or humans, have partnered with phage at every opening to the outside world, where they attach to scaffolding in mucus ready to attack incoming bacteria. “Thus, the animal host is protected from infection, and the viruses have a steady supply of bacteria in which to reproduce,” notes Jeremy Barr, of Monash University in Australia, who discovered this ancient symbiotic relationship.
Phage therapy is already used to treat patients in Eastern Europe, but reliable clinical studies are lacking. This is why the European Commission is funding what was planned as two 3-year trials of topical phage cocktails for infected burn patients: one against E. coli and the other against Pseudomonas aeruginosa.
The project, called “PhagoBurn,” was begun in 2013, and its ambitious combined phase-one and -two clinical investigations were supposed to yield their first results this past summer, but all did not go as planned.
For example, 12 months were budgeted to establish good manufacturing practices, but it took almost twice as long because the addition of each new phage took considerably more time than had been anticipated. Enrollment was also a problem, and the E. coli arm of the study had to be dropped because there were too few eligible patients.
To put this in perspective, it took 3 years and a world war to ready penicillin for human use. However, that 3-year investment has paid off in 75 years of protection against a range of formerly deadly diseases. It seems about time to move on and, perhaps, even save penicillin in the process.