Bacteriophage Clinical Use as Antibacterial “Drugs”: Utility and Precedent

Abstract

For phage therapy-the treatment of bacterial infections using bacterial viruses-a key issue is the conflict between apparent ease of clinical application, on the one hand, and on the other hand, numerous difficulties that can be associated with undertaking preclinical development. These conflicts between achieving efficacy in the real world versus rigorously understanding that efficacy should not be surprising because equivalent conflicts have been observed in applied biology for millennia: exploiting the inherent, holistic tendencies of useful systems, e.g., of dairy cows, inevitably is easier than modeling those systems or maintaining effectiveness while reducing such systems to isolated parts. Trial and error alone, in other words, can be a powerful means toward technological development. Undertaking trial and error-based programs, especially in the clinic, nonetheless is highly dependent on those technologies possessing both inherent safety and intrinsic tendencies toward effectiveness, but in this modern era we tend to forget that ideally there would exist antibacterials which could be thus developed, that is, with tendencies toward both safety and effectiveness, and which are even relatively inexpensive. Consequently, we tend to demand rigor as well as expense of development even to the point of potentially squandering such utility, were it to exist. In this review I lay out evidence that in phage therapy such potential, in fact, does exist. Advancement of phage therapy unquestionably requires effective regulation as well as rigorous demonstration of efficacy, but after nearly 100 years of clinical practice, perhaps not as much emphasis on strictly laboratory-based proof of principle.

Correlation of Host Range Expansion of Therapeutic Bacteriophage Sb-1 with Allele State at a Hypervariable Repeat Locus

“…Recently, phages and their lysins were identified by the National Institute of Allergy and Infectious Diseases (NIAID) as one of the viable alternatives to antibiotic treatment (5). Phages specifically infect and kill target bacteria but leave mammalian cells intact and do not have a detrimental effect on normal microflora; thus, they are considered nontoxic and safe for clinical use (6)(7)(8). Phages have been shown to disperse S. aureus biofilms (9,10) and to provide successful treatment against various experimental and veterinary S. aureus infections, including septicemia (11)(12)(13) and skin infection (14) in mice, tibial implant infection in rats (15), and cutaneous abscesses (16) and biofilm-infected wounds in rabbits (17).…”

Indications and Limitations of Phage Therapy in Human Medicine: Personal Experience and Literature Review

“…But although it is the object of several thousand publications, phage therapy must be reconsidered in the light of new knowledge, often very recent, concerning the bacteriophages. It would be regrettable if innumerable observations were not taken into account [162,163], some of which have been published decades ago and constitute a prime source of information. Further research is needed to better understand the biology of bacteriophages, their behaviour in the natural environment as well as in the human body, as well as the parameters that affect their interactions with their bacterial hosts.…”

Is Genetic Mobilization Considered When Using Bacteriophages in Antimicrobial Therapy?

“…After their discovery in the second decade of the 20th century, the capacity of phages to kill pathogenic bacteria led to their therapeutic application against infectious diseases. However, during the early trials of phage therapy (for an extensive review, see [ 6 ]), several mistakes were made, mostly attributed to insufficient knowledge about the biological nature of phages. Low titers, preparations contaminated with bacterial antigens, or phages with no infectivity for the bacterial target were used [ 7 ].…”

“…The phages were mostly administered by intraperitoneal injection, although subcutaneous injection and oral administration were also used in some cases. Clinical trials have also been performed, mostly against antibiotic-resistant S. aureus and P. aeruginosa (for an extensive review, see [ 6 ]). However, these have been primarily focused on safety rather than efficacy [ 9 ], since safety concerns are still a major hurdle for the development of phage therapy.…”

“…Phages are also self-limiting, multiplying only as long as host bacteria are present, and they have an inherent low toxicity, since they consist exclusively of proteins and DNA [ 13 ]. As clinical trials show, phages are effective against antibiotic-resistant pathogens [ 6 ], indicating a lack of cross-resistance with antibiotics.…”