Clinical Indications and Compassionate Use of Phage Therapy: Personal Experience and Literature Review with a Focus on Osteoarticular Infections

Abstract

The history of phage therapy started with its first clinical application in 1919 and continues its development to this day. Phages continue to lack any market approval in Western medicine as a recognized drug, but are increasingly used as an experimental therapy for the compassionate treatment of patients experiencing antibiotic failure. The few formal experimental phage clinical trials that have been completed to date have produced inconclusive results on the efficacy of phage therapy, which contradicts the many successful treatment outcomes observed in historical accounts and recent individual case reports. It would therefore be wise to identify why such a discordance exists between trials and compassionate use in order to better develop future phage treatment and clinical applications. The multitude of observations reported over the years in the literature constitutes an invaluable experience, and we add to this by presenting a number of cases of patients treated compassionately with phages throughout the past decade with a focus on osteoarticular infections. Additionally, an abundance of scientific literature into phage-related areas is transforming our knowledge base, creating a greater understanding that should be applied for future clinical applications. Due to the increasing number of treatment failures anticipatedfrom the perspective of a possible post-antibiotic era, we believe that the introduction of bacteriophages into the therapeutic arsenal seems a scientifically sound and eminently practicable consideration today as a substitute or adjuvant to antibiotic therapy.

Therapeutic bacteriophages as a rescue treatment for drug‐resistant infections – anin vivostudies overview

“…Clinical improvement was observed in 92% of bacteriophages-treated patients. Bacteria were eliminated from the urine in 84% of patients (Perepanova et al 1995). Unfortunately, clinical trials conducted in Eastern Europe are poorly documented, and some reports are available in Russian or Georgian only (Chanishvili et al 2001).…”

Phage therapy for severe bacterial infections: a narrative review

“…However, after a century of use, there is increasing demand for rigorous evaluation of phage therapy, including in the most severe infections . There are case series with generally good outcomes, particularly in osteoarticular infections, diabetic foot infections, and chronic prostatitis . Two reviews detail the history of phage therapy in Russia and Eastern European countries and its application in specific human infections, a 2012 article provides a historical review of phage therapy over the years, and comprehensive up‐to‐date reviews are now also available …”

Implications of Bacteriophage- and Bacteriophage Component-Based Therapies for the Clinical Microbiology Laboratory

“…Case studies of phage therapy continue to be added to the published literature (Table 1). Patey et al note that the generally positive results reported from isolated applications stand in contrast to the negative results of some clinical trials ( Table 2) (42). The routes of phage administration and dosing intervals, as well as the diversity of target bacteria and infection types, portend that the investigational use of phage therapy will likely continue for some time in the United States.…”

“…Phages may be used as a complementary approach to currently available antimicrobial strategies rather than a replacement (42). As viruses, they and their components may be recognized by the immune system and eliminated via innate and/or adaptive defenses before reaching sites of infection, and their use may also compromise the future use of similar species in the same patient.…”

“…How phage therapy would be regulated in the United States is presently unclear, with some questioning whether this can be done within the existing drug and device approval infrastructure of the U.S. Food and Drug Administration, founded on the concept of drugs as small molecules of fixed composition (42,44,45). Subjecting the production and oversight of therapeutic phage to current good manufacturing practice and evaluation within conventional randomized clinical trials will be associated with significant cost and incite process development inefficiencies (e.g., in a phage cocktail, each phage as well as the final cocktail may require FDA approval; the composition of off-the-shelf phage products might require updating at regular intervals to avoid resistance and to maintain clinical relevance to current pathogens), culminating in approval delays (42,44,46,47). Some countries in which phages are used therapeutically operate under different regulatory guidelines; for example, Belgium uses magistral preparations, the adoption of which some favor on a broader scale (27,46).…”