The Safety and Efficacy of Phage Therapy: A Systematic Review of Clinical and Safety Trials

Abstract

Trials of phage therapy have not consistently reported efficacy. This contrasts with promising efficacy rates from a sizeable and compelling body of observational literature. This systematic review explores the reasons why many phage trials have not demonstrated efficacy. Four electronic databases were systematically searched for safety and/or efficacy trials of phage therapy. Sixteen trials of phage therapy were included, in which 378 patients received phage. These were divided into historical (pre-2000; N = 3; n = 76) and modern (post-2000; N = 13; n = 302) trials. All 13 modern trials concluded that phage therapy was safe. Six of the 13 modern trials were exclusively safety trials. Seven modern trials investigated both safety and efficacy; efficacy was observed in two. Two of three historical trials did not comment on safety, while adverse effects in the third likely reflected the use of phage preparations contaminated with bacterial debris. None of the historical trials contained evidence of efficacy. The evidence from trials is that phage therapy is safe. For efficacy to be observed a therapeutic amount of the right phage(s) must be delivered to the right place to treat infections containing enough susceptible bacterial cells. Trials that have not demonstrated efficacy have not fulfilled one or more elements of this principle.

The Future of Clinical Phage Therapy in the United Kingdom

“…However, there is an explainable discrepancy between the efficacy of phage therapy reported by observational and clinical trial data. This is because it is difficult for trials to consistently achieve the “goldilocks constellation” of getting a sufficient quantity of phages with the correct specificity to the site of infection; an in-depth exploration of trial data has been published elsewhere [ 37 ]. Nevertheless, the Antibiotic Resistance Leadership Group in the United States and Healthcare Improvement Scotland have concluded that there is sufficient evidence to consider phage therapy as a treatment option in patients with difficult-to-treat infections [ 38 , 39 ].…”

Managing Patient and Clinician Expectations of Phage Therapy in the United Kingdom

“…The use of phage therapy as an unlicensed medicine is underpinned by a sizeable body of reassuring evidence about the safety and efficacy of phage therapy. For example, there have been 13 safety or clinical trials of phages since the year 2000, all of which have shown phages to be safe by a variety of routes of administration [ 9 ]. Meanwhile, there have been >2200 clinical reports of phage since the year 2000, among which 79% of 1904 patients showed clinical improvement and 87% of 1461 patients achieved bacterial eradication; many of these cases were refractory to antibiotic therapy [ 10 ].…”

“…Meanwhile, there have been >2200 clinical reports of phage since the year 2000, among which 79% of 1904 patients showed clinical improvement and 87% of 1461 patients achieved bacterial eradication; many of these cases were refractory to antibiotic therapy [ 10 ]. Clinical trials meanwhile have not consistently demonstrated efficacy, although this is considered to arise from shortcomings in the trials themselves and not to reflect the mechanistic ability of lytic phages to infect and kill their bacterial hosts [ 9 ].…”

EGFR-targeted bacteriophage lambda penetrates model stromal and colorectal carcinoma tissues, is taken up into carcinoma cells, and interferes with 3-dimensional tumor formation

“…Bacteriophages ('phages') offer an alternative antibacterial strategy to conventional antimicrobial drugs and may be of enhanced value in the current antimicrobial drug-resistant era (44)(45)(46)(47)(48). They may be useful in combination with existing antibacterial agents (46,49).…”