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

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  • Author: Stephen T. Abedon1
  • Editors: Robert Allen Britton2, Patrice D. Cani3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology, The Ohio State University, Mansfield, OH 44906; 2: Baylor College of Medicine, Houston, TX; 3: Université catholique de Louvain, Brussels, Belgium
  • Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0003-2016
  • Received 09 December 2016 Accepted 25 January 2017 Published 25 August 2017
  • Stephen T. Abedon, abedon.1@osu.edu
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  • 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.

  • Citation: Abedon S. 2017. Bacteriophage Clinical Use as Antibacterial “Drugs”: Utility and Precedent. Microbiol Spectrum 5(4):BAD-0003-2016. doi:10.1128/microbiolspec.BAD-0003-2016.

Key Concept Ranking

Urinary Tract Infections
0.41148105
Humoral Immune Response
0.4079641
0.41148105

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/content/journal/microbiolspec/10.1128/microbiolspec.BAD-0003-2016
2017-08-25
2017-09-23

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.

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FIGURE 1

Prevalence of use of the phrase “phage therapy” in the literature. Google Scholar searches were performed without “include patents” or “include citations” checked. Shown are searches on “phage therapy” (in quotation marks, ●), “antibiotic resistant” OR “antibiotic resistance” (as written, ○), “bacteriophage” (▼), and “microbiology” (△). To limit presentation of spurious results, the axis begins at four hits. Results and discussion: ●: “phage therapy” as a phrase is present to a small degree during the skepticism period (early 1930s through mid 1940s) and just prior to the recent revival (mid 1980s through mid to late 1990s) but then displays what appears to be renewed enthusiasm leading up to 2001. Starting from 2003 there then is a steady if less steep climb with a doubling approximately every 4 years. Relative lack of use especially prior to 1950 could reflect the popularity of alternative phrasing for “phage therapy,” including in non-English publications, though this possibility was not explored. ○: Reference to antibiotic resistance goes through an initial spurt beginning around 1950 and peaking in about 1960. This is followed by a nadir in 1963 and then a steady if less steep rise with a doubling approximately every 7 years. The presented curve first comes to exceed that of “bacteriophage” in 2005. ▼: Reference to the word “bacteriophage” likely is less representative early on due to non-English publications. Nevertheless, again there is early enthusiasm that is discernible starting around 1920 and peaking in the early 1930s. This is followed by a slow decline that levels out during 1943 through 1945, i.e., toward the end of World War II. A steady climb follows that parallels the rise in the use of the term “microbiology,” as indeed, so does the rise in reference to antibiotic resistance, but which to a degree plateaus for “bacteriophage” around 1990. Though not explored here, it can be speculated that the slower increase in use of “bacteriophage” starting in 1990 is a consequence of a greater prominence of the use of “phage” instead in publications, though alternatively, this switch may reflect a real decline in the rate of growth of the field; for additional data on the prevalence of bacteriophage publications, see reference 205 . △: Reference to “microbiology” is presented as a general growth-in-the-literature control. The peak in 2007 and subsequent steady, ultimately multifold decline in its use is inexplicable, but similar drops are also seen with searches on “biology,” “chemistry,” “physics,” and “physiology” (not shown), so this likely reflects indexing lags by Google.

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0003-2016
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TABLE 1

Modern clinical or human experimental phage therapy (English-language literature)

Source: microbiolspec August 2017 vol. 5 no. 4 doi:10.1128/microbiolspec.BAD-0003-2016

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