Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?

Abstract

Bacteria can evolve resistance to antibiotics. Even without changing genetically, bacteria also can display tolerance to antibiotic treatments. Many antibiotics are also broadly acting, as can result in excessive modifications of body microbiomes. Particularly for antibiotics of last resort or in treating extremely ill patients, antibiotics furthermore can display excessive toxicities. Antibiotics nevertheless remain the standard of care for bacterial infections, and rightly so given their long track records of both antibacterial efficacy and infrequency of severe side effects. Antibiotics do not successfully cure all treated bacterial infections, however, thereby providing a utility to alternative antibacterial approaches. One such approach is the use of bacteriophages, the viruses of bacteria. This nearly 100-year-old bactericidal, anti-infection technology can be effective against antibiotic-resistant or -tolerant bacteria, including bacterial biofilms and persister cells. Ideally phages could be used in combination with standard antibiotics while retaining their anti-bacterial pharmacodynamic activity, this despite antibiotics interfering with aspects of bacterial metabolism that are also required for full phage infection activity. Here I examine the literature of pre-clinical phage-antibiotic combination treatments, with emphasis on antibiotic-susceptible bacterial targets. I review evidence of antibiotic interference with phage infection activity along with its converse: phage antibacterial functioning despite antibiotic presence.

Keywords: bactericidal; bacteriolytic; bacteriophage therapy; phage productive; phage therapy; productive infection; virion productive.

Figure 1

Progression of phage life cycles (top to bottom) and illustration of different phage therapy strategies (left to right) as requiring different degrees of phage infection activity. All terms refer to phage activities rather than antibiotic activities, including phage killing of bacteria (bactericidal), phage lysing of bacteria (bacteriolytic), and phage-infection generation and release of new virion particles (production). Boxes indicate key phage infection activities for a given strategy. Arrows indicate phage infection progressions from top to bottom, i.e., from bacterial adsorption, to bacterial infection, to bacteria killing, to lysing of bacteria, and then to release of new virions (production). Graying of arrows indicates a lack of requirement for this progression (dashed gray arrows) or lack of strict requirement (solid gray arrows) for a given phage therapy strategy (which are named across the top row). Passive treatment (first column) uses bacteria-overwhelming (inundative) phage dosing and thus requires only bactericidal activity from phage infections rather than necessarily also bacterial lysis or virion production. Active treatment (third column) does not use bacteria-overwhelming phage dosing so does require in situ phage virion production, often in substantial amounts. Active penetration (second column, but not otherwise discussed in the main text) is hypothesized as being involved in phage anti-biofilm activity and as being aided by phage bacteriolytic activity; it does not necessarily also require phage virion production. (Mixed) Passive-active treatment (fourth column, and also not otherwise discussed in the main text) is passive treatment that is hypothesized to be aided in its antibacterial activity by increases in phage numbers due to in situ phage virion production (solid gray arrows), which is unlike strictly passive treatments, which by definition do not necessarily involve such activities [94]. See Abedon and Thomas-Abedon [95] and Abedon [96,97] for review and further discussion. This figure is a modification of that presented in Abedon [97].