Phage Therapy: The Pharmacology of Antibacterial Viruses

Abstract

Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug's impact on the body while pharmacokinetics describes the body's impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or 'phages') that we consider here are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial 'drugs', allow for more rational post hoc debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, caister.com/cimb 81 Curr. Issues Mol. Biol. Vol. 40bacteriophages also can amplify phage numbers, in situ. Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects.

Phage Therapy in the 21st Century: Is There Modern, Clinical Evidence of Phage-Mediated Efficacy?

“…Cultures taken at 8 months were negative for the targeted bacteria, though the authors note that (p. 2018) "it is too early to know whether the infection has resolved completely." Though numbers of phages supplied in this case were fairly low for intravenous delivery [22], the infections targeted were localized. Therefore, it is certainly possible that phage replication in association with infecting bacteria could have made up for this delivered phage-titer deficit [119].…”

“…Phage treatments generally are thought to be more effective against newer, acute bacterial infections, e.g., when phage treatments are initiated days rather than months after the start of infections or indeed prophylactically [22], and this preference presumably stems from target bacteria not having yet entered into more phage-resistant physical or physiological states (e.g., [23]). In practice, however, published clinical treatments are typically of chronic or persistent bacterial infections [24], and particularly infections which antibiotic treatments have failed to cure [25][26][27][28].…”

Clinical Pharmacology of Bacteriophage Therapy: A Focus on Multidrug-Resistant Pseudomonas aeruginosa Infections

“…It has also been shown that penetration to the bladder by Gram-negative phages, such as the T2 phage, is dose-dependent, and a minimum of 10 9 PFU/mL is needed for phage detection in the urine of mice after IV administration [89]. In addition, phage concentration in plasma was dependent on both dose and the route of administration, as explained previously [90,91].…”

Isolation and Characterization of Group III Campylobacter jejuni–Specific Bacteriophages From Germany and Their Suitability for Use in Food Production

“…The growth of two C. jejuni field strains, Cj18 or LH86, with and without exposure to four different Campylobacter bacteriophages vB_CjM-LmqsCP1-4 (CP1-4), vB_CjM-LmqsCP1-5 (CP1-5), vB_CjM-LmqsCP74-2c1 (CP74-2c1), and vB_CjM-LmqsCP132-3c (CP132-3c) at five different multiplicities of infection (MOI input of 10, 1, 0.1, 0.01, and 0.001) ( Danis-Wlodarczyk et al, 2021 ) was examined in liquid cultures using a Tecan Spark Microplate Reader with O 2 and CO 2 control, similar to methods described by Xie et al (2018) ; Rajnovic et al (2019) , and Zachary et al (2020) with some modifications. Briefly, phage suspensions were adjusted to 10 8 , 10 7 , 10 6 , 10 5 , and 10 4 PFU/ml, which were further diluted 10-fold with CBHI to achieve final dilutions of 10 7 , 10 6 , 10 5 , 10 4 , and 10 3 PFU/ml.…”