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, 49 bacteriophages 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. Abd El-Aziz, A.M., Elgaml, A., and Ali, Y.M. (2019). Bacteriophage therapy increases complement-mediated lysis of bacteria and enhances bacterial clearance after acute lung infection with multidrug-resistant Pseudomonas aeruginosa.

Complete Genome Sequences of Novel Bovine T4, rv5-Like, and Dhillonviruses Effective against Escherichia coli O157

“…The role of bacteriophages as alternative antimicrobial agents has gained renewed interest in the past years ( 1 ). Enterohemorrhagic Escherichia coli (EHEC) strains, particularly of the O157:H7 serotype, are serious foodborne zoonotic pathogens, and several phages which show effective lysis of these have previously been characterized ( 2 , 3 ).…”

Improving Phage-Biofilm In Vitro Experimentation

“…As a consequence, there can be no means of knowing how long initial phage doses are retained, whether phage numbers decline over time, or instead whether phage numbers increase in the course of phage in situ propagation ( Figure 3 ). In clinical settings, declines in concentrations of antibacterials found in association with targeted bacteria would suggest a need for drug re-application, and in clinical practice phages often are delivered not as only a single dose per treatment [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Thus, measuring phage titers over time, minimally such as at time zero in combination with end-point determinations, can be relevant to translating phage treatments of biofilm from in vitro or in vivo experimentation to clinical settings, or otherwise toward better appreciation of the ecology of phage-biofilm interactions.…”

“…Note that in either case, at least in terms of phage treatments of in vitro biofilms, we can avoid these complications by starting with relatively high phage numbers, e.g., 10 7 PFU/mL or ideally [ 75 ] even higher. That is, when phages are applied to biofilms in higher numbers, then there should be less concern about the buildup of phage numbers around biofilms by means other than due to dosing or due to phage propagation within biofilms.…”

“…Even if conditions are well matched between in situ and in vitro conditions, there can still be differences in biofilm properties that are a function simply of the duration of biofilm growth prior to phage application [ 163 ]. Indeed, this can occur in situ as well, perhaps most notably with distinctions in the characteristics of acute vs. chronic bacterial infections, which can also be a challenge to distinguish in terms of in vivo infection models [ 30 , 75 ]. Above all, we caution against assumptions of equivalence between in vitro-grown biofilms and those grown in situ, as well as in situ vs. ex situ phage treatments, unless such equivalence has been rigorously demonstrated.…”

Determination of the drug Fagomast effectiveness with different titers of Phage SAvB14

“…Однак перешкодами активного типу може бути те, що бактерії, які наявні в природному середовищі можуть бути менш фізіологічно активними та не підтримувати ті розміри фагових вибухів, які є в лабораторних умовах [14,15]. Водночас зміни у фізіології бактерій або зміни в експресії бактеріальних генів у відповідь на вплив зовнішніх чинників можуть зменшувати кількість молекул рецепторів на поверхні бактеріальної клітини, необхідних для адсорбції фагів [16,17]. Крім того не всі бактеріальні штами здатні підтримувати великі розміри вибуху або швидку адсорбцію віріонів.…”