Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization

Abstract

Pulmonary bacterial infections present a significant health risk to those with chronic respiratory diseases (CRDs) including cystic fibrosis (CF) and chronic-obstructive pulmonary disease (COPD). With the emergence of antimicrobial resistance (AMR), novel therapeutics are desperately needed to combat the emergence of resistant superbugs. Phage therapy is one possible alternative or adjunct to current antibiotics with activity against antimicrobial-resistant pathogens. How phages are administered will depend on the site of infection. For respiratory infections, a number of factors must be considered to deliver active phages to sites deep within the lung. The inhalation of phages via nebulization is a promising method of delivery to distal lung sites; however, it has been shown to result in a loss of phage viability. Although preliminary studies have assessed the use of nebulization for phage therapy both in vitro and in vivo, the factors that determine phage stability during nebulized delivery have yet to be characterized. This review summarizes current findings on the formulation and stability of liquid phage formulations designed for nebulization, providing insights to maximize phage stability and bactericidal activity via this delivery method.

Keywords: aerosolized delivery; antimicrobial resistance; bacteriophages; nebulization; respiratory infections.

Figure 1

Devices used for liquid aerosolization of phages. Diagrams represent the general principle of phage delivery using: (A) Compression/jet nebulization, (B) Ultrasonic nebulization, (C) Vibrating mesh nebulization, (D) Static mesh nebulization.

Figure 2

Timeline of aerosolized phage delivery to sites in the lower respiratory tract. Various points (A–D) along the timeline of aerosolized phage delivery highlight where phage volume and/or titer may be reduced; (A): Titer reduction due to instability during storage. (B): Mechanical stress destroys phage particles during nebulization. (C): Secondary deposition in the upper respiratory tract and in extra-thoracic regions. (D): In vivo phage clearance by the host, e.g., anti-phage immune response and mucociliary clearance. Y-axis is a demonstrative hypothetical representation of titer loss during aerosolization.