Prospects of Inhaled Phage Therapy for Combatting Pulmonary Infections

Abstract

With respiratory infections accounting for significant morbidity and mortality, the issue of antibiotic resistance has added to the gravity of the situation. Treatment of pulmonary infections (bacterial pneumonia, cystic fibrosis-associated bacterial infections, tuberculosis) is more challenging with the involvement of multi-drug resistant bacterial strains, which act as etiological agents. Furthermore, with the dearth of new antibiotics available and old antibiotics losing efficacy, it is prudent to switch to non-antibiotic approaches to fight this battle. Phage therapy represents one such approach that has proven effective against a range of bacterial pathogens including drug resistant strains. Inhaled phage therapy encompasses the use of stable phage preparations given via aerosol delivery. This therapy can be used as an adjunct treatment option in both prophylactic and therapeutic modes. In the present review, we first highlight the role and action of phages against pulmonary pathogens, followed by delineating the different methods of delivery of inhaled phage therapy with evidence of success. The review aims to focus on recent advances and developments in improving the final success and outcome of pulmonary phage therapy. It details the use of electrospray for targeted delivery, advances in nebulization techniques, individualized controlled inhalation with software control, and liposome-encapsulated nebulized phages to take pulmonary phage delivery to the next level. The review expands knowledge on the pulmonary delivery of phages and the advances that have been made for improved outcomes in the treatment of respiratory infections.

Activity of Phage–Lactoferrin Mixture against Multi Drug Resistant Staphylococcus aureus Biofilms

“…Furthermore, we have observed that the use of lactoferrin prolonged the activity of bacteriophages on the biofilm and prevented its re-growth; this was observed after 24 h of incubation if phages were used alone. This corresponds with the reports of other researchers, which suggests that lactoferrin boosts and prolongs the effects of other antimicrobials [ 44 , 45 , 47 ]. Therefore, it can be assumed that the use of the phage–lactoferrin cocktail has potential application against biofilms formed by multi-drug-resistant bacteria, though the detailed mechanism remains to be determined [ 15 , 16 , 47 ].…”

“…This corresponds with the reports of other researchers, which suggests that lactoferrin boosts and prolongs the effects of other antimicrobials [ 44 , 45 , 47 ]. Therefore, it can be assumed that the use of the phage–lactoferrin cocktail has potential application against biofilms formed by multi-drug-resistant bacteria, though the detailed mechanism remains to be determined [ 15 , 16 , 47 ]. We believe that more in vitro studies involving other phage types and bacterial genera, followed by in vivo studies, i.e., on Galleria mellonella or Caenorhabditis elegans models, could deliver more detailed data on phage–lactoferrin synergy and effectivity, helping to answer the question if phage–AMPs mixtures can be used as one of the treatment methods of multi-drug-resistant infections.…”

“…However, data on the use of the phage-lactoferrin mixture are very scarce. There are reports that the use of lactoferrin increased phage stability and tolerance to environmental factors [ 45 , 46 , 47 ], and there are few in vivo studies of phage–lactoferrin mixture’s effectiveness. Experiments performed by Zimecki et al on mice models reported that a combination of lactoferrin (10 mg i.v.)…”

Pulmonary Delivery of Emerging Antibacterials for Bacterial Lung Infections Treatment

“…Dry powder formulations for phage inhalation have attracted increasing interests, partly because of the advantages of enhanced stability and shelf-life of phages in dry states [ 106 ]. SD, freeze drying and SFD are the commonly-used technique to prepare phage-based dry powders.…”

“…Regardless of the powder production technology, excipients play critical roles in stabilizing phages in the dry powder formulations upon production and storage. Amino acids, such as leucine and trileucine, are often used as dispersibility enhancers and moisture protectors, while sugars, including lactose, mannitol, trehalose and sucrose, are used as the stabilizers to preserve phages activities [ 106 ]. Table III summarizes the production methods and excipients used for phage powder production.…”