Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections

Abstract

Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site. Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation. Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy's clinical positioning in the antimicrobial arsenal against RTIs.

Phages of life – the path to pharma

“…The key challenges for delivery of inhalable phages for respiratory tract infection have been outlined by Bodier‐Montagutelli et al . (). They pointed out that the sensitivity of phages to external factors is highly variable between and within morphological families, which should be a consideration for cocktails containing different morphotypes.…”

“…The pharmacology of phage delivery depends to a large extent on the targeted site of action and the route of administration (Bodier‐Montagutelli et al, ; Cisek et al, ; Malik et al, ). The main concern with oral delivery is phage inactivation due to the acidic and proteolytic environment of the stomach (Zelasko et al, ).…”

<p>How Phages Overcome the Challenges of Drug Resistant Bacteria in Clinical Infections</p>

“…However, the production of new antibiotics is no longer cost-effective, because of the development of resistance to antibiotics immediately after their production. 33,34 So, the available options for treatment of major MDR bacteria, such as Enterococcus faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter were so limited that an urgent need for discovery of alternative antibiotics to fight antibiotic-resistant infections was felt. 27 Using of bacteriophage as a natural and non-conventional antimicrobial agent in this period of progressive spread of MDR, XDR and PDR bacteria with a paucity of new antibiotics presents a new solution.…”

“…They have special characteristics, such as bactericidal effect, low inherent toxicity, high selectivity, lack of cross-resistance with antibiotic classes as well as self-multiplication in the presence of the bacterial host that distinguish them from conventional antibiotics. 18,27,33,[35][36][37] Also, unlike broad-spectrum antibiotics, phage spare the commensal microbiota due to their strain-specific activity, which is particularly important for malnourished and immunodeficient people. Eventually, they can be prepared in dry powder formulations that do not require a cold chain.…”

Indications and Limitations of Phage Therapy in Human Medicine: Personal Experience and Literature Review

“…The lung is vulnerable to many occasional opportunistic environmental bacteria. Bacteriophages have been isolated for almost all of these bacteria and sometimes tested in experimental models, but their use in human pathology using appropriate vectorization for inhalation [127] remains to be evaluated.…”