The Efficacy of Phage Therapy in a Murine Model of Pseudomonas aeruginosa Pneumonia and Sepsis

Abstract

The emergence of multi-drug resistant Pseudomonas aeruginosa necessitates the search for treatment options other than antibiotic use. The use of bacteriophages is currently being considered as an alternative to antibiotics for the treatment of bacterial infections. A number of bacteriophages were introduced to treat pneumonia in past reports. However, there are still lack of knowledge regarding the dosages, application time, mechanism and safety of phage therapy against P. aeruginosa pneumonia. We used the bacteriophage KPP10 against P. aeruginosa strain D4-induced pneumonia mouse models and observed their outcomes in comparison to control models. We found that the nasal inhalation of highly concentrated KPP10 (MOI = 80) significantly improved survival rate in pneumonia models (P < 0.01). The number of viable bacteria in both lungs and in serum were significantly decreased (P < 0.01) in phage-treated mice in comparison to the control mice. Pathological examination showed that phage-treated group had significantly reduced bleeding, inflammatory cell infiltration, and mucus secretion in lung interstitium. We also measured inflammatory cytokine levels in the serum and lung homogenates of mice. In phage-treated models, serum TNFα, IL-1β, and IFN-γ levels were significantly lower (P < 0.05, P < 0.01, and P < 0.05, respectively) than those in the control models. In the lung homogenate, the mean IL-1β level in phage-treated models was significantly lower (P < 0.05) than that of the control group. We confirmed the presence of phage in blood and lungs, and evaluated the safety of bacteriophage use in living models since bacteriophage mediated bacterial lysis arise concern of endotoxic shock. The study results suggest that phage therapy can potentially be used in treating lung infections caused by Pseudomonas aeruginosa.

Isolation and characterization of two homolog phages infecting Pseudomonas aeruginosa

“…P. aeruginosa, a Gram-negative, widespread, multidrug-resistant pathogen causes complex diseases that are difficult to cure ( Azam and Khan, 2019 ). In recent years, phages have received increasing attention, and are believed to replace antibiotics as a solution to antibiotic resistance in bacteria ( Yang et al, 2021 ). Previous studies have shown that phage infection inhibits bacterial growth, which increases with increasing MOI ( Imam et al, 2019 ).…”

Evaluation of Phage Therapy for Pulmonary Infection of Mouse by Liquid Aerosol-Exposure Pseudomonas aeruginosa

“…20 Yang et al demonstrated that inhaled phage KPP10 exerted a significant protective effect against pneumonia caused by P. aeruginosa D4. 21 Morello et al demonstrated that two different bacteriophages (PAK-P3 and P3-CHA) administered intranasally are effective in treating lung infections by two different P. aeruginosa strains. 22 Forti et al demonstrated a broad-range bacteriophage cocktail (PYO2, DEV, E215, E217, PAK_P1 and PAK_P4) can reduce P. aeruginosa biofilms and treat acute infections in two animal models (Galleria larva and mice).…”

Bacteriophage as a potential therapy to control antibiotic-resistant Pseudomonas aeruginosa infection through topical application onto a full-thickness wound in a rat model

“…Many research studies have highlighted the use of phages to control biofilm-forming bacteria, including P. aeruginosa and demonstrated the ability of phages to eradicate the P. aeruginosa infections [28,29] and biofilm-forming bacterial cells [16,[30][31][32][33]. However, previous studies have focused mainly on the treatment of cystic fibrosis caused by P. aeruginosa by phages in vivo [29,[34][35][36]. Moreover, using phage therapy against MDR P. aeruginosa in wound infection shows high efficacy and safety through topical and oral administrations [29,[37][38][39].…”