Preclinical Assessment of Bacteriophage Therapy against Experimental Acinetobacter baumannii Lung Infection

Abstract

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

Repetitive Exposure to Bacteriophage Cocktails against Pseudomonas aeruginosa or Escherichia coli Provokes Marginal Humoral Immunity in Naïve Mice

“…In the context of lung infections with MDR-bacteria, phage therapy is of great interest for treating VAP patients. While recent studies used intratracheal applications [ 74 ] or nebulized phage suspensions [ 7 , 75 , 76 ], here we show that systemic applications of two different phage cocktails are suitable for the dissemination of phages to the lung. The phage cocktails are well-tolerated and do not induce a marked immune response in naïve mice warranting their future evaluation as antibacterial therapeutics.…”

“…An increasing number of in vivo studies in animal models [ 7 , 8 , 9 ], as well as human case reports [ 10 , 11 , 12 , 13 , 14 , 15 ], have suggested the efficacy of phage therapy over the past two decades. To date, however, only a few clinical trials of phage therapy have been attempted in humans [ 16 , 17 , 18 , 19 ].…”

How to treat severe Acinetobacter baumannii infections

“…There is already data in ABI suggesting the efficacy of phage therapy in animal or in vitro models [195 ▪ ,196 ▪ ,198 ▪ ,209 ▪ –211 ▪ ,212–214,215 ▪ ].…”

Biological Properties of 12 Newly Isolated Acinetobacter baumannii-Specific Bacteriophages

“…Other studies on the effectiveness of phage therapy in the treatment of respiratory infections with the clinical isolate A. baumannii RUH 2037 in a mouse model and in a human lung tissue model showed that mice, after a single intratracheal administration of the lytic phage vB_AbaM_Acibel004, recovered faster than untreated mice and had a lower bacterial burden in the lungs. The bactericidal effect of the purified phage on A. baumannii after a single dose was also confirmed in an ex vivo human lung infection model [ 29 ]. In 2021, a paper was published presenting the results of phage therapy along with antibiotic therapy in an 88-year-old man who was diagnosed with nosocomial pneumonia caused by carbapenem-resistant A. baumannii .…”