Inhalational Gentamicin Treatment Is Effective Against Pneumonic Plague in a Mouse Model

Abstract

Pneumonic plague is an infectious disease characterized by rapid and fulminant development of acute pneumonia and septicemia that results in death within days of exposure. The causative agent of pneumonic plague, Yersinia pestis (Y. pestis), is a Tier-1 bio-threat agent. Parenteral antibiotic treatment is effective when given within a narrow therapeutic window after symptom onset. However, the non-specific “flu-like” symptoms often lead to delayed diagnosis and therapy. In this study, we evaluated inhalational gentamicin therapy in an infected mouse model as a means to improve antibiotic treatment efficacy. Inhalation is an attractive route for treating lung infections. The advantages include directly dosing the main infection site, the relative accessibility for administration and the lack of extensive enzymatic drug degradation machinery. In this study, we show that inhalational gentamicin treatment administered 24 h post-infection, prior to the appearance of symptoms, protected against lethal intranasal challenge with the fully virulent Y. pestis Kimberley53 strain (Kim53). Similarly, a high survival rate was demonstrated in mice treated by inhalation with another aminoglycoside, tobramycin, for which an FDA-approved inhaled formulation is clinically available for cystic fibrosis patients. Inhalational treatment with gentamicin 48 h post-infection (to symptomatic mice) was also successful against a Y. pestis challenge dose of 10 i.n.LD50. Whole-body imaging using IVIS technology demonstrated that adding inhalational gentamicin to parenteral therapy accelerated the clearance of Y. pestis from the lungs of infected animals. This may reduce disease severity and the risk of secondary infections. In conclusion, our data suggest that inhalational therapy with aerosolized gentamicin may be an effective prophylactic treatment against pneumonic plague. We also demonstrate the benefit of combining this treatment with a conventional parenteral treatment against this rapidly progressing infectious disease. We suggest the inhalational administration route as a clinically relevant treatment modality against pneumonic plague and other respiratory bacterial pathogens.

Characterization of Yersinia pestis Phage Lytic Activity in Human Whole Blood for the Selection of Efficient Therapeutic Phages

“…The bacterial strains used in this study were the Y. pestis EV76 live vaccine strain (accession no. PRJNA647169) and its bioluminescence recombinant derivate EV76:: lux containing the luxCDABE cassette [ 31 ]. Nonvirulent Y. pestis Kimberley53∆70∆10 [ 32 ] served as a host for phage lysate preparation and phage titration.…”

Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights

“…Today, despite extreme precautions that were taken in order to prevent the outbreak of Y. pestis , cases of Y. pestis infection that frequently result in patient deaths were still reported now and then [3]. Infection of Y. pestis is commonly mediated by bacteria-containing aerosol inhalation or flea bite that transmits the bacterium from pathogen-carrying reservoir mammal hosts to human, leading to rapid progression of symptoms from fever to pneumonia, to hemoptysis, and eventually to patient deaths in 3–4 days [4, 5].…”

Antibiotic Therapy of Plague: A Review

“…The efficacy of aminoglycosides, tetracyclines, fluoroquinolones, β-lactams, rifamycin, chloramphenicol, sulfonamides and ketolides has been evaluated in rodent (rat and mouse) models of plague and (less frequently) in non-human primate models of pneumonic plague ( Table 2 ) [ 17 , 52 , 56 , 61 , 63 , 69 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ]. The resulting degree of protection against plague often varies from one animal study to another.…”

“…Following the marketing authorization of inhaled tobramycin in 1997, this approach was used to successfully treat patients with cystic fibrosis infected with Pseudomonas aeruginosa [ 120 ]. A comparative study of mice intranasally infected with pulmonary plague showed that inhalation of an aminoglycoside antibiotic (gentamicin) was more efficacious than subcutaneous injection [ 110 ]. Interestingly, the researchers results suggested that although subcutaneously injected antibiotics reached and protected deep organs, the drugs did not necessarily reach the lungs (depending on differences in diffusion properties, e.g., ciprofloxacin vs. gentamicin): hence, protection in the lungs might be mediated solely by the host’s immune system.…”