Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague

Abstract

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis , is a fatal disease that causes death within six days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 hours after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of IL-6 and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague, and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

Pulmonary Expression of Interleukin-17 Contributes to Neutrophil Infiltration into the Lungs during Pneumonic Plague

“…IL-17 has been described as one of the cytokines most highly upregulated during the proinflammatory disease phase ( 12 , 24 ), and we discovered that while it does not control bacterial survival in the lung, it does contribute to the massive influx of neutrophils during the proinflammatory disease phase ( 1 , 3 , 8 , 12 ). This implicates IL-17 as a player in the transition to a lethal proinflammatory state of infection in the lung and has therapeutic implications, as limiting pulmonary inflammation (including neutrophil infiltration) has been shown to enhance treatment of late-stage infection ( 47 ). However, the loss of IL-17 did not impact the formation and organization of inflammatory pulmonary lesions, not surprisingly indicating that progression into the proinflammatory disease phase is multifactorial and involves expression of IL-17 in tandem with other signals.…”

Clinically Evaluated COVID-19 Drugs with Therapeutic Potential for Biological Warfare Agents

“…Combining antibodies directed against Y. pestis with methylprednisolone in mice exposed subcutaneously to Y. pestis improved survival and inflammatory markers tested [ 141 ]. In a pneumonic plague model, pre-exposure treatment with the inhaled steroid Fluticasone followed by late antibiotic treatment also led to decreased inflammatory markers and increased survival rates [ 142 ]. In addition, treatment with steroids [ 143 ] or Anakinra [ 144 ] in pre-clinical models of respiratory exposure to ricin led to increased survival rates and improved pathology (in the case of toxins, where the damage is sterile, there is no concern regarding immune modulation and infectivity).…”