Project Details
Projekt
Effect of inhaled Nitric Oxide on bacterial burden and disease outcome in a murine model of Klebsiella pneumonia
Applicant
Dr. Steffen Wiegand
Subject Area
Anaesthesiology
Term
from 2019 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 434095988
Health care-associated infections are an important problem throughout the world and are associated with increased morbidity and mortality, especially in intensive care units. There are various risk factors for health care-associated infections in the intensive care unit, including congestive heart failure, renal dysfunction and immunosuppression. In addition, patients in the intensive care unit may have invasive devices placed, such as an endotracheal tube or a Foley catheter, which further increase the risk of infection. A frequent complication of endotracheal intubation is ventilator-associated pneumonia, which is the most common acquired infection and the leading cause of death from infection in the intensive care unit. Treatment of ventilator-associated pneumonia requires early diagnosis and an initial empiric choice of antibiotics. In the last two decades, bacteria with resistance to different classes of antibiotics have emerged, which complicates antibiotic therapy. These so-called multiple drug resistant organisms contribute to adverse clinical outcomes. There are relatively few antibiotics available for the treatment of these pathogens. The so-called “last line of defense” antibiotics have a limited effect on multiple drug resistant organisms and these drugs are associated with significant side effects including nephro- and neurotoxicity. The ideal new anti-microbial agent would have a completely different mechanism of action, thereby having potential synergistic effects with currently available antibiotics. Nitric oxide, a gas which is used for the treatment of pulmonary hypertension of the newborn and pulmonary hypertension during cardiac surgery, has been shown to have direct and indirect bactericidal effect. In general the cost of administering nitric oxide is very high, but my host’s lab constructed a “mini nitric oxide generator”, which produce nitric oxide from room air. Soon, this less expensive mechanism of delivering will become widely available and use of inhaled nitric oxide will become a feasible option for the cure of patients with difficult to treat pneumonia.In this project, I will study the effect of inhaled nitric oxide on Klebsiella pneumoniae, a frequent cause of ventilator-associated pneumonia. This strain of bacteria often develops drug resistance. I will use in-vitro studies to determine the optimal concentration of nitric oxide to kill Klebsiella pneumoniae. I will then determine the optimal nitric oxide concentration and timing of nitric oxide administration to work in a murine model of Klebsiella pneumonia. As a proof-of-concept experiment, I will further analyze the effect of nitric oxide therapy on multiple drug resistance Klebsiella pneumonia. The proposed studies will increase our knowledge of the potential role of nitric oxide as an adjunctive therapy for lung infection. It is anticipated that the results of this study will permit a novel approach to treat patients with health care-associated pneumonia.
DFG Programme
Research Fellowships
International Connection
USA
