Pneumonia is responsible for more deaths in the United States than any other
infectious disease. Severe
pneumonia is a common cause of acute
respiratory failure and
acute respiratory distress syndrome (ARDS). Despite the introduction of effective
antibiotics and intensive supportive care in the 20th century, death rates from community-acquired
pneumonia among patients in the intensive care unit remain as high
as 35%. Beyond antimicrobial treatment, no
targeted molecular therapies have yet proven effective, highlighting the need for additional research. Despite some limitations, small animal models of
pneumonia and the mechanistic insights they produce are likely to continue to play an important role in generating new therapeutic targets. Here we describe the development of an innovative mouse model of
pneumococcal pneumonia developed for enhanced clinical relevance. We first reviewed the literature of small animal models of
bacterial pneumonia that incorporated
antibiotics. We then did a series of experiments in mice in which we systematically varied the pneumococcal inoculum and the timing of
antibiotics while measuring systemic and lung-specific end points, producing a range of models that mirrors the spectrum of pneumococcal
lung disease in patients, from mild self-resolving
infection to severe
pneumonia refractory to
antibiotics. A delay in
antibiotic treatment resulted in ongoing
inflammation and renal and hepatic dysfunction despite effective bacterial killing. The addition of fluid
resuscitation to the model improved renal function but worsened the severity of
lung injury based on direct measurements of
pulmonary edema and lung compliance, analogous to patients with
pneumonia and
sepsis who develop ARDS following fluid administration.