Delay in Adequate Antiobiotic Therapy Results in Fatal Disease Outcome in a Mouse Model of CAP

Community Acquired Pneumonia (CAP) is one of the world's leading causes of death and Streptococcus pneumoniae (S.pn.) is the most prevalent causative pathogen. Despite antibiotic therapy and comorbidity management, mortality has remained about 12 – 13 %. To investigate host factors putatively responsible for different disease outcomes despite adequate antibiotic therapy, S.pn.-infected mice were treated with ampicillin starting at different times post infection (p.i.).

Early antibiotic intervention (24h p.i.) rescued mice from established pneumonia, limited clinical symptoms and restored fitness, whereas delayed therapy (48h p.i.) resulted in high mortality rates. Obviously, general residence time of streptococci was prolonged with delayed treatment, resulting in an extended exposure period. However, following antibiotic therapy, eradication of bacteria occurred at a similar rate in both groups, indicating that antibiotic treatment failure was not responsible for different outcomes in survival. Likewise, recruitment of innate immune cells remained unaffected by antibiotic therapy. Furthermore, both early and late antibiotic intervention dampened local levels of cytokines and chemokines in the alveolar spaces. At 24h p.i., the alveolar-capillary barrier was still intact. Early treatment protected from barrier breakdown, reduced levels of VEGF, a growth factor promoting endothelial destabilization and significantly reduced interstitial (perivascular) and alveolar edema formation. Contrary, at 48h p.i., increased pulmonary leakage was apparent and not reversed by late antibiotic therapy. In line, levels of VEGF remained high despite therapy and no beneficial effect on edema formation was evident. Moreover, early but not late treatment protected mice from ensuing liver damage and a vast systemic inflammatory response which was manifested 48h p.i.. Our study suggests that an intact alveolar-capillary barrier and controlled systemic response are critical for the outcome of pneumonia. Future studies will analyze whether barrier-stabilizing substances, alone or in combination with immunomodulatory agents, can avert host-related therapy failure and might aid in the management of severe pneumonia.

^*Authors contributed equally