Combination therapy in sepsis and septic shock. Sequence of antibiotics and bacterial clearance in a peritonitis rat model of septic shock

Higher microbial load and antibiotic delay are associated with increased morbidity and mortality in septic shock. Antibiotic combination is the basis of empiric treatment for sepsis and septic shock, current recommendations suggest the use of a combination of antibiotics to broaden the initial spectrum of coverage to treat some multi-resistant bacteria. Antibiotic combination therapy leads to more rapid pathogen clearance, which may translate into improved patient outcome. The systematic review in this thesis based on the available randomized clinical trials, does not support the use of combination therapy as the initial treatment for sepsis and septic shock. Although, this could have been due to study design differences, variable degree of severity and even sequence of antibiotic administration. While antimicrobial synergy has been established for beta-lactam combinations with aminoglycosides or fluoroquinolones, antimicrobial sequence has only been studied in vitro. These studies suggest that giving the beta-lactam first or at the same time as an aminoglycoside improves bacterial clearance. Herein we sought to confirm this in the first in vivo study of antimicrobial sequence in septic shock. This thesis confirmed better bacterial clearance using antibiotic combination therapy, but failed to show significant differences in bacterial clearance depending on the sequence of administration of antibiotics in our E. coli and S. pneumoniae models of septic shock. This study sheds light on sequence of administration of antibiotics in sepsis, helping to inform further research.