Antibacterial Effect and Inflammatory Response in Relation to Antibiotic Treatment of Sepsis

Sammanfattning: Sepsis defines as life-threatening organ dysfunction caused by a dysregulated host response to infection. The importance of early administration of antibiotics in septic shock is undisputed, but the optimal antibiotic choice remains uncertain. Some national guidelines advocate single β-lactam antibiotic treatment while others recommend a combination of β-lactam and aminoglycoside. This thesis aimed to investigate the anti-bacterial properties and antibiotic-induced inflammatory responses of ß-lactam antibiotic compared with effects of the addition of an aminoglycoside in clinically relevant E. coli porcine intensive care sepsis/septic shock models. We also studied the host's antibacterial capacities in primary and secondary sepsis.In Paper I the addition of an aminoglycoside, in comparison with single β-lactam antibiotic treatment,  caused decreased bacterial growth in the liver and greater antibiotic-induced blood killing activity ex vivo. The results thereby constitute possible mechanisms to the previously reported improved survival in the most critically ill sepsis patients receiving the β-lactam/aminoglycoside combination. Also observed in this paper was that individual blood bactericidal capacity may have significant effects on antimicrobial outcome.  In Paper II we investigated endotoxin release in vivo after antibiotic treatment in comparison with no treatment. There were no differences, however, antibiotics did increase an inflammatory IL-6 response that was associated with leukocyte activation and pulmonary organ dysfunction. A secondary finding was that the addition of an aminoglycoside to a β-lactam induced trends towards less inflammation compared with β-lactam alone.Paper III compared how challenge with different pre-killed E. coli activates the inflammatory response, resulting in higher cytokine responses, more leucocyte activation and inflammatory capillary leakage after single β-lactam compared with live or heat-killed bacteria. The addition of an aminoglycoside lowered the β-lactam-induced responses.Paper IV demonstrated that animals with secondary sepsis exhibited an attenuated inflammatory response as expected; however, contrary to our hypothesis, the animals’ antibacterial capacities were intact and partly enhanced.We conclude that there are likely several beneficial effects of the addition of an aminoglycoside to a β-lactam therapy regimen in septic shock. Because host antibacterial capacities in secondary sepsis are enhanced, the need for bactericidal antibiotic combinations is not greater in secondary than in primary sepsis.