Pathogenesis and pathophysiology: potential adjunctive therapies

Abstract number: S119

Koedel U.

Acute bacterial meningitis (ABM), especifically when caused by infection with Streptococcus pneumoniae, still has an unacceptably poor prognosis with a mortality of 10–30%.

Bacterial infection of the meninges causes one of the most powerful inflammatory reactions known in medicine. Yet 50 years ago, this inflammatory reaction was suggested to contribute substantially to brain damage. This concept underlies the use of anti-inflammatory agents as adjunctive therapy in ABM. Of all adjunctive treatments in ABM, only corticosteroids have been properly evaluated in clinical trials. These trials recommend corticosteroids in patients with Haemophilus influenzae type B and pneumococcal meningitis (PM). However, adjunctive corticosteroid therapy has several weaknesses such as a narrow treatment window and borderline effects on neurologic sequelae. Thus, there is still the need for additional or alternate adjuvants in the therapy of ABM.

Experimental studies using animal models (predominantly of PM) have provided insight into the pathogenic mechanisms underlying brain injury in ABM. It is now clear that the autodestructive inflammatory reaction is initiated by the interaction of bacterial components with host pattern recognition receptors (PRR) like Toll-like receptors (TLR). PRR signaling results in the activation of transcription factors like NF-kB which up-regulate the production of proinflammatory cytokines. Cytokines like IL-1b are also potent triggers of NF-kB activation and therefore can exaggerate the inflammatory reaction (via positive feedback loops). As a consequence, great numbers of neutrophils are recruited to the meninges. Activated neutrophils release many potentially cytotoxic agents including oxidants and matrix metalloproteinases that can cause collateral damage to brain tissue. Additionally to the inflammatory response, direct bacterial cytotoxicty has been identified as a contributor to tissue damage in ABM.

Thus, experimental studies point at four different targets of adjunctive therapy, namely interference with (I) the induction of inflammation (e.g., TLR blockade), (II) the exaggeration of inflammation (e.g., IL-1 antagonism), and (III+IV) the generation of cytotoxic factors (either of host or bacterial origin, e.g., scavenging of oxidants). This presentation will give an overview of the pathophysiology of ABM (with special emphasis on PM) and highlight promising targets for adjunctive therapy in ABM, as deduced from experimental studies.