Minimizing the release of proinflammatory and toxic bacterial products within the host: A promising approach to improve outcome in life-threatening infections

Abstract

Various bacterial components (e.g., endotoxin, teichoic and lipoteichoic acids, peptidoglycans, DNA) induce or enhance inflammation by stimulating the innate immune system and/or are directly toxic in eukariotic cells (e.g., hemolysins). When antibiotics which inhibit bacterial protein synthesis kill bacteria, smaller quantities of proinflammatory or toxic compounds are released in vitro and in vivo than during killing of bacteria by beta-lactams and other cell-wall active drugs. In general, high antibiotic concentrations liberate lower quantities of bacterial proinflammatory or toxic compounds than concentrations close to the minimum inhibitory concentration. In animal models of Escherichia coli Pseudomonas aeruginosa and Staphylococcus aureus peritonitis/sepsis and of Streptococcus pneumoniae meningitis, a lower release of proinflammatory bacterial compounds was associated with a reduced mortality or neuronal injury. Pre-treatment with a bacterial protein synthesis inhibitor reduced the strong release of bacterial products usually observed during treatment with a beta-lactam antibiotic. Data available strongly encourage clinical trials comparing antibiotic regimens with different release of proinflammatory/toxic bacterial products. The benefit of the approach to reduce the liberation of bacterial products should be greatest in patients with a high bacterial load.

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

“…The released bacterial products are highly immunogenic and may lead to an increased inflammatory response in the host (489). Bactericidal antibiotics causing bacterial lysis may also induce a similar effect and lead to a temporarily increased host inflammatory response and increased disease severity (344,345,483).…”

“…In part, the inflammatory response is determined by bacterial lysis products, as shown in experimental pneumococcal meningitis models where inoculation with PCW led to massive inflammation and neuronal damage (489,490). Although bacteriolytic antibiotic regimens may limit the overall amount of release of bacterial products, temporary increases in the release of bacterial components have been documented following treatment (344). These observations have fueled the study of nonbacteriolytic antimicrobials as future therapy options.…”

Dexamethasone Increases Hippocampal Neuronal Apoptosis in a Rabbit Model of Escherichia coli Meningitis

“…Apoptotic cells were identified by in situ labeling of DNA strand breaks and confirmed by morphologic criteria. In experimental E. coli meningitis the rate of apoptotic neurons ranged from 38.6 to 570 per mm 2 (area of the granule cell layer). To ensure that the observed neuronal apoptosis was caused by meningitis, control animals without bacterial infection were investigated.…”

“…Standard therapy for bacterial meningitis is based on high doses of bactericidal cell wall-acting antibiotics such as ␤-lactams or vancomycin, which act by bacteriolysis. Despite rapid sterilization of the CSF, worsening of clinical symptoms after initiation of antibiotic treatment during meningitis has been frequently observed, most probably as a consequence of a burst of inflammation caused by the liberation of proinflammatory bacterial compounds (2). In accord with these clinical observations, a mouse model of pneumococcal meningitis showed an immediate massive increase of glial fibrillary acidic protein as an indicator of parenchymal glial activation after onset of bacterial killing by ceftriaxone (3).…”

Bioluminescence and 19 F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models

“…It has been reported that ␤-lactam antibiotics induce proinflammatory cytokine production due to the release of cell wall components (40,41). In general, decreased release of proinflammatory bacterial compounds is associated with reduced mortality (42). However, additional work is needed to dissect the impact of antibiotic treatment on the inflammatory response and the outcome of infections due to S. aureus specifically.…”