Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial

Groeneveld, Geert H; van der Reyden, Tanny J; Joosten, Simone A; Bootsma, Hester J; Cobbaert, Christa M; de Vries, Jutte J C; Kuijper, Ed J; van Dissel, Jaap T

The host inflammatory response in pneumococcal disease contributes significantly to morbidity and mortality. 1 As in other infections with Gram-positive bacteria, the inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)] or the release of intracellular proteins. 2 LTA is recognized by Toll-like receptor 2 (TLR2), a pattern recognition receptor on macrophages. Binding of LTA to TLR2 induces the release of pro-inflammatory cytokines (e.g. IL-1, IL-6 and TNF) and neutrophil influx. 3, 4 Bacterial cell wall components are released when bacteria are killed by autolysis or host immune cells, and are important determinants of the severity of inflammation. 5 An acute breakdown of the bacterial cell wall occurs upon exposure to b-lactam antibiotics, 6 the first-line treatment for pneumococcal infections in many guidelines. 7, 8 Reduction of release of bacterial cell wall products may decrease inflammation, reduce tissue damage and, ultimately, reduce morbidity and mortality. Strategies to dampen the host inflammatory response have been studied extensively. Currently, dexamethasone adjunctive treatment in patients with pneumococcal meningitis is used in high-income countries to diminish inflammatory responses and, consequently, neurological sequelae. 9 In community-acquired pneumonia, macrolides seem to have an immune modulatory effect by enhancing the antibacterial effect of neutrophils and by quashing the immune response after bacterial killing. 10 However, in a clinical trial, b-lactam monotherapy was non-inferior to macrolide with b-lactam combination therapy. 11 Another potential approach is to kill the bacteria without immediately lysing them, thus preventing the release of pro-inflammatory cell wall products. 12 This would reduce the complete inflammatory trigger by interfering at the beginning of the inflammation cascade.