The effect of three broad-spectrum antimicrobials on mononuclear cell responses to encapsulated bacteria: evidence for down-regulation of cytokine mRNA transcription by trovafloxacin

The effect of trovafloxacin, ciprofloxacin and ceftriaxone on cytokine prod uction of human peripheral blood mononuclear cells (PBMCs) was examined. PB MC responses were measured after stimulation with lipopolysaccharide (LPS), lipoteichoic acid (LTA) or killed or viable Streptococcus pneumoniae and H aemophilus influenzae. Trovafloxacin inhibited the production of tumour nec rosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6 and IL -8 by PBMCs after stimulation with either LPS or LTA by greater than or equ al to 83%. Similar inhibition occurred in PBMCs incubated with killed or li ve bacteria and trovafloxacin, but not with ciprofloxacin or ceftriaxone. T he relevance of this in vitro observation was explored by examining TNF-alp ha and IL-6 responses in trovafloxacin-treated mice. Serum concentrations o f both cytokines 1 h after LPS challenge were 95% less than serum concentra tions in mice that were not given trovafloxacin. Reverse transcription-poly merase chain reaction studies of the:mechanisms determining cytokine down-r egulation demonstrated that trovafloxacin reduced TNF-alpha, IL-1 beta and IL-6 mRNA to revels similar to those of unstimulated cells. These observati ons indicate that trovafloxacin can consistently and significantly reduce p roduction of cytokines that play an important role in sepsis. In vitro, thi s effect can occur in the presence of bacteriolysis and is associated with inhibition of transcription of cytokine genes.