Linezolid Effects on Bacterial Toxin Production and Host Immune Response: Review of the Evidence

BACKGROUND: Linezolid is active against a broad range of gram-positive pathogens and has the potential to also affect production of bacterial toxins and host immune function. OBJECTIVE: To assess the evidence for direct effects of linezolid on bacterial toxin synthesis and modulation of host immune responses. METHODS: Literature searches were performed of the PubMed and OVID databases. Reviews and non English language articles were excluded. Articles with information on the effect of linezolid on bacterial toxin synthesis and immune responses were selected for further review, and data were summarized. RESULTS: Substantial in vitro evidence supports effects of linezolid on bacterial toxin production; however, the strength of the evidence and the nature of the effects are mixed. In the case of Staphylococcus aureus, repeated observations support the inhibition of production of certain staphylococcal toxins (Panton-Valentine leukocidin, protein A, and alpha- and beta-hemolysin) by linezolid, whereas only solitary reports indicate inhibition (toxic shock syndrome toxin-1, coagulase, autolysins, and enterotoxins A and B) or stimulation (phenol-soluble modulins) of toxin production by linezolid. In the case of Streptococcus pyogenes, there are solitary reports of linezolid inhibition (protein M, deoxyribonuclease, and streptococcal pyrogenic exotoxins A, B, and F) or stimulation (immunogenic secreted protein 2 and streptococcal inhibitor of complement-mediated lysis) of toxin production, whereas published evidence for effects on streptolysin 0 production is conflicting. In vitro data are limited, but suggest that linezolid might also have indirect effects on host cytokine expression through inhibition of bacterial production of toxins. In vivo data from preclinical animal studies and a single clinical study in humans are limited and equivocal insofar as a potential role for linezolid in modulating the host inflammatory response; this is due in part to the difficulty in isolating antimicrobial effects and toxin synthesis inhibitory effects of linezolid from any secondary effects on host inflammatory response. CONCLUSIONS: Available evidence supports the possibility that linezolid can inhibit, and in some cases stimulate, toxin production in clinically relevant pathogens. However, more research will be needed to determine the potential clinical relevance of those findings for linezolid. (Curr Ther Res Clin Exp. 2012;73:86-102) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.