Short communication
Tigecycline has no effect on cytokine release in an ex vivo endotoxin model of human whole blood

https://doi.org/10.1016/j.ijantimicag.2008.11.008Get rights and content

Abstract

In previous studies, tetracyclines have been shown to decrease the release of cytokines in experimental settings of endotoxaemia. Tigecycline is the first member of the closely related glycylglycines and, due to its broad antimicrobial spectrum, it is considered useful in the treatment of sepsis. We therefore tested its ability to influence the concentrations of the proinflammatory cytokines interleukin (IL)-1β, tumour necrosis factor-alpha (TNFα) and IL-6 in an established ex vivo model of human endotoxaemia. Whole blood from ten healthy volunteers was incubated with either saline (negative control), tigecycline (1 μg/mL [therapeutic concentration] or 100 μg/mL [supratherapeutic concentration]), lipopolysaccharide (LPS; 50 pg/mL, control) or a combination of tigecycline plus LPS (test group). Concentrations of IL-1β, TNFα and IL-6 in the supernatant were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. As expected, incubation with LPS significantly increased the cytokine concentrations in whole blood compared with baseline (P < 0.05). The combination of tigecycline plus LPS did not exert any significant effect on the concentrations of IL-1β, IL-6 and TNFα after 2 h and 4 h of incubation compared with LPS alone. These results indicate that proinflammatory cytokines remained unaffected by tigecycline in an established ex vivo model of systemic inflammatory response.

Introduction

Tigecycline, the first member of the antibiotic class of glycylglycines, exhibits a long plasma elimination half-life of ca. 50–70 h and exerts broad antimicrobial activity, including meticillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing bacilli [1]. These characteristics render tigecycline an attractive therapeutic option in the therapy of bacteraemia emanating from complicated infections of soft tissue, the intra-abdominal compartment or the urinary tract.

It is well known from numerous in vitro and animal models that certain classes of antibiotics, i.e. fluoroquinolones, oxazolidinones (linezolid), clindamycin, fosfomycin and tetracyclines, are able to modulate the cytokine response in experimental endotoxaemia [2], [3], [4], [5], [6], [7], [8]. Among others, antibiotics of the tetracycline family were found to protect mice against lethal doses of lipopolysaccharide (LPS). In addition, the tetracyclines are considered to reduce significantly the liberation of tumour necrosis factor-alpha (TNFα) and interleukin (IL)-1β by LPS-stimulated murine and human monocytes in a concentration-dependent manner [6], [7], [8].

Hence, the aim of the present study was to investigate the potential ability of the structurally closely related compound tigecycline to influence the release of the most relevant proinflammatory cytokines IL-1β, IL-6 and TNFα. These cytokines are critically involved in the early phase of systemic inflammation [9]. An established model of endotoxaemia in whole blood was used in an ex vivo setting [5], [6], [7], [8], [9], [10].

Section snippets

General and study subjects

The study took place at associated medical centers and research laboratories of J&P Medical Research Ltd., Vienna, Austria. Ten healthy subjects underwent routine health screening examination including extensive blood laboratory testing. After informed consent was obtained, fresh whole blood (which otherwise would have been discarded) from these anonymised subjects was used for the present in vitro experiment. Whole blood from seven subjects was incubated with a tigecycline concentration of 1 

ELISA measurements of IL-1β, IL-6 and TNFα

The concentration versus time profiles of IL-1β, IL-6 and TNFα in the supernatant after incubation of whole blood over a period of 2 h and 4 h with saline, tigecycline, LPS, or LPS plus tigecycline (1 μg/mL and 100 μg/mL) are depicted in Fig. 1 and Table 1.

As shown, the concentrations of all tested cytokines increased significantly after 4 h of incubation with 50 pg/mL LPS compared with baseline. No significant difference in proinflammatory cytokine concentrations was shown between incubation with

Discussion

A large number of in vitro and in vivo models of LPS-induced systemic inflammation have convincingly shown that the class of tetracyclines is able to exert immunomodulatory effects [6], [7], [8]. Because of the structurally close relationship of tigecycline to the tetracyclines, we hypothesised that an immunomodulatory action might also be expected for this new compound.

This speculation is triggered by the fact that tigecycline accumulates in body cells and is rapidly taken up by peripheral

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