Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4–40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.
Highlights
Ventilator-associated pneumonia (VAP) is an important infection acquired in the intensive care unit (ICU) and can occur in up to 20% of patients mechanically ventilated for periods greater than 48 h 1
Neutrophils are viable as confirmed by full respiratory burst in healthy and dysfunctional neutrophils (Fig. 2B)
The current study extends our previous model of C5a-induced dysfunction in response to P. aeruginosa[12,13] and S. epidermidis biofilm accumulation in whole blood[21] to investigate the potential of the oxazolidinone, linezolid, to modulate important innate immune responses in healthy and dysfunctional neutrophils
Summary
Ventilator-associated pneumonia (VAP) is an important infection acquired in the intensive care unit (ICU) and can occur in up to 20% of patients mechanically ventilated for periods greater than 48 h 1. Pascual and co-workers have shown that linezolid penetrates the neutrophil rapidly as intracellular concentrations greater than those of the external environment are reached within 20 min[18]. This ability to cross biological membranes is reflected in its high concentrations in lung epithelial lining fluid (ELF). These studies suggest that linezolid in concentrations far in excess of its MIC (4 mg/L)[19] are not cytotoxic to healthy neutrophils using a variety of functional assays. Using our established model of C5a-induced neutrophil dysfunction[12,13], we investigated the effect of linezolid on both healthy and clinically relevant C5a-impaired neutrophils in a variety of relevant functional assays
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