Influence of linezolid on phagocytosis and killing of Gram-negative bacteria by polymorphonuclear neutrophils
Abstract number: P762
Grüger T., Schnitzler N., Nidermajer S., Brandenburg K., Zündorf J.
Objectives: In a recent phase III clinical trial on linezolid it became obvious that in the linezolid treatment arm more patients acquired Gram-negative catheter related blood stream infections. It was postulated, that linezolid may trigger the acquisition of Gram-negative infections associated with higher mortality rates despite adequate anti-Gram-negative therapy. Therefore, we analysed the impact of linezolid on phagocytosis and killing of Gram-negative bacteria by polymorphonuclear neutrophils (PMN). Phagocytosis and killing of pathogenic microorganisms by PMN are of high relevance for the prognosis of patients suffering from bacterial infections.
Methods: Whole-blood samples were taken from healthy volunteers and incubated with linezolid in clinical relevant concentrations (5, 20 and 50 mg/L) and compared to a drug-free control. CD11b-expression of PMN was evaluated using fluorescence-labelled mAB. To measure phagocytosis, fluorescence-labelled Gram-negative bacteria (Escherichia coli, Burkholderia cepacia, Pseudomonas aeruginosa) and Gram-positive control (Staphylococcus aureus) were added to the blood. Bacteria : PMN ratio was adjusted to 5:1. Phagocytosis was stopped after 5, 15, 30, and 60 min, respectively. Samples were subsequently analysed by flow-cytometry.
To evaluate the influence of linezolid on killing of bacteria whole blood was incubated with 0 (control), 5, 20 and 50 mg/L linezolid, respectively. Killing of bacteria in whole blood was determined after three hours of incubation by plate counting.
Results: Linezolid impaired CD11b-expression of PMN in a concentration-dependent manner up to about 15 percent. Additionally, linezolid also impaired phagocytosis of E. coli (5 to 29%) and to a lower extend of B. cepacia ( 15%) and P. aeruginosa ( 10%) in a concentration-dependent manner. In contrast killing of tested Gram-negative and Gram-positive bacteria were not affected by linezolid compared to the control.
Conclusion: Our data reveal a negative, concentration-depended influence of linezolid on the CD11b-expression of PMN and on phagocytosis of E. coli and to a lower extent of B. cepacia and P. aeruginosa but not of S. aureus. Despite no observable influence of linezolid on the killing of S. aureus, E. coli, B. cepacia, and P. aeruginosa an impaired phagocytosis of Gram-negative bacteria might be critical, especially, in patients with otherwise impaired immune system even if patients receive additional adequate anti-Gram-negative therapy.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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