Effect of Clarithromycin in Inflammatory Markers of Patients with Ventilator-Associated Pneumonia and Sepsis Caused by Gram-Negative Bacteria: Results from a Randomized Clinical Study

Abstract

dOne recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-␣) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-␣, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.

Macrolides and Mortality in Critically Ill Patients With Community-Acquired Pneumonia

“…In addition, macrolides have been shown to inhibit biofilm formation and decrease mucus hypersecretion, leading to improved mucociliary clearance (51). Furthermore, in a recent study in critically ill patients with ventilator-associated pneumonia (53), treatment with clarithromycin restored the balance between pro-and anti-inflammatory mediators in patients with sepsis. Furthermore, in a recent study in critically ill patients with ventilator-associated pneumonia (53), treatment with clarithromycin restored the balance between pro-and anti-inflammatory mediators in patients with sepsis.…”

The Value of Macrolide-Based Regimens for Community-Acquired Pneumonia

“…In addition, the authors measured markers of inflammation (serum IL-10, TNF-alpha, as well as the expression of various cytokines in stimulation assays) and apoptosis at baseline and for 6 days following treatment [41]. They found that treatment with clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators, resulted in more efficient antigen presentation, and increased apoptosis.…”

Azithromycin use and outcomes in severe sepsis patients with and without pneumonia

“…Furthermore, our cohort was mainly comprised of severe sepsis patients without pneumonia and we identified a beneficial outcome from azithromycin use in these patients as well, which few studies have previously reported. A trend for diminished number of days requiring ventilator support was also observed, potentially limited by sample size and high variability, as other studies have shown shorter times to successful discontinuation of mechanical ventilation with a macrolide in severe sepsis patients [26]. Further investigations are warranted to clarify the association of macrolide use on clinical outcomes in different phenotypes of critically ill patients, especially severe sepsis patients without pneumonia.…”

“…Recently, more randomized controlled trials (RCTs) have investigated outcomes from macrolide use in severe sepsis, specifically in patients with ventilator-associated pneumonia, but clinical equipoise remains in clinical trials. For example, one recent RCT found no mortality benefit in patients with gram-negative sepsis treated with clarithromycin [14], while another study of severe sepsis patients with ventilator-associated pneumonia reported decreased risk of death from septic shock and multiple organ dysfunctions associated with the same agent [26]. Our study in severe sepsis patients found that early use of azithromycin for at least 48 hours, independent of other risk factors and accounting for organ dysfunction and presence of shock, was associated with six more days free of ICU care compared to the group not receiving azithromycin.…”