Time and Concentration Dependent Influence of Dirithromycin on Neutrophils Oxidative Burst.

Abstract

Dirithromycin is a 14-membered macrolide antibiotic, well known to yield high intragranulocytic levels after several hour exposure. Wechose therefore to investigate oxidative metabolism after prolonged incubation periods with neutrophils.Neutrophil generation of reactive oxygen species, represented by superoxide anion, was assessed after fMLPor Staphylococcus aureus-induccd activation of the respiratory burst. Cellular uptake of the drug was assessed concurrently, in order to attempt a correlation with time-dependent modifications of the cellular oxidative status.For 1 hour exposure time, a pro-oxidant effect was reported for lower concentrations, achievable during therapeutic administration, whereas the highest ones promoted a potent anti-oxidant effect. After prolonged incubation times, the anti-oxidant effect alone was reported, with time-dependent modifications of IC50 values. These values could be correlated with intracellular accumulation of the drug. The anti-inflammatory activity reported here for high dirithromycin concentrations, could be nevertheless clinically relevant, since dirithromycin cellular uptake extends beyond 4 hours.

Intracellular Penetration and Effects of Antibiotics on Staphylococcus aureus Inside Human Neutrophils: A Comprehensive Review

“…Uptake of macrolides into neutrophils can be divided into two distinct groups. First, there is erythromycin (C/E between 4.4 and 13.3) [29,38,41,52,89,90], clarithromycin (C/E of 9.2) [52], roxithromycin (C/E between 14 and 34) [41,53,90], dirithromycin (C/E of 16.3) [54] and josamycin (C/E of 21.4) [55]. These macrolides penetrate neutrophils moderately well, generally reaching maximal C/E values after 10 to 90 min of incubation [52,56,57,58,89].…”

“…At therapeutic levels, macrolides do not show clear effects on neutrophil function [57,74,75], yet some evidence suggests a slight induction of ROS production [54,74,76,77,78]. However, at higher doses or longer exposure times, an inhibitory effect on ROS production becomes prominent [30,54,74,76,77,78,79,80]. No consensus is reached on the underlying mechanism of the inhibitory effect.…”

“…No consensus is reached on the underlying mechanism of the inhibitory effect. Different theories have been proposed: Reduced expression of beta-2-integrins [81], inhibition of the phospholipase D-phosphatidic acid phosphohydrolase (PAH) interaction with protein kinase C activity and altered construction of the NADPH oxidase enzyme [54,78,82], membrane stabilization [54], elevation of cyclic adenosine monophosphate (cAMP) levels and higher protein kinase A (PKA) activity [32,80]. Erythromycin is also seen to induce LDH release and neutrophil death even at clinically relevant concentrations (1–10 mg/L) [32].…”

Suppressive Activity of Macrolide Antibiotics on Nitric Oxide Production from Nasal Polyp Fibroblasts In Vitro

“…Long-term administration of macrolide antibiotics to patients with inflammatory airway diseases is reported to inhibit neutrophil migration and activation in the airways (1,5,7). In vitro studies have also shown the suppressive activity of macrolide antibiotics on polymorphonuclear leukocyte activation, including inflammatory cytokine production and superoxide generation (6,20,21). Together with these reports, the present results are interpreted to suggest that the suppressive effects of RXM, but not JM, on NO generation from fibroblasts may be one of the mechanisms leading to the favorable modification of airway inflammation as a result of macrolide therapy.…”

Ανοσοπαρεμβατική Δράση Της Κλαριθρομυκίνης Στην Δευτεροπαθή Περιτονίτιτδα

“…Πέξαλ ηεο αληηκηθξνβηαθήο δξάζεο ηνπο νη καθξνιίδεο εκθαλίδνπλ θαη αλνζνπαξεκβαηηθή δξάζε 9,127,136 . πγθεθξηκέλα απφ δηάθνξεο κειέηεο θπξίσο in vitro, πξνθχπηεη φηη κεηαμχ άιισλ νη καθξνιίδεο: 1) αλαζηέιινπλ ηελ παξαγσγή ROS απφ ηα νπδεηεξφθηια 137 θαη ηελ ρεκεηνηαμία ησλ θπηηάξσλ απηψλ 138 , ελψ πξνάγνπλ ηελ απφπησζε ηνπο 139 , 2) αλαζηέιινπλ ζηηο πεξηζζφηεξεο πεξηπηψζεηο ηελ έθθξηζε πξνθιεγκνλσδψλ θπηνθηλψλ (TNFα, IL-6, IL-8) απφ ηα κνλνθχηηαξα θαη ηα καθξνθάγα 14,18,140,141 , 3) αλαζηέιινπλ ηελ έθθξαζε κνξίσλ πξνζθφιιεζεο ζηα ιεπθά αηκνζθαίξηα 142 , 4) αλαζηέιινπλ ηελ έθθξηζε ηνπ NO απφ ηα θπςειηδηθά καθξνθάγα θαη πξνάγνπλ ηελ θαγνθπηηαξηθή δξάζε ησλ θπηηάξσλ απηψλ 11,143 , 5) αλαζηέιινπλ ηελ έθθξηζε ηεο IL-4 144 θαη απμάλνπλ ηελ παξαγσγή ηεο IL-10 απφ ηα Σιεκθνθχηηαξα 145 , 6) ζηαζεξνπνηνχλ ηνπο ειεθηξνζηαηηθνχο δεζκνχο (tight junctions) κεηαμχ ησλ επηζειηαθψλ θπηηάξσλ ησλ βξφγρσλ 11 . Πνιιέο απφ ηηο παξαπάλσ δξάζεηο ησλ καθξνιηδψλ εθθξάδνληαη κέζσ αλαζηνιήο ηεο ελεξγνπνίεζεο ηνπ NF-kB θαη ηεο AP-1 18,146 .…”