Clindamycin, erythromycin, and roxithromycin inhibit the proinflammatory interactions of Pseudomonas aeruginosa pigments with human neutrophils in vitro

Abstract

The Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) prime human neutrophils for enhanced, stimulus-activated release of superoxide and myeloperoxidase (MPO), respectively. In the present study, the modulatory potentials of the antimicrobial agents clindamycin, eythromycin, and roxithromycin (10 and 20 ,ug/ml) on the prooxidative interactions of pyocyanin and 1-hp (12.5 FM) with human neutrophils have been investigated. Clindamycin, erythromycin, and especially roxithromycin caused dose-related inhibition of the generation of superoxide by both untreated and pyocyanin-treated neutrophils during activation with either the synthetic chemotactic tripeptide N-formyl-Lmethionyl-L-leucyl-L-phenylalanine (FMLP) or the calcium ionophore A23187. The antimicrobial agents also inhibited the generation of reactive oxidants by the MPO-H202-halide system during activation of both untreated and 1-hp-treated neutrophils by FMLP. These effects appeared to be due to drug-related interference with membrane-associated oxidative metabolism, since none of the antimicrobial agents inhibited the release of MPO by activated neutrophils, nor did they possess oxidant-scavenging properties. These data demonstrate that clindamycin, erythromycin, and especially roxithromycin antagonize the proinflammatory interactions of pyocyanin and 1-hp with neutrophils and indicate a possible therapeutic role for these antimicrobial agents in the prevention of tissue damage in diseases characterized by P. aeruginosa infection.The Pseudomonas aeruginosa-derived phenazine pigment pyocyanin, at pathologically relevant concentrations, primes human neutrophils for increased oxygen consumption and increased generation of superoxide when the cells are subsequently exposed to stimuli of membrane-associated oxidative metabolism (25,31). The prooxidative potential of pyocyanin is amplified by its degradation product, 1-hydroxyphenazine (1-hp), which is also synthesized byP. aeruginosa and which primes neutrophils for enhanced release of myeloperoxidase (MPO) (31). Pigment-neutrophil interaction during P. aeruginosa infection may cause reactive oxidantmediated damage to host tissues, particularly during chronic colonization of the bronchial tree in bronchiectasis. In this situation, damage to the bronchial epithelium may be inflicted by prolonged exposure to oxidants and proteases released by chronically activated phagocytes (6,7,21). Moreover, in patients with P. aeruginosa pneumonia, pulmonary parenchymal destruction might also be related to the release of oxidants and granule enzymes by pigment-primed hyperactive neutrophils (9,17,28).Broad-spectrum antibiotic treatment with currently available agents is insufficient to eradicate P. aeruginosa from the bronchial tree of patients with bronchiectasis and cystic fibrosis once colonization has occurred (19). Inhibition of the reactive-oxidant component of neutrophil-induced chronic bronchial inflammation might therefore introduce a new * Corresponding author.strategy to preve...

The in vitro Effect of Macrolides on the Interaction of Human Polymorphonuclear Leukocytes with Pseudomonas aeruginosa in Biofilm

“…A considerable amount of evidences have also accumulated showing that several macrolides are capable of influencing the function of phagocytic cells [22][23][24][25][26]. In most of those experiments, the concentrations of macrolides affecting the PMN function were much higher than the respective achievable serum concentrations.…”

Therapy with Macrolides in Patients with Cystic Fibrosis

“…40,46 Preventing neutrophil migration and suppressing neutrophil chemotactic activity at inflammatory sites of the lungs is thought to contribute to the clinical effectiveness of macrolides in the treatment of chronic inflammatory airway disease. 39,58,59 One theory as to why the drugs are effective in reducing neutrophil activity is the high intracellular concentrations they achieve. Macrolides are neutral compounds in the blood and readily cross cell membranes.…”

“…62 Possible antioxidant action was theorized to be partly responsible for the clinical effectiveness of macrolide antibiotics in inflammatory diseases. 46,56,58 Treatment with erythromycin significantly decreased intracellular oxidative capacity in neutrophils. 46 Substantial inhibition of superoxide generation by human neutrophils in vitro was seen after treatment with erythromycin and roxithromycin.…”

“…46 Substantial inhibition of superoxide generation by human neutrophils in vitro was seen after treatment with erythromycin and roxithromycin. 58…”

Clindamycin Suppresses Endotoxin Released by Ceftazidime-Treated Escherichia coli O55:B5 and Subsequent Production of Tumor Necrosis Factor Alpha and Interleukin-1β

“…However, it has recently been reported that subminimal inhibitory concentrations of CLDM may influence bacterial viability, toxin production, and host response. For example, CLDM promotes phagocytosis of bacteria by neutrophils (29,30), suppresses the production of hemolysin by E. coli (1), inhibits the proinflammatory interactions of Pseudomonas aeruginosa-derived pigments by neutrophils (21), and reduces the amount of exotoxin released by Clostridium perfringens (26). On the other hand, ceftazidime (CAZ) is an effective antibiotic against E. coli, but when E. coli is killed by CAZ, large quantities of endotoxin are released (3,4,10,25).…”