Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes

Abstract

Recently we found that certain antibiotics which are markedly concentrated by human polymorphonuclear leukocytes (PMN) failed to kill susceptible, intraphagocytic Staphylococcus aureus, even though cellular drug levels were quite high. The possibility that specific antibiotics might adversely affect phagocyte antibacterial function was considered. Thus, we studied the effects of multiple antibiotics and adenosine, a known modulator of the PMN respiratory burst response, on neutrophil antibacterial function. At nontoxic concentrations, these drugs had no effect on degranulation in stimulated PMN. Adenosine was a potent inhibitor of formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated superoxide and hydrogen peroxide generation in PMN but produced less inhibition of microbial particle-induced respiratory burst activity. Three of the tested antibiotics, all of which reach high concentrations in phagocytic cels, had a marked modulatory effect on the PMN respiratory burst. Clindamycin, which enters phagocytes by the ceUl membrane adenosine (nucleoside) transport system, had only a modest effect on FMLP-mediated superoxide production but inhibited the microbial particle-induced response by -50%. Roxithromycin and trimethoprim were efficient inhibitors of PMN superoxide generation stimulated by FMLP and concanavalin A (also inhibited by erythromycin) but had less effect on zymosan-mediated respiratory burst activity. Antibiotics which entered phagocytes less readily had no effect on the respiratory burst response in PMN. These results, as well as those of experiments with inhibitors of cell membrane nucleoside receptors, indicated that the antibiotic effect is mediated through intraphagocytic pathways. The possibility that antibiotic-associated inhibition of the PMN respiratory burst response might alter leukocyte antimicrobial and inflammatory function deserves further evaluation.The interaction of antimicrobial agents with leukocytes, and especially any influence on the fate of bacteria ingested by these phagocytic cells, may be of therapeutic importance. Entry of antibiotics into phagocytes is obviously a prerequisite for activity against intracellular organisms, but we recently demonstrated a discrepancy between uptake of certain antibiotics by human neutrophilic polymorphonuclear leukocytes (PMN) and the subsequent effect of these drugs on intraphagocytic bactericidal activity (18). Thus, clindamycin and erythromycin, which were markedly concentrated by PMN, exhibited poor activity against intraphagocytic Staphylococcus aureus, even though the intracellular drug levels exceeded the MBCs for this organism (18). The possibility that certain antibiotics might adversely influence phagocyte antibacterial function was considered. In the case of cindamycin, a potential modulatory role has been identified. We have shown that clindamycin enters PMN and macrophages by means of the cell membrane nucleoside (adenosine) transport system (16, 36). Since adenosine (by binding external cell membrane nucleoside receptors) regula...

Effect of Macrolide Antibiotics on Macrophage Functions

“…In addition, it is hypothesized that this high concentration of EM within the neutrophil cytoplasm may modulate neutrophil functions. In fact, EM-mediated inhibition of neutrophil chemotaxis (9,27,29,31,32), oxidant generation (1,13,27), and phagocytosis (27) have been reported. In addition, EM also shortens neutrophil survival by accelerating apoptosis (2).…”

“…Figure 4 shows the effects of pretreatment with macrolide antibiotics (EM, CAM, RXM, and AZM) on macrophage cytocidal activity against Candida albi- Antibiotics have biological properties other than direct antimicrobial activity. These include interactions with and alteration in the functions of host phagocytic cells (4,13,15,28). This subject is of importance, since phagocytic cells are essential for controlling almost all infections and are mediators of inflammation.…”

Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression

“…However, only recently have investigators begun to elucidate the mechanisms by which such antibiotics counteract inflammation. These mechanisms may include the reduction of PMN and mononuclear leukocyte infiltration [25,31], the inhibition of pro-inflammatory cytokine expression in PMN, monocytes, and epithelial cells [24,27,32,44], the inhibition of PMN adhesion to epithelial cells [24,26], and the suppression of the PMN oxidative burst [15,32,45]. In addition, recent studies have demonstrated the ability of several macrolides and azalides, including erythromycin and azithromycin, to induce PMN apoptosis in vitro [7,16,20,28].…”

Phytochemical-induced reduction of pulmonary inflammation during Klebsiella pneumoniae lung infection in mice

“…It has been observed that antibiotics with antibacterial and antiinflammatory action are good options in containing both the infectious agent as well as the harmful action of the overstimulated immune response. The macrolide group of antibiotics have been known to affect several pathways of inflammatory processes such as migration of neutrophils, oxidative burst in macrophages, and the production of pro-inflammatory cytokine [5,6], but because of the various side effects of antibiotics and the problem of ever-increasing antibiotic resistance, there has been a shift towards alternative or complementary ways of medicine. One such approach being explored is the use of herbal compounds.…”