Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or “Immuno-Fairy Tales”?

Abstract

SUMMARY Professional phagocytes (polymorphonuclear neutrophils and monocytes/macrophages) are a main component of the immune system. These cells are involved in both host defenses and various pathological settings characterized by excessive inflammation. Accordingly, they are key targets for immunomodulatory drugs, among which antibacterial agents are promising candidates. The basic and historical concepts of immunomodulation will first be briefly reviewed. Phagocyte complexity will then be unravelled (at least in terms of what we know about the origin, subsets, ambivalent roles, functional capacities, and transductional pathways of this cell and how to explore them). The core subject of this review will be the many possible interactions between antibacterial agents and phagocytes, classified according to demonstrated or potential clinical relevance (e.g., neutropenia, intracellular accumulation, and modulation of bacterial virulence). A detailed review of direct in vitro effects will be provided for the various antibacterial drug families, followed by a discussion of the clinical relevance of these effects in two particular settings: immune deficiency and inflammatory diseases. The prophylactic and therapeutic use of immunomodulatory antibiotics will be considered before conclusions are drawn about the emerging (optimistic) vision of future therapeutic prospects to deal with largely unknown new diseases and new pathogens by using new agents, new techniques, and a better understanding of the phagocyte in particular and the immune system in general.

Influence of antibacterial drugs on the immune system

“…Two clinically relevant effects of antibacterials are currently recognized, namely toxic and immunotoxic effects, and intracellular BIOACTIVITY. Other possibilities are modulation of bacterial virulence (leading to antibacterial synergy or a proinflammatory effect); ABA activation/inactivation by host cell activities; and modulation of cell functions or products by ABA (resulting in immunostimulation, immunodepression or antiinflammatory activity).These general aspects of ABA IMMUNOMODULATO-RY effects are reviewed in [4,6,9] and summarized here in Table 1 [9][10][11][12][13][14][15][16].…”

“…influenced the therapeutic choice early in the antimicrobial era, but attention has gradually shifted to beneficial "IMMUNOMODULATORY"properties. Many papers in this field have been published and periodically reviewed over the last three decades [1][2][3][4][5][6][7][8][9]. Interest in "immunostimulation" peaked in the 1970s.…”

“…Two clinically relevant effects of antibacterials are currently recognized, namely toxic and immunotoxic effects, and intracellular BIOACTIVITY. Other possibilities are modulation of bacterial virulence (leading to antibacterial synergy or a proinflammatory effect); ABA activation/inactivation by host cell activities; and modulation of cell functions or products by ABA (resulting in immunostimulation, immunodepression or antiinflammatory activity).These general aspects of ABA IMMUNOMODULATO-RY effects are reviewed in [4,6,9] and summarized here in Table 1 [9-16].Modulation (stimulation/inhibition) of host cell activities is the most widely investigated and most controversial area. Some ABA can either increase or decrease a given function in vitro, depending on the cell type, the technique used, and other variables such as the drug concentration and cell activation status.Effects observed in vitro may differ from those occurring ex vivo/in vivo,which result from the combined activities of the different players: the host and its cellular and humoral (redundant) effectors, the pathogen and its virulence mechanisms, and the physicochemical, pharmacokinetic (concentration, tissue distribution, metabolism) and antibacterial properties of the ABA in question.…”

Effects of a derivative thiazoline/thiazolidine azine ligand and its cadmium complexes on phagocytic activity by human neutrophils

“…In this way, 1,3-thiazoline ring systems are contained in penicilins frame, a b-lactam antibiotic family that bases its action mechanism on the inhibition of the bacterial cell wall syntheses [6]. It is known that antibiotics may also exhibit immunological effects, either inhibiting or stimulating immune response mechanisms [7][8][9][10][11]. This is the case of cefmetazole, cefoxitin and imipenen, b-lactam antibiotics with an unusually broad antibacterial spectrum, which stimulate neutrophils phagocytic capacity [12][13][14][15].…”

Synthesis, structural characterization and influence on the phagocytic activity of human neutrophils of thiazoline and thiazine derivative ligands and their zinc(II) complexes

“…It is known that antibiotics may also exhibit immunological effects, either inhibiting or stimulating immune response mechanisms [6][7][8][9][10]. This is the case of cefmetazole, cefoxitin and imipenem, b-lactam antibiotics with an unusually broad antibacterial spectrum, that stimulate neutrophils phagocytic capacity [11][12][13][14].…”