Uptake, transport, delivery, and intracellular activity of antimicrobial agents.

Antibiotic interactions with cells, including polymorphonuclear neutrophils, may influence therapeutic outcomes. Selected microbes (e.g., Legionella pneumophila) may survive ingestion by polymorphonuclear neutrophils and are thus protected from the action of antimicrobial agents that remain extracellular. Antibiotics that penetrate the cell can kill these microbes. Certain antibiotics are concentrated inside phagocytes, and when the phagocyte migrates toward the site of infection, the antibiotic-loaded cell carries the active agent to the infecting microbes. Active antibiotic may be released when the short-lived phagocyte dies. Even microbes considered to be extracellular pathogens, such as pneumococci, may survive high concentrations of antibiotic by entering cells. Antibiotics that penetrate and are active in cells may aid in enhancing therapeutic outcomes and in eliminating the carrier state for some pathogens.

Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function.

The effects of purified toxin A in vitro on the shape and function of polymorphonuclear leukocytes (PMNL) were examined. Toxin A induced changes in adherent PMNL shape from a compact spherical or pyramidal shape to a thin and rope-like shape. This change in shape was accompanied by rearrangement of the F-actin cytoskeleton into aggregates. Toxin A-treated PMNL exhibited increased adherence and expressed less L-selectin and more Mac-1, compared with untreated PMNL. In contrast to these proinflammatory actions, toxin A impaired both directed and non-directed PMNL migration in response to N-formylmethionylleucylphenylalanine. In addition, toxin A decreased the oxidative activity of adherent PMNL stimulated by recombinant human tumor necrosis factor-alpha. These effects could be explained by toxin A-induced glucosylation of the signaling small-size guanine 5'-triphosphate-binding proteins of the Rho family in human PMNL.

Effect of antipyretic agents on uptake, transport, and release of antimicrobial agents by human polymorphonuclear leukocytes.

Polymorphonuclear leukocytes (PMNL) concentrate, transport, and release certain antimicrobial agents as they move in a chemotactic gradient. Antipyretic agents are frequently used in febrile patients receiving antimicrobial agents. Thus, the influence of ibuprofen, acetaminophen, and acetylsalicylic acid on uptake, transport, and release of azithromycin and moxifloxacin was studied. Uptake of the antimicrobial agents by human PMNL and the effect of the antipyretics were quantitated by bioassay of released antimicrobial agent. Transport and release were determined in chemotactic plates overlaid with sentinel bacteria that could detect transported and released antimicrobial agent. None of the antipyretics altered PMNL directed or non-directed movement. Uptake of azithromycin was significantly inhibited by acetylsalicylic acid but not by the other antipyretics. All of the antipyretic agents studied at therapeutic levels inhibited transport and release of both azithromycin and moxifloxacin. Administration of any of these antipyretic agents with antimicrobial agents that are transported and released by PMNL could compromise the efficacy of therapy.