Antimicrobial agents as biological response modifiers (BRM) and chrono-immunomodulation: an emerging relationship

Immune defense mechanisms play an essential protective role against infections caused by a wide array of pathogenic microorganisms. Although the growing number of the available antimicrobial agents has certainly improved the overall clinical outcome of such infections, antimicrobial therapy not rarely fails whenever the host's immune function is depressed. On the other hand, recently introduced therapeutic and diagnostic procedures (antineoplastic chemotherapy causing severe neutropenia and mucositis; organ transplantation requiring conditioning regimens; the widespread use of intravascular catheters and prosthetic devices; administration of adrenal corticosteroids and/or other immunosuppressive agents) have resulted in an unprecedented number of immunocompromised hosts. In addition, a variety of antibiotics have been found to display adverse effects on specific and non-specific immune functions, thus further impairing the already depressed immune system of the host. Antibiotic-mediated immunomodulation hence is explored with the introduction of a third-generation cephalosporin, namely cefodizime (CDZ), which has been shown to possess immunostimulating properties in preliminary in vitro and ex vivo studies as well as in a few experimental animal models. A chronoimmunopharmacological approach to CDZ-induced immunomodulation has been started by ourselves. The study, which is still in progress, includes patients with multiple myeloma (MM), selective IgA deficiency and chronic uremia, and matched healthy subjects. A number of immunological parameters are being assessed on blood samples drawn every 6h in the 24-h span prior to CDZ administration (a single 2 g daily dose i.v. for 6 days to the patients and for 4 days to healthy subjects), and in the 24h following the last CDZ injection. Healthy subjects and patients are randomly assigned to two groups, depending on whether they are given the antibiotic at 0800 or at 1800. Although a full evaluation of the results will be reported elsewhere, the group of MM now includes 24 patients. A circadian stage-dependent chronoimmunomodulating effect has been unequivocally shown for the monocytic chemotactic responsiveness to CDZ in MM. Immunostimulating 'side-effects' suggest that CDZ should possibly be regarded as a prototype antimicrobial agent for patients with impaired immune functions. Conceivably, a better knowledge of such properties will help synthesize new antibiotics with specific immunomodulating effects.