Curr. Med. Chem. - Anti-Infective Agents, 2004, 3, 1-13 1 1568-0126/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. The Leading Role of Antimicrobial Agents in Modulating the Binomial Host-Microorganism Anna Maria Cuffini*, Vivian Tullio, Narcisa Mandras, Janira Roana, Giuliana Banche and Nicola A. Carlone Department of Public Health and Microbiology Microbiology Section University of Turin, Turin, Italy Abstract: The current trend of therapy requires the use of antibiotics, which combine a high level in vitro antibacterial activity with the capacity to act in concert with the immune system in a way that potentiates the host's defence mechanisms. Whilst such additional effects on the immune system by the antibiotic may be of secondary importance in patients with normal host defence mechanisms, they are of primary importance in patients with depression of the immune system, who are highly susceptible to infections, often difficult to treat, even with the current and modern antimicrobial agents. This investigation delineates our own results regarding the impact of some antimicrobial agents such as the most recent β- lactams, carbapenems, trinems, glycopeptides, quinolones, aminoglycosides and macrolides upon the primary functions of phagocytes, namely human polymorphonuclear granulocytes and macrophages. The ability of the above mentioned drugs to penetrate human phagocytes and their consequences upon subsequent phagocytic ingestion and killing of ingested bacteria, both Gram-positive and Gram-negative, are here reported. Moreover the influence exerted by some of these antibiotics either on phagocytic functions or on the release of cytokines is illustrated. The beneficial properties of some β-lactams, which result in “restoring” the depressed phagocyte-dependent response in patients on chronic hemodialysis or in renal transplant recipients, are also focused. Keywords: PMNs, macrophages, antimicrobial agents, phagocytosis, killing, drug uptake, phagocyte functions. INTRODUCTION Currently antibacterial activity is measured primarily via in vitro laboratory tests. An evolving concept is to utilize pharmacodynamic and pharmacokinetic drug properties in addition to in vitro susceptibility reports to assess the potential effectiveness of an antibacterial agent against a specific pathogen [1]. The host following contact with the pathogen rapidly develops specific responses to invading pathogens in order to eliminate or restrict bacterial replication. Thus successful bacterial pathogens must be able to avoid or adapt to evolving host defenses and their microbial mechanisms for phase and antigenic variation can reduce the restrictive effect of host immune responses [2]. Moreover in the few years, the frequency and types of microbial infections increased dramatically in immuno- compromised patients due to numerous factors, such as chemotherapy-induced neutropenia, extensive surgery, use of prosthetic devices and vascular catheters, treatment with glucorticosteroids, peritoneal dialysis or hemodialysis, organ transplant-associated immunosuppressive therapy, malig- nancy and malnutrition, HIV infection. In these individuals infections can be more aggressive than in normal hosts, and often difficult to treat even with current antimicrobial agents. In these cases, the failure of antibiotic therapy is often related to the inability of the patient’s immune system *Address correspondence to this author at the Professor in Microbiology Department of Public Health and Microbiology Microbiology Section Via Santena , 9 10126 Turin – Italy; Tel: 39- 011-6706613; Fax: 39- 011- 6636436; E-mail: annamaria.cuffini@unito.it to provide the support that antibiotics need for eradication of the infection. Besides the growing number of new categories of so-called immunocompromised patients, other two events a) the acknowledged increasing importance of intracellular pathogens resistant to classical β-lactams and amino- glycosides and b) the emergence of antibiotic-resistant bacteria, stimulated the search for new anti-infective approach: the emerging concept of immunomodulation by antimicrobial agents [3]. Thus the current trend level of therapy requires the use of antibiotics which combine high level of antibacterial activity, optimal pharmacodynamic and pharmacokinetic properties with the capacity to act in concert with the immune system in a way that potentiates the host’s defense mechanisms (Table 1). As soon as a microbial pathogen enters the host, a localized beneficial inflammatory response is generated with specific design to halt the invasion and destroy the invader pathogens. The features of the inflammatory process vary greatly with the different causative organisms and are significantly related to the disease-producing capacity of the microbe. Two phagocytic lineages respond as defenders against infection: polymorphonuclear cells (PMNs) and monocyte- derived macrophages. PMNs, short-lived and extremely abundant cells, are the first line of defense and play a key role against acute microbial infection. Monocyte-derived macrophages, long-lived cells, either take part in the earliest and latest phases of infection (by preparing and presenting antigen for T cell recognition, by directly fighting the