Beneficial and Harmful Interactions of Antibiotics with Microbial Pathogens and the Host Innate Immune System

Abstract

In general antibiotics interact cooperatively with host defences, weakening and decreasing the virulence of microbial pathogens, thereby increasing vulnerability to phagocytosis and eradication by the intrinsic antimicrobial systems of the host. Antibiotics, however, also interact with host defences by several other mechanisms, some harmful, others beneficial. Harmful activities include exacerbation of potentially damaging inflammatory responses, a property of cell-wall targeted agents, which promotes the release of pro-inflammatory microbial cytotoxins and cell-wall components. On the other hand, inhibitors of bacterial protein synthesis, especially macrolides, possess beneficial anti-inflammatory/cytoprotective activities, which result from interference with the production of microbial virulence factors/cytotoxins. In addition to these pathogen-directed, anti-inflammatory activities, some classes of antimicrobial agent possess secondary anti-inflammatory properties, unrelated to their conventional antimicrobial activities, which target cells of the innate immune system, particularly neutrophils. This is a relatively uncommon, potentially beneficial property of antibiotics, which has been described for macrolides, imidazole anti-mycotics, fluoroquinolones, and tetracyclines. Although of largely unproven significance in the clinical setting, increasing awareness of the pro-inflammatory and anti-inflammatory properties of antibiotics may contribute to a more discerning and effective use of these agents.

Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin

“…Fluoroquinolones have been proposed to possess secondary anti-inflammatory properties, targeting the production of proinflammatory cytokines both in vitro and in vivo (58). Neutrophil infiltration into the inflammatory site is the hallmark of acute inflammation.…”

Lack of effect of cell-wall targeted antibacterials on biofilm formation and antifungal susceptibility of Candidaspecies

“…This effect may exacerbate the inflammatory reactions damaging the host cell and tissues, worsening the patient's condition. However this same effect has not been observed with antibacterials such as macrolides, fluoroquinolones and tetracyclines, as these prevent the release of pro-inflammatory toxins of Gram positive and Gram-negative bacteria and also inhibit other virulence factors working against the excessive production of several potent inflammatory mediators (Anderson et al, 2010). This difference in the mechanism of action of these classes of antibacterials may explain, in part, why all epidemiological risk factors point to the cell-wall targeted antibacterials and not to the protein-synthesis targeted antibacterials.…”

Prevalence, pathogenesis, therapy, and prevention of cardiovascular events in patients with community-acquired pneumonia

“…These inhibitory effects of macrolides on the production of pneumolysin, which are evident at sub-inhibitory concentrations of these agents [59, 60] even in the setting of macrolide resistance [61], may underpin their utility as adjuncts to beta-lactams in the treatment of severe pneumococcal disease [58, 62]. …”