ANTIBACTERIAL AGENTS WITH IMMUNE MODULATING ACTIVITIES
Two decades ago, Kudoh et al1 in Japan observed the beneficial effects of prolonged low-dose erythromycin (600 mg/d) therapy in patients with diffuse panbronchiolitis. They suggested that the significant reduction in mortality among the patients in the erythromycin treated may be related to the anti-inflammatory effects of this antibiotic. Recently, the immune modulating activities and other nonantimicrobial effects of certain antibacterial agents have caught the interest of many investigators. Recent reviews published in Clinical Infectious Disease,2 Journal of Antimicrobial Chemotherapy,3 and supplements from Chest and the American Journal of Medicine2-12 provide information on recent investigation in the other actions of known antibacterial agents. Most of the articles in the abovementioned supplements are dealing mainly with macrolides.
The 14-member and 15-member macrolides appear to have stimulated the most interest. The nonantibacterial effects of macrolides for the treatment of airway diseases are classified by Tamaoki et al8 into anti-inflammatory and antisecretory. The anti-inflammatory actions of macrolides include decrease in chemotactic response, reduction in cytokine production, decrease in reactive oxygen species production, and decrease in the expression of adhesion molecule expression. The antisecretory action results in decreased mucus secretion.
Traditionally, macrolides are not used to treat infection associated with Pseudomonas aeruginosa because of their poor antibacterial activity against Pseudomonas. Tsai et al13 showed that azithromycin reduced airway inflammation by inhibiting neutrophil recruitment in murine endobronchial Pseudomonas infection. However, they also showed that azithromycin had no effect on the clearance of Pseudomonas.
Macrolides may also have non-anti-inflammatory effects but antibacterial product activity such as biofilm production. In Pseudomonas infection, the biofilms from the bacteria provide protection from phagocytosis, antibiotic action, and other host immune mechanisms. When Pseudomonas is incubated with subinhibitory levels of clarithromycin, the formation of biofilm matrix is retarded.11 Another study showed that azithromycin also retards Pseudomonas biofilm formation.14
Tetracyclines, in addition to their antibacterial properties, have other biologic activities such as inhibition of metalloproteinases which are important for wound healing and bone resorption as well as control of metastatic potential of tumor cells.2 Tetracyclines are also known to decrease the production of inflammatory mediators. This includes the ability to down-regulate proinflammatory cytokines that may be involved in superantigen-induced toxic shock syndrome.15
The immunomodulating activities of quinolones were recently reviewed by Dalhoff and Shalit.16 Quinolones induce in vitro synthesis interleukin 2 and inhibit the production of interleukin 1, interleukin 8, and tumor necrosis factor-α.
These nonantibacterial immunomodulating activities found in antimicrobial agents that act on the bacterial ribosomes are indeed interesting and important in the treatment of infectious diseases. The improved outcome among patients with community-acquired pneumonia treated with a cephalosporin plus a macrolide, compared with those treated with cephalosporin as well as a better outcome in those treated a quinolone alone, provides an interesting speculation. Is the better outcome associated with the immunomodulating effect of these antimicrobial agents with the target site on the ribosome? Further studies focusing on the exact mode of actions on the host defense will help elucidate the reasons for their beneficial effects and define the indications for their utility in the treatment of various inflammatory diseases.
1. Kudoh S, Azuma A, Yamamoto M, et al. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med
2. Pasquale TR, Tan JS. Nonantimicrobial effects of antibacterial agents. Clin Infect Dis
. 2005;40(January 1):127-135.
3. Amsden GW. Anti-inflammatory effects of macrolides-An underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother
4. Kudoh S. Applying lessons learned in the treatment of diffuse panbronchiolitis to other chronic inflammatory diseases. Am J Med Suppl
5. Majima Y. Clinical implications of the immunomodulatory effects of macrolides on sinusitis. Am J Med Suppl
6. Rubin BK. Immunomodulatory properties of macrolides: overview and historical perspective. Am J Med Suppl
7. Siddiqui J. Immunomodulatory effects of macrolides: implications for practicing clinicians. Am J Med Suppl
8. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med Suppl
9. Tamaoki J. The effects of macrolides on inflammatory cells. Chest
10. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest
11. Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa
12. Rubin BK, Henke MO. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest
13. Tsai WC, Rodriguez ML, Young KS, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med
14. Gillis RJ, Iglewski BH. Azithromycin retards Pseudomonas aeruginosa
biofilm formation. J Clin Microbiol
15. Krakauer T, Buckley M. Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines. Antimicrob Agents Chemother
16. Dalhoff A, Shalit I. Immunomodulatory effects of quinolones. Lancet Infect Dis