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Antibiotics

Immunomodulatory and Anti-Inflammatory Properties

At the 2002 European Congress of Clinical Microbiology and Infectious Diseases, a paper was presented showing antibiotics have anti-inflammatory properties in addition to their traditional antimicrobial effects.

Why is this important to us as patients? Many of us are helped by antibiotics, despite negative cultures. Why is that? From research in the last decade or so, it appears that many antibiotics can, in some people and for a limited time, act as anti-inflammatories or immunomodulatory agents.

The acceptance of the anti-inflammatory and immunomodulatory aspects of antibiotics came mostly from the inflammatory bowel disease experts, who long pondered why antibiotics helped many patients with Crohn's disease despite no obvious infection. In 1999 they came to some startling conclusions.

The Official View

In 2001, Dr Shoskes wrote a key paper on antibiotics and prostatitis which covers these issues. Read it here.

American urologists officially recognized the anti-inflammatory effects of antibiotics in CP/CPPS in a February 2003 Editorial in the Journal of Urology.Read it here.

Finally, in 2005 Prof Schaeffer stated that "the beneficial effect of antimicrobial drugs may not be due to their antibacterial action, but to their anti-inflammatory action."Read it here.
People ask why antibiotics help them even though traditional NSAID drugs don't. The answer is that some antibiotics have different anti-inflammatory effects to NSAIDS.

Tetracyclines are useful in rheumatoid arthritis by inhibiting the expression of nitric oxide. Minocycline too is a powerful immunomodulant which can subdue rheumatoid arthritis and is believed to have anti-inflammatory and immunosuppressive effects similar to those of steroids. Tetracycline and doxycycline may also act as anti-inflammatories by modulation of nitric oxide synthesis. Studies also suggest that the clinical effectiveness of doxycycline in the treatment of acne inflammation is due partly to its antioxidant effect on neutrophils.

Gentamycin, an aminoglycoside antibiotic, may exhibit an anti-inflammatory action due to inhibition of neutrophil NADPH oxidase activation.

The quinolones (Cipro and many more) show anti-inflammatory activity by reducing the potent reactive oxygen species excessively generated by neutrophils at the sites of inflammation. This leads to a reduction in oxidative tissue injury. Another recent study of cipro states that "ciprofloxacin decreases the accumulation of interleukin (IL)-6". A study on Inflammatory Bowel Disease concluded that "ciprofloxacin [has] both anti-inflammatory and immuno-suppressant effects that may be more important than [its] antimicrobial effects". It is therefore generally agreed that quinolones such as ciprofloxacin inhibit production of TNF-alpha, IL-6, IL-1, and PGE(2). One quinolone, perfloxacin, has even been able to induce remission in nephrotic syndrome. Quinolones are usually made up of a ring structure of 4 quinolinones. A quinolinone derivative called TA-270 has proved to be more effective than anti-asthmatic drugs in controlling asthma in guinea pigs by scavenging reactive oxygen species. Ciprofloxacin's anti-inflammatory effect was shown to help mice with induced colitis, suggesting it may be used to treat IBD patients.

Erythromycin may inhibit cytokine production too. A 2000 study confirms that macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithromycin [Zithromax]) prevent the production of proinflammatory mediators and cytokines. Macrolide antibiotics are now being considered for use in treating asthma. Clarithromycin is thought to be effective in chronic sinusitis by reducing gene expression of proinflammatory cytokines and adhesion molecules from nasal mucosa at the transcriptional factor level, thereby exerting an anti-inflammatory effect on nasal mucosa.

Amoxycillin (Imacillin) has been shown to decrease bowel inflammation in ulcerative colitis.

Bactrim (trimethoprim-sulfamethoxazole) has recently been shown useful in the treatment of autoimmune diseases, such as rheumatoid arthritis. Bactrim therapy also reduced the elevated levels of soluble IL-2 receptor and IL-6 in parallel in another inflammatory disease, Wegener's granulomatosis.

The beneficial effects of metronidazole (Flagyl) in acne vulgaris are attributable to its anti-inflammatory activities rather than its antibacterial ones.

Cephalexin, penicillin G, chloramphenicol, and streptomycin inhibit reactive oxygen species generation via their effect on polymorphonuclear leukocytes cell function directly, with resultant anti-inflammatory effects on the inflammatory processes.

Clindamycin is a powerful anti-inflammatory useful in sterile conditions like Fox-Fordyce disease. Clindamycin suppresses the complement-derived chemotaxis of polymorphonuclear leukocytes in vitro, thereby reducing the potential for inflammation.

Still doubtful? See "Key Paper on Antibiotics as Immunomodulators" (in Miscellaneous section) at the International Prostatitis Research Foundation website. This 36-page paper puts to rest any doubt that antibiotics are indeed both anti-inflammatories and immunomodulators. A small sample:

"The use of antibacterial agents as anti-inflammatory drugs falls into four categories: (i) agents which have been in use for a long time (sulfones, sulfonamides, and clofazimine); (ii) drugs which have recently triggered interest, particularly in rheumatoid arthritis (cyclines and ansamycins); (iii) drugs which are effective in specific diseases (for example, macrolides in diffuse panbronchiolitis) and show promise in other inflammatory settings; and (iv) drugs which could be developed in the near future but are at present only being studied in animal models. Classical use of antibacterial agents in inflammatory diseases. In addition to its antimycobacterial activity, dapsone exhibits significant anti-inflammatory activity and has been utilized in many neutrophilic dermatoses and other inflammatory diseases such as dermatitis herpetiformis, leukocytoclastic vasculitis, bullous lupus erythematosus, pustular psoriasis, erythema elevatum diutinum, and Crohn's disease (36, 96, 169, 303). Similar indications have been put forward for another antimycobacterial drug, clofazimine, which has proven effective in vitiligo, discoid lupus erythematosus, pyoderma gangrenosum, and pustular psoriasis (53, 233). The effectiveness of these two drugs in mycobacterial diseases has been also ascribed at least partly to their anti-inflammatory activity. As indicated above, both dapsone and clofazimine significantly depress the inflammatory potential of phagocytes; this property clearly seems to underlie their anti-inflammatory efficacy. Similarly, sulfonamides have proved effective in the treatment of Wegener's granulomatosis (325), and sulfasalazine (and sulfapyridine?) displays antirheumatic activity (308)." [CLINICAL MICROBIOLOGY REVIEWS, 10 Oct. 2000, p. 615-650 Vol. 13, No. 4 Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"? Marie-Therese Labro].

Antibiotics: More than just "bug" killers

Critical Care Medicine Volume 25, #8, 08/97
Dr. Larry C. Casey MD PhD


Selected quotes:

There are at least three different ways by which antibiotics may affect the immune system: a) by causing the release of endotoxin; b) through the regulation of cytokine synthesis; and c) by inhibition of components of the immune response, including chemotaxis, lymphocyte transformation, delayed hypersensitivity, antibody production, phagocytosis, and oxidative metabolism of phagocytes.

...

IL-6 is thought to represent a "marker" of endothelial cell injury/activation and may represent an index of systemic inflammation caused by proinflammatory cytokines. Dr. Galley and colleagues [1] showed that ciprofloxacin inhibited endothelial cell production of IL-6 in response to TNF plus IL-1 stimulation. Thus, because of ciprofloxacin's ability to attenuate cytokine-mediated endothelial cell dysfunction, it is possible that ciprofloxacin may have additional beneficial roles in treating infections, independent of its ability to kill bacteria.

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