Why do antibiotics help ... for a while only?

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Why do antibiotics help ... for a while only?

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Antibiotics: immunomodulatory and anti-inflammatory properties
The surprising truth about why antibiotics give temporary help

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Antibiotics help men with chronic prostatitis (CPPS) by subduing inflammation, not by killing bacteria. That’s now accepted science, although this knowledge only emerged early this century. 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.
Anti-inflammatory effect of several antibiotics
MILAN, Italy, April 29, 2002 – Antibiotics appear to have anti-inflammatory properties in addition to their traditional antimicrobial effects, according to the results of several studies presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases underway here this week. The properties of antimicrobial and anti-inflammatory drugs closely overlap “and it is difficult to differentiate them very clearly in vivo,” said Professor Jos van der Meer, of Nimègue, the Netherlands, one of two panel speakers. … the findings of an in vitro study presented as a poster by Dr. Hisham Ziglam and his colleagues in Nottingham, UK, suggest an anti-inflammatory effect of several antibiotics in concentrations comparable those administered therapeutically. Dr. Ziglam’s group showed that therapeutic doses of isoniazid decreased the production of free radicals, produced by neutrophils, and reduced the amount of some pro-inflammatory cytokines, such as IL-1 alpha and IL-10, produced by monocytes. “These results could explain the quick anti-inflammatory response observed during anti-tuberculosis treatment,” Dr. Ziglam said. The British team also showed that ciprofloxacin did not have an inhibiting effect on free radicals produced by neutrophils, but did inhibit the production of all cytokines examined, including interferon-1 alpha, interleukin-10, interleukin-6 and TNF-alpha. “The impact of antibiotics on the immune system can already be significant in patients whose immune functions are intact. But it can be even more significant in subjects with immune deficiencies,” Dr. Ziglam added.
Why is this important to us as patients? Many of us (but not all1) are helped by antibiotics, despite negative cultures, even if only temporarily (in the end, their effect is not durable and they are no more effective than placebo). Why is that? Recent research (this century) has discovered that many antibiotics can, in some people and at least for a limited time, act as anti-inflammatories or immunomodulatory agents. The connection between the anti-inflammatory and immunomodulatory effects of antibiotics and the temporary amelioration of symptoms in CP/CPPS was first recognised by me, the webmaster of ucpps.men, and posted to Usenet in the 1990s. Dr Daniel Shoskes, a reader and contributor to the old Usenet newsgroup for prostatitis, sci.med.prostate.prostatitis, followed up on the connection I had made and published a paper on it (see below).

The initial 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 following extract from an early study on antibiotics and inflammatory bowel disease shows how the medical profession started becoming aware of the different actions of antibiotics:
Primary Care; Clinics in Office Practice Volume 26, Number 1, March 1999

INFLAMMATORY BOWEL DISEASE

Maureen O'Reilly Brown MD, MPH
Department of Family Medicine, Swedish Family Practice Residency, University of Washington School of Medicine, Seattle, Washington

Although microbial pathogens have long been suspected to play a role in the etiology of IBD, broad-spectrum antibiotics have not proved to be effective therapy. The two antibiotics that have shown benefit, metronidazole and ciprofloxacin, both have anti-inflammatory and immuno-suppressant effects that may be more important than their antimicrobial effects. Metronidazole has no demonstrated efficacy in the treatment of acute ulcerative colitis. It may have some benefit for these patients in maintaining remission, however, and it is an effective drug for treating pouchitis, a common postoperative complication following continence-sparing colectomy surgery. Metronidazole, 10 to 20 mg/kg/d, is an effective drug for many patients with perianal Crohn's disease. When the dose is reduced or discontinued, however, recurrence of disease is the rule. Most patients respond to reinstitution of therapy. Paresthesias are the major side effect of long-term metronidazole therapy, developing in one-half of all patients after a mean of 6 months of therapy. These usually are pedal and bilateral and can persist for up to 2 years after the drug is stopped. Minor side effects include metallic taste, dark urine, nausea, anorexia, headache, and reversible neutropenia. No carcinogenic or teratogenic effects have been seen.

Ciprofloxacin, a fluoroquinolone antibiotic, has shown some promise as an adjuct to mesalazine, metronidazole, and steroids or immunosuppressants for the treatment of severe perianal disease or fistulae. In combination with metronidazole, it may also have some efficacy in active Crohn's disease. A small, randomized trial found this combination of antibiotics to be as effective as prednisone for achieving remission, with a 46% response rate after 12 weeks of treatment. Twenty-seven percent of patients, however, stopped treatment because of side effects. Ciprofloxacin has shown some early promise for the treatment of moderate-to-severe ulcerative colitis. As an adjuct to mesalazine and prednisone, it appears to decrease rates of treatment failure and colectomy. This beneficial effect may not be evident before 3 months of treatment, and may be most marked in patients previously refractory to steroids. For most patients, ciprofloxacin is well-tolerated, with effective doses ranging from 500 to 750 mg twice daily.
Urology Researchers

https://www.ucpps.men/images/pills.svgIn 2001, researching urologist Dr Daniel Shoskes wrote a key paper on antibiotics and prostatitis covering the anti-inflammatory effects of antibiotics. From the paper:
Finally,the antibiotics may be helping by a mechanism completely independent of their antimicrobial effects.Antibiotics such as quinolones, tetracyclines and macrolides have direct anti-inflammatory properties in the absence of infection, blocking cytokines such as interleukin-1 (IL-1), IL-8 and tumor necrosis factor (TNF), which coincidentally are the same cytokines found to be elevated in the semen and EPS of men with prostatitis
Journal of Urology

https://www.ucpps.men/images/pills1.svgAmerican urologists officially recognized the anti-inflammatory effects of antibiotics in CP/CPPS in a February 2003 Editorial in the Journal of Urology (read editorial at the end of this page).

Experts agree…

https://www.ucpps.men/images/surgeon.svgIn 2005 Urology Prof. A. Schaeffer said “the beneficial effect of antimicrobial drugs may not be due to their antibacterial action, but to their anti-inflammatory action.” (read abstract)

In 2015, the fact that antibiotics offer only temporary anti-inflammatory effects and should be avoided in CPPS patients was featured at the American Urological Association meeting (start video at 12 minutes):

A detailed look at the antibiotics we know are anti-inflammatories

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. Fosfomycin strongly inhibits the release of pro-inflammatory cytokines. Fosfomycin's immunomodulatory and anti-inflammatory effects include the suppression of TNF-α and IL-1β (inflammatory cytokines) and production increase of of IL-10 (anti-inflammatory cytokine).

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.

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Erythromycinmay 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. More: The Anti-inflammatory effects of Macrolides.

The cephalosporin antibiotic, cefaclor, inhibits IL-4 production (IL-4 drives allergies) as well as IL-6, a pro-inflammatory cytokine. Cefaclor is closely related to cefalexin.

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. Sulfamethizole was shown to have the anti-inflammatory and analgesic activity equivalent to aspirin 200mg/kg (a massive dose).

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

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.

Rifaximin has been shown to reverse and normalize a vast array of inflammatory cytokines including IL-17, IL-1β and TNF-α, and normalize gene expression of occludin, a tight junction protein.

Ertapenem, a carbapenem antibiotic, is highly effective in the control of inflammation.

Still doubtful? See “Key Paper on Antibiotics as Immunomodulators” (in Miscellaneous section) in our archive. 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]
2021: Antibiotics with therapeutic effects on spinal cord injury: a review:
Accumulating evidence indicates that a considerable number of antibiotics exert anti-inflammatory and neuroprotective effects in different central and peripheral nervous system diseases including spinal cord injury
https://pubmed.ncbi.nlm.nih.gov/33464681/

Immunomodulatory effects of quinolones
We review data on the in-vitro, ex-vivo, in-vivo, and clinical effects of fluoroquinolones on the synthesis of cytokines and their mechanisms of immunomodulation.
https://pubmed.ncbi.nlm.nih.gov/12781508/

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. ….
More reading :
  • Link Anti-inflammatory and Immunomodulatory Effects of Antibiotics and Their Use in Dermatology (2016)
  • Link Immunomodulatory and anti-inflammatory properties of macrolides (2016)
  • Link Antibiotics as Anti-Inflammatory and Immunomodulatory Agents (2005 book)
... and numerous other recent papers

Note: since this website (in its original iteration as chronicprostatitis.com), with its phrase “Immunomodulatory and anti-inflammatory properties of antibiotics” was written in the 1990s and pre-dates the abovementioned papers and book, it is possible that this website was used as an (unacknowledged) source.

Antimicrobials are Anti-inflammatory Agents
Editorial: Emerging Concepts in the Management of Prostatitis/Chronic Pelvic Pain Syndrome
Anthony J. Schaeffer
Department of Urology Northwestern University Medical School Chicago, Illinois


The etiology of the chronic pelvic pain syndrome remains an enigma. Traditional thinking implicates the prostate as a primary source of the discomfort and bacteria and/or inflammatory cells as the cause of prostate malfunction. To this end, a lot of time and effort have been spent using traditional culture and more sophisticated polymerase chain reaction techniques to identify putative bacterial pathogens that could infect the prostate and lead to the development of the chronic pelvic pain syndrome. Previous studies using sophisticated polymerase chain reaction technology have failed to identify evidence of bacteria in prostatic tissue obtained from young, presumably healthy cadaver specimens. Traditional techniques to identify bacteria in the prostate are based on localization studies that identify bacteria in prostatic fluid and/or post-prostatic massage voided urine. Obviously, contamination of these specimens from urethral organisms is a common concern and the significance of low numbers of bacteria in expressed prostatic secretions is questionable.

To avoid this problem, Lee et al (2003) performed transperineal tissue biopsies of the prostate. Contamination of the skin was negligible. Using aggressive culture techniques, they identified low numbers of nonpathogenic bacteria in about 30% of the patients and controls. Older men were more likely to have positive cultures, as were those with inflammation in the prostatic fluid. None of the counts was high enough and/or associated with recognized pathogenic bacteria and, therefore, these bacteria are probably colonizing bacteria rather than infecting strains. Since the patients in these studies were older, it is likely that in time urethral bacteria colonized the prostatic ducts. However, these bacteria apparently do not lead to a host response and, particularly, there is no evidence that they are associated with symptoms.

It is well recognized that even if pathogenic bacteria are present in the prostate, as in men with established chronic bacterial prostatitis, they do not cause chronic pelvic pain unless acute urinary tract infection develops. Taken together, these data suggest that bacteria do not have a significant role in the development of the chronic pelvic pain syndrome. The clinical observation that antimicrobial therapy reduces symptomatology in men with chronic pelvic pain syndrome is being tested in a double-blinded NIH controlled study.

Since antimicrobials may have anti-inflammatory activity, it is possible that these drugs may benefit the patient by reducing inflammation rather than eradicating bacteria.
1 -- Note that due to our genetic differences, some people react more to the anti-inflammatory effects of antibiotics and some people less, or not at all. This is known as pharmacogenetics.

More: [Cytokines, inflammation and pain](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785020/)
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