Secondary Effects / Mechanisms of Antibiotics

[ferroportin]

I was wondering whether any CC or ID people can weigh in on some of the secondary, less-defined effects of antibiotics.

For example, clindamycin is a protein synthesis inhibitor used for anaerobic infections, but it's also used for MRSA infections due to its inhibition of TSST.

Macrolides are antibiotics used in a number of situations, but they may also have anti-inflammatory properties and are used as such in chronic respiratory diseases like cystic fibrosis, panbronchiolitis, etc.

Any other examples?

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[VentdependenT]

good question. I cant think of much else besides using abx for variceal bleeds to help prevent HRS in cirrhotics.

Biggest MISUSE of antibiotics is their application as ANTIPYRETICS. Abx dont treat fever they treat infection...

 

[Bostonredsox]

All I can think of at is really practical is the macrolides and their antiinflammatory properties. Personally that's 3/4 of the reason I give my inpatient COPD flares azithro despite them not having evidence of pneumonia.

 

[pseudoknot]

You're still using them as antibiotics. It doesn't matter what you give for COPD, you're just reducing colony counts in the lungs and thus reducing baseline chronic inflammation.

Same with clindamycin and toxic shock (only theoretical I think): it works as an antibiotic by inhibiting ribosomes, so it also stops production of toxins. There's no specific inhibition.

 

[ferroportin]

You're still using them as antibiotics. It doesn't matter what you give for COPD, you're just reducing colony counts in the lungs and thus reducing baseline chronic inflammation.

Same with clindamycin and toxic shock (only theoretical I think): it works as an antibiotic by inhibiting ribosomes, so it also stops production of toxins. There's no specific inhibition.

Well, I suppose I was getting more at clinical use than secondary mechanisms per se. But, at least for azithromycin, there may indeed be a separate mechanism:

We found that AZM reduced TNF-α expression at both transcript and protein levels in all of our CF cell lines, bringing it to the levels of untreated isogenic non-CF cells. Conversely, IL-6 mRNA expression was not significantly affected by AZM treatment. As we found higher expression of TNF-α, but not of IL-6, in CF cells than in non-CF cells, we can speculate that AZM may be effective towards those proinflammatory molecules induced in the constitutive inflammation.
...
The possibility that AZM may act at the transcriptional level was tested by measuring the DNA binding activities of two transcription factors relevant in the regulation of the TNF-α gene, NF-κB (27) and Sp1 (42).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803122/

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD).

AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-alpha stimulation also increased the degradation of IkappaB-alpha, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.
http://www.ncbi.nlm.nih.gov/pubmed/17667842

 

[Bostonredsox]

Well, I suppose I was getting more at clinical use than secondary mechanisms per se. But, at least for azithromycin, there may indeed be a separate mechanism:

That is why I use it over resp FQs for COPD pts without pneumonia.

 

[ihearttriangles]

While we are on it, what's the deal with amp/gent for gram+ endocarditis? I get it if you are using this combo for broad spectrum coverage including gram negatives, but if you have already identified the causative agent as being gram+ shouldn't you switch to something more specific?

 

[Bostonredsox]

Gent has a synergistic effect with vanc. Maybe others too

 

[Hernandez]

There are people who use erythromycin or azithro for chronic tx of COPD and COP.

 

[Bostonredsox]

There are people who use erythromycin or azithro for chronic tx of COPD and COP.

Yeah there was an article on it in NEJM not too long ago. Routine regular use led to less COPD exacerbation and such but like 4% of people had significant hearing loss

 

[ferroportin]

I actually did just find a couple of articles that give some other examples, though from the previous posts I gather that clinda and azithro are the only ones frequently used and many of the others are more theoretical at this time.

Dapsone
Inflammatory and autoimmune dermatoses, acne
Immune thrombocytopenia
Polyarteritis nodosa

Clofazimine
Chronic discoid lupus erythematosus, psoriasis
Crohn’s disease, ulcerative colitis
Multiple sclerosis
Type I diabetes mellitus?

Cyclines
Rheumatoid arthritis, Scleroderma (minocycline)
Periodontal diseases
Skin diseases: pemphigus vulgaris, foliaceous and bullous pemphigoid, acne vulgaris, rosacea (doxycycline)
Diabetic nephropathy (doxycycline)
Chronic airway inflammation (asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and cystic fibrosis)
Cardiovascular diseases?
Neurodegenerative diseases? Adjunct to antipsychotic medications (minocycline)
Cancer (chemically modified tetracyclines†)
Anti-allergy
Ophthalmic diseases (cataract, diabetic retinopathy, corneal neovascularization, age-related macular degeneration)

Ansamycins
Juvenile pauci/polyarticular rheumatoid arthritis (intra-articular rifamycin SV)
Crohn’s disease (rifaximin)
Cancer (geldanamycin derivatives†)

Macrolides
(erythromycin A and derivatives)
Diffuse panbronchiolitis, cystic fibrosis
Respiratory diseases associated with chronic inflammation
Asthma?
Inflammatory skin diseases
Chronic recurrent multifocal osteomyelitis (azithromycin)
Cancer (clarithromycin)

Gentamicin: Cystic fibrosis (class 1 mutation)? HIV?
Quinolones: Cancer?
Ceftriaxone: Amyotrophic lateral sclerosis?

Ribavirin Inhibits Th2 response; autoimmunity?

Ritonavir, indinavir, nelfinavir, lopinavir
↑ROS production (adipocytes), ↑MIP-1a and MCP1 (macrophages), ↑apoptosis (cancer cells), cancer?

Zanamivir, oseltamivir Suppress NO production

Immunomodulatory effects of antimicrobial agents. Part I: antibacterial and antiviral agents.
Expert Rev Anti Infect Ther. 2012 Mar;10(3):319-40.
http://www.ncbi.nlm.nih.gov/pubmed/22397566

quinine, chloroquine,
↓PMN functions
Interference with lysosomal acidification, inhibition of proteolysis and antigen presentation
↓IL-1, IL-6
Inhibition of matrix metalloproteinases

Metronidazole ROS scavenging
↑PHA-stimulated mitogenic transformation
Suppress DTH in animal models

Miltefosine Stimulates T cells and macrophages: ↑ROS and IFN‑γ production
In patients: ↑IFN‑γ, triggers a Th1 response

Oltipraz Activates Nrf2, antiangionesis Anticancer?

Amphotericin B
↑/↓oxidative burst, alters cytokine production (depending on formulation)
Proinflammatory

Azoles
Anti-inflammatory
Inhibit PMN functions, ↓IL‑4, IL‑5 secretion

Voriconazole: differential regulation of TLR2/TLR4 receptors;
different responses according to fungal (conidia/hyphae) challenge

Naftifine, terbinafine Priming effect on PMN

Ciclopirox Anti-inflammatory effects

Immunomodulatory effects of antimicrobial agents. Part II: antiparasitic and antifungal agents.
Expert Rev Anti Infect Ther. 2012 Mar;10(3):341-57
http://www.ncbi.nlm.nih.gov/pubmed/22397567

 

[nlax30]

Haven't seen it used but could throw minocycline in on a rheumatoid arthritis regimen or even Demeclocycline for SIADH.

 

[Farcus]

While we are on it, what's the deal with amp/gent for gram+ endocarditis? I get it if you are using this combo for broad spectrum coverage including gram negatives, but if you have already identified the causative agent as being gram+ shouldn't you switch to something more specific?

Dropped in ICU thread since on i'm on ICU rotation.

As far as the synergistic mechanism goes, versus entercoccus AMG+AMP provides bactericidal activity while natural AMP or any ABX is bacteriostatic. Against Strep or Staph it relates to better entry of AMG into cytoplasm to allow 30s inhibition after the cell wall is inhibited by beta-lactams. Even the dosing for AMG is different in synergy role with an aim peak of 3ishmcg/ml and not typical 6-8mcg/ml.

As for secondary mechanism for other ABX. One I found interesting while doing a Pro vs Con Linezolid presentation was that it has shown to have anti-toxin effect vs Pantoin Valentin Leukozidin released in straph.a species. So potentially in MRSA (+) with PVL toxin but i never seen it in real life lol...

 

[Praziquantel86]

I was wondering whether any CC or ID people can weigh in on some of the secondary, less-defined effects of antibiotics.

For example, clindamycin is a protein synthesis inhibitor used for anaerobic infections, but it's also used for MRSA infections due to its inhibition of TSST.

Macrolides are antibiotics used in a number of situations, but they may also have anti-inflammatory properties and are used as such in chronic respiratory diseases like cystic fibrosis, panbronchiolitis, etc.

Any other examples?

Clinda also has the "Eagle Effect" where you see efficacy against group A strep at high innocula where penicillin doesn't touch them. Provides the rationale (in addition to the mentioned toxin synthesis inhibition) for its use in necrotizing fasciitis.

The tetracyclines also have antiinflammatory effects independent of their antimicrobial properties, explaining some of their role in dental and dermatologic conditions.

The penicillins all, to varying degrees, inhibit platelet aggregation through multiple membrane effects - there was thought for using carbenicillin as a rapid-acting antiplatelet in the early '80s.