Sunday, June 24, 2018

C. Diff and doxycycline magic


C diff is a dread complication of antibiotic therapy. Clostridia difficile, an anaerobic bacterium may reside in gut as an innocent bystander, causing no trouble unless something happens.  We call this germ an opportunistic pathogen.  It causes disease only when favorable circumstances present.  The degree of illness varies.  It may present as diarrhea which resolves when antibiotics are stopped or a life threatening disease. 
Risk factors  for C diff are well known.  Antibiotics are at the top of the lists. Other risk factors include age (greater than 65), chronic medical illness, hospitalization and admission to long-term care facilities, including nursing homes. 
C diff patients may have diarrhea:  frequent, watery stools. There may be associated mucous and/or blood and stools may be fowl swelling.  Symptoms and signs of more serious infection include:  fever, elevated white blood cell count, abdominal pain, abdominal swelling and shock. 
In the past Flagyl and Vancomycin were effective therapy. A new drug, Dificid is approved for C. diff.  Drug resistance strains have started appearing, of great concern. 
Sometimes infection is like a runaway wildfire and very hard to stop.  Surgery may be required. Fecal transplants are sometimes used.  Fatal cases occur. 
We like to think probiotics ward off the disease, but this is far from certain.  Traditional probiotics may have some benefits, but limited.  Florastor or Saccharomyces boulardii may be slightly beneficial.
There is something else to consider before we discard long-term antibiotics. 
The choice of antibiotic makes an enormous difference. 
When first described, C diff was tied to clindamycin. Later it was learned that other or most antibiotics can cause C diff colitis. Sometimes it is writ that “any antibiotic” can cause C diff.  Maybe not.
There is a hierarchy of which antibiotics and classes of antibiotics are most likely to cause C diff.
Clindamycin is at the top. Quinolones including Cipro and Levaquin are a close second. Cephalosporins, including Ceftin are next. Penicillins like amoxicillin are on the next rung. These drugs are all considered high-risk.  The next group, medium-risk, includes Macrolides such as Biaxin and Zithromax and Sulfa drugs such as Bactrim. Low-risk drugs include tetracyclines, doxycycline and minocycline, rifamycin including rifampin and certain antiparasitic drugs including Flagyl. 
And this brings us to my next topic. Doxycycline: the magical drug. 
It turns out that studies show not only that doxycycline is a C diff low-risk drug, but doxycycline seems to reduce the incidence of acquiring C diff when compared to a control group taking no antibiotics.  In other words, doxycycline may protect against getting C diff. 
This is huge.
No wonder dermatologists prescribe doxycycline to armies of 15-year-olds with impunity. 
Rifampin may have a similar benefit, lowering the risk of C diff. 
 Although there is not data regarding Flagyl, claims to the contrary, it is likely the risk of Flagyl is very low since this is one of the traditional drugs used to treat C diff. 
The prejudice against doxycycline percolating up through internet sources is unfounded.
It stems from the fact that doxycycline is ineffective against Lyme persister forms, round forms and biofilm communities. Take another look.
Doxycycline is the most active drug against spirochete forms.  No one drug does a great job killing persister forms, except daptomycin which is not a realistic option.  Cocktail therapy always works best. There is one drug which shows up in every cocktail group proposed through Zang’s research, with on exception, that is doxycycline. In the other group minocycline was used instead. 
Doxycycline appears to have unique, broad synergy when combined with a host of other antibiotics from other classes. 
Lyme killing cocktails rely on synergy between or amongst chosen antimicrobial agents. The above data show possible advantages of cocktail combining doxycycline, rifampin and Flagyl (Tindamax) and/or artemisinin, in some form (in theory).  Informational purposes. I am not recommending any specific therapy.  

Test tube data are really important, especially at this stage of our understanding,. This data cannot be and should not be translated directly into clinical recommendations. Please. 
There are other factors the Zhang data cannot take into account.  Antibiotics in a test tube are judged based on concentration in a culture broth, a surrogate for serum concentration. It turns out that the ability of drugs to concentrate in tissue is extremely variable.  Tissue concentration of an antibiotic, for example doxycycline, are frequently many fold higher than serum level.
This might seem irrelevant because after all, doxycycline has no impact on non-spirochete forms. Right? 
Maybe not.  In the 2017 study round forms of Borrelia burgdorferi, Lyme bacteria were cultivated the effects of many agents tested.  A goal of the study was to test the effects of sulfa drugs. Sulfa drugs performed poorly.  Drugs were tested at three different concentrations: low, medium and high. Concentrations are reported in molar values and I have no idea how this compares to real life serum values. The data show that as serum concentration increase the ability of the drugs to kill the round, persister form increases. At higher concentration doxycycline starts to diverge from the control and show benefits comparable to other drugs and drug combinations (still poor), having an impact on round forms. 
 Other factors are: bioavailability, tolerability and toxicity, clinical factors outside the sphere of test tube studies. Clinically, these are all very important.
Doxycycline has unique bioavailability, nearly 100% when taken orally. It is not metabolized by either the liver or kidneys. It has very low toxicity and is often well tolerated. These factors are clinically very important. 
Then there is the other thing, when it comes to treating and/or preventing tickborne infections.
Only one drug can kill germs associated with:  ehrlichiosis, anaplasmosis, STARI associated Borrelia species, Rickettsia (including Rocky Mountain Spotted Fever), Mycoplasma, Chlamydia pneumonia, tularemia, brucellosis and prevent early bartonellosis and babesiosis. 
You guessed it:  Doxycycline. 
Sure, a lot of people don’t tolerate it well in the summer and a lot of people experience GI upset.
Minocycline may be second choice, although I can’t say it has all the same benefits.
Keep this is mind when amoxicillin is offered as the second choice drug after a tick bite.

3 comments:

bolavita kari said...
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Unknown said...

In an infection these conditions may not be met and one thing we do know is that bacteria often thrive where tissue is dead - which is one reason why they are having such problems clearing the infection from your fractured bone. Fractures kill off bits of bone and soft tissue.

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warwick wood said...

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