Physician as Communicator

Teresa L. Schraeder, M.D.
November 2008

When Sir Alexander Fleming first published his work on the ability of penicillin mold to kill bacteria, he most likely never dreamed that nearly 80 years later antibiotics would save millions of lives and account for 35 billion dollars of drug sales each year. The primary use of antibiotics was and still is to disable bacteria so the body can defeat an infection and prevent disability and death.

But today, antibiotics are being evaluated and clinically used for another purpose – one that neither Fleming nor his colleagues might ever have predicted.

Pulmonologists, dermatologists, gastroenterologists, rheumatologists, ophthalmologists, and other specialists are testing antibiotics against diseases that are not known to be directly caused by or associated with infectious organisms. There is now both clinical and laboratory evidence indicating that many antibiotics appear to act as anti-inflammatory medicines. Similar to NSAIDS (nonsteroidal anti-inflammatory drugs) or corticosteroids, antibiotics dampen down local inflammation in the respiratory tract, the GI tract, the bone, the eyes, and the skin. Why is this radical approach happening in various fields of clinical medicine and research and are there any risks? What does it say about our understanding and use of antibiotics as well as our management of various disease states and knowledge of the immune system?
Antibiotics either alone or in combination with other drugs appear effective, in varying degrees, for the treatment of Crohn’s disease, ulcerative colitis, rheumatoid arthritis, acne, dry eye conditions, cystic fibrosis, Sjogren’s disease, scleroderma, asthma and other disorders --- yet none of these inflammatory diseases has a known bacterial cause.

While understanding the science behind this treatment is preliminary and the practice is mostly limited to an “off-label” use of the drugs, in a few areas it has been practiced for decades. But it is not without its opponents or naysayers – including infectious disease specialists who constantly rail against the misuse of antibiotics pointing to development of antibiotic resistance. Or others who think the use of antibiotics as anti-inflammatory medicine is nonsense even though clinical evidence indicates otherwise.

Pulmonologists may be leading the way in researching (but not yet routinely using) antibiotics as anti-inflammatory medication when there is no overt infection. Several studies have shown that macrolide antibiotics such as clarithromycin, erythromycin, and azithromycin are helpful in treating inflammatory diseases of the lungs: asthma, panbronchiolitis, cystic fibrosis and bronchiectasis. Recently, the use of antibiotics in this way has become a hotly debated topic at many pulmonary and other medical conferences.

The hypothesis is that there is a direct immunosuppressive effect of macrolide antibiotics on neutrophils and T-cell functions of the immune system – and evidence that antibiotics decrease the inflammatory chemicals called cytokines emitted by white blood cells.
Many physicians are cautious and skeptical, even with a decade of in vitro evidence of antibiotic-induced immune modulation. Most are not ready to make any clinical conclusions about direct disease effects – and, of course, there may be more than one explanation of why patients feel improvement.

“It is these cytokines that make you feel bad when you are sick so taking anything that reduces them will obviously just make you feel better,” said Dr. Robert C. Moellering, a leading infectious disease specialist at Beth Israel Deaconess Medical Center in Boston.

For years, gastroenterologists have prescribed antibiotics for inflammatory bowel disease (IBD) like Crohn’s and ulcerative colitis. These autoimmune maladies are marked by the body’s immune response, and hence inflammation, attacking the intestinal tract. Antibiotics such as metronidazole and ciprofloxacin are prescribed for disease flare-ups and to keep the disorders at bay. The antibiotics work by directly targeting the tissue inflammation more than any effect on bacteria in the gut.

Dermatologists have prescribed antibiotics to adolescents with acne for decades. At first, doctors thought tetracycline worked against acne because the drug’s effect on the bacterial component of the disorder (Propionibacterium acnes, a normal inhabitant of the skin). But now it is understood that the drug’s most important effect is to reduce the inflammation by reducing the inflammatory chemicals in the skin.

Ophthalmologists and orthopedists are also exploring and exploiting the potential anti-inflammatory benefits.

Meibomian gland dysfunction is a sterile eye condition causing dry eye, irritation and abnormal tearing. It is first treated with warm compresses, eye lid massage and artificial tears. But when those conservative measures do not work, oral doxycycline is prescribed, often for months at a time. Topical or oral antibiotics thin out the sludging of the oil glands in the eyelids.

Orthopedic researcher David Markel at Wayne State University is experimenting with erythromycin to prevent osteolysis (or bone degradation) around hip prostheses that causes joint loosening and prosthetic failure. At the 2008 Orthopaedic Research Society meetings, Markel presented a placebo controlled trial showing a reduction in inflammation markers in the joint fluid (and the blood) in patients taking oral erythromycin for one month before their failing artificial hips were replaced. His paper called the antibiotic treatment “a promising strategy to prevent or reduce the formation of chronic inflammation” in bone.

Teleologically, why might antibiotics modify inflammatory cells? One theory is that certain antibiotics are designed to disable bacteria by disrupting protein synthesis inside bacterial cells. They may target our human cells the same way. After all, we are evolutionary cousins of bacteria, so the antibiotics may not make a distinction.

Dr. David Trentham, a rheumatologist at Boston’s Beth Israel Hospital, estimates that 5 to 10% of rheumatoid arthritis patients in the United States (the numbers are higher in other countries) have taken antibiotics such as tetracycline, minocycline or doxycycline for their disease. He spent much of his career studying the effects of tetracycline on rheumatoid arthritis – initially with the thought that there may be an infectious cause to the disorder – perhaps Mycoplasma. But no such infectious link to the disease has ever been found.

“The jury is still out really, researchers are still looking for an infectious agent as a cause of rheumatoid arthritis in part because antibiotics do have a therapeutic effect,” Trentham said in an interview, “but really the antibiotics in this disease may be working all through their anti-inflammatory effects against inflammation, we just don’t know.”

And there are reasons all of this is difficult to get a handle on for scientists and clinicians. It is more difficult to determine the clinical efficacy of antibiotics against inflammation to everyone’s satisfaction than to pin down their anti-inflammatory mechanism of action in the test tube. First, many of these diseases are characterized by waxing and waning symptoms, so it is problematic, if not impossible to prove the antibiotics are working in this anti-inflammatory manner. Of course, there is always the possibility of the placebo effect. Furthermore, the difficulty with evaluating all of this is that the signs of inflammation are the same as the signs of infection -- fever, pain, erythema, and swelling. Infection is almost always associated with inflammation; the converse is not always true. Without any evidence of bacteria in these diseases then one must assume there is no infection – only inflammation. But could there actually be a “subclinical infection” in some of these diseases that no current test can find? Or might the antibiotics possibly be working as a prophylaxis against an impending infection? Or are the symptoms really just inflammation after an infection has been naturally cleared by the immune system – long before the antibiotics were started or the cultures taken? There is likely a spectrum between inflammation and infection that is not yet fully elucidated.

And, if the antibiotics do rein in or emasculate inflammatory cells, then they do so at such a local level that they merely diminish the symptoms of inflammation but do not adversely affect the body’s ability to protect itself.

Regardless of the chronic inflammatory illness where antibiotics might be used, there are many skeptics of this practice or any new research being conducted.

“The problem as I see it is that the ‘research’ using antibiotics for non-infectious disorders is underpowered and not sufficiently scientific, so with a few exceptions (acne, for example) we never do find out reliably whether the treatment has benefit. All we have are anecdotes,” wrote Dr. Jerome P. Kassirer, Distinguished Professor, Tufts University School of Medicine, in a recent email correspondence.

Also, antibiotics, like all drugs carry side-effects including yeast infections, serious bacterial infections such as Clostridium difficile of the intestines, and other problems such as tinnitus, photosensitivity, kidney damage, and interactions with other drugs. And there is the unwanted increase in antibiotic resistant bacteria.

Side-effects and increases in antibiotic resistance not withstanding, is using antibiotics in this way the equivalent of pharmacologic "punting" in medicine? Perhaps prescribing an antibiotic just to "calm" things down on a cellular level is just the equivalent of what doctors did in centuries past when they prescribed elixirs made mostly of alcohol or other sedatives. Or maybe the use of antibiotics in this way in fact treats the very cause of the major symptoms in so many disease states - inflamed cells, tissues, and membranes.

If more clinical evidence is uncovered, what could this possible dual action of antibiotics tell us about the use of antibiotics in infectious diseases? Perhaps a synergistic immune mechanism of eradicating the disease stimulus (the bacteria) as well as decreasing local signals from the immune cells will explain more fully how antibiotics work inside the body.

Robert Moellering acknowledges that there is little discussion of the use of antibiotics as anti-inflammatory medicine between various specialists in medicine; he thinks there should be – especially if it becomes more pervasive.

“We need to do more studies comparing antibiotics to anti-inflammatory medications such as NSAIDS or steroids or other drugs. The data are just not there yet,” urged Moellering.

And until there are more data?

“I would hope physicians would try to use other agents that have anti-inflammatory activity,” Moellering encouraged, “we should not be using antibiotics if no infection is present.”

In the meantime, research about the possible anti-inflammatory properties of antibiotics continues – and perhaps how any immune-modulating properties can be reproduced in the development of new non-antibiotic drugs.

Not surprisingly, the approach illustrates how the medical profession is so subdivided into specialties, that it sometimes takes awhile to realize that an unusual practice has become somewhat widespread – at least on an experimental basis. Perhaps it is not unusual that physicians from such widely disparate fields have empirically come to a similar strategy of treating inflammatory disorders – especially with such a common class of drugs that appears to have similar effects. Perhaps our lack of understanding of the mechanism merely illustrates our lack of knowledge of the mechanisms of the immune system.

And if antibiotics ever become a recommended viable clinical option for chronic inflammatory diseases -- it won’t be the first time, an unknown use of a common drug was discovered long after its introduction.

For now, at least we may have another explanation, besides the placebo effect, why some individuals feel better when they inappropriately take (and physicians inappropriately prescribe) an antibiotic for viral bronchitis.

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