Repeated use of an antibiotic that is considered generally benign, because users seldom incur obvious side effects, induces cumulative and persistent changes in the composition of the beneficial microbial species inhabiting the human gut

[Oliver Crangle]

text-to-speech podcast


Repeated antibiotic use alters gut's composition of beneficial
microbes, study shows

Repeated use of an antibiotic that is considered generally benign,
because users seldom incur obvious side effects, induces cumulative
and persistent changes in the composition of the beneficial microbial
species inhabiting the human gut, researchers at the Stanford
University School of Medicine have found.

By a conservative estimate, something like 1,000 different varieties
of microbes coexist harmoniously within a typical healthy person's
gut, said David Relman, MD, professor of medicine and of microbiology
and immunology at the medical school and chief of the infectious
diseases division at the Veterans Affairs Palo Alto Health Care
System. Relman is the senior author of a paper, which will appear
online Sept. 13 in Proceedings of the National Academy of Sciences.

The study examined the effects of ciprofloxacin (trade name Cipro), an
antibiotic that is widely prescribed for intestinal, urinary and a
variety of systemic infections. In an earlier, short-term study,
Relman's group had concluded that people's intestinal microbial
communities seem to bounce back reasonably well within weeks after a
five-day regimen of ciprofloxacin. This new study involved two courses
of antibiotic administration, six months apart, and it revealed more-
subtle, long-term effects of ciprofloxacin use - such as the
replacement of multiple resident bacterial species by other, closely
related varieties and the occasional complete eradication of a
species.

The infrequent occurrence of easily visible side effects such as
bloating and diarrhea from ciprofloxacin use has given rise to an
assumption that the drug spares most beneficial gut-dwelling bacteria.
Overall similarities between pre-regimen gut bacterial strains and
their post-regimen replacements explain why such side effects aren't
typically seen after ciprofloxacin use. Still, the more nuanced
differences between the pre-existing communities and those that appear
in the wake of this repeated disturbance present a new set of
problems, said Relman, who is also the Thomas C. and Joan M. Merigan
Professor at the medical school. A bacterial species whose presence
was lost or diminished may have been performing a valuable job - for
example, secreting a protein that's toxic to a particular pathogen -
that is shirked by its replacement. The abandoned function might not
be noticed until, perhaps, years later when the pathogen in question
invaded the person's gut.

While the study's findings shouldn't be interpreted to mean that
ciprofloxacin is dangerous and should be avoided, Relman said, they do
raise questions about possible long-term effects of antibiotic
administration, in addition to concerns about spurring the evolution
of drug-resistant organisms. The new findings underscore the
desirability of finding ways to pinpoint not just which bacteria have
been lost or whose numbers were diminished by an antibiotic, but also
which important beneficial functions performed by the patient's gut
microbial community as a whole have been impaired - such as signaling
cells of the intestinal lining, which are constantly turning over, to
maintain an appropriate barrier against ingested toxic compounds, or
secreting anti-inflammatory substances that may prevent allergic or
autoimmune diseases.

For this study, the Stanford scientists collected more than 50 stool
samples from each of three healthy adult females over a period of 10
months. Then they used advanced, molecular techniques to count the
number of different microbial species represented in each sample, as
well as relative population sizes of the different species in that
sample.

Twice during this 10-month period, the researchers perturbed their
subjects' gut ecosystems by giving them five-day courses of
ciprofloxacin at a standard dose. During the first course, overall
bacterial populations in each subject - which had previously waxed and
waned but, on the whole, been quite stable - plummeted and remained
depressed for about a week. Roughly one-third to one-half of the
resident species' populations declined, with some disappearing
entirely. A few originally less-abundant species grew in number, as
they filled in the ecological niche abandoned by bugs adversely
affected by the drug.

Within a week after the first course's completion, two of the three
subjects' internal microbial ecosystems had largely returned to a
state fairly similar to that before the regimen, as measured by the
broad classes to which the microbial constituents belonged. One
subject's overall ecosystem, however, still had not recovered even by
that rough measure a full six months later.

The second course of antibiotic administration produced a stronger
effect. "Even the one subject whose gut bacterial community fully
recovered after the first ciprofloxacin course experienced an
incomplete recovery after the second one," said Relman. The
communities in the other two subjects partially recovered from the
second course, but never returned to their original state. In essence,
each subject's community of gut-dwelling microbes shifted to a new,
"alternative" state and remained in that state for at least two months
after the second antibiotic course had been completed. Thus, all three
subjects experienced significant and lasting changes in the specific
membership of their internal microbial communities at the end of the
10-month study period.

"Ecologists have found that an ecosystem, such as a wildlife refuge,
that is quite capable of rebounding from even huge occasional
perturbations - forest fire, volcanic eruption, pests - may yet be
undone by too rapid a series of such perturbations," said Les
Dethlefsen, PhD, a research scientist in Relman's lab and the study's
first author. "In the same way, recurring antibiotic use may produce a
cumulative effect on our internal microbial ecosystems with
potentially debilitating, if as yet unpredictable, consequences."

"It's as if your beneficial bacteria 'remember' the bad things done to
them in the past," said Relman. "Clinical signs and symptoms may be
the last thing to show up."

The precise counts of gut-dwelling microbes in this study were made
possible by a new technique, pioneered in recent years by Relman and
others. The older method - growing the microbes in culture - simply
doesn't work for many species and, even when it does, rare species are
often swamped by more common ones and don't get counted. The new
technique reads short, telltale DNA snippets that distinguish microbes
both from human cells and one from another. This allowed the Stanford
researchers to assess both the total number of different microbial
varieties and the relative size of each variety's population.

Similar techniques now make it possible to assess, before and after
antibiotic administration, the abundance in a patient's gut of
microbial genes known to code for important functions performed by one
or more members of the patient's gut community, Relman said. In the
future, if it becomes known that a key function has been impaired,
clinicians might perhaps restore that function by prescribing specific
probiotics or nutrients that encourage the return of appropriate
beneficial bugs.

Provided by Stanford University Medical Center





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Reactions to Cipro, Levaquin, and Other Fluoroquinolone Antibiotics - joint, muscle, or tendon pain or rupture, nerve pain (burning, electrical sensations, tingling), muscle weakness, thinking or memory problems, heart palpitations, rapid heart...

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Reactions to Cipro, Levaquin, and Other Fluoroquinolone Antibiotics


Since the December, 2001, publication of my article in the Annals of Pharmacotherapy,1 I've received hundreds of e-mails from people suffering from devastating, long-lasting side effects associated with Cipro, Levaquin, Floxin, and other fluoroquinolone antibiotics. Most of these people are young and had been healthy and active.
These antibiotics have legitimate uses in treating infectious diseases, but they are overused for minor conditions such as sinusitis, prostatitis, and bladder infections. My stance is that Cipro, Levaquin, and similar antibiotics should be used only when other, safer drugs are ineffective, or for organisms that are only sensitive to fluoroquinolones.
As I said on National Public Radio in October 2001, I strongly believe that all people placed on these antibiotics should be warned about infrequent yet serious reactions that may cause joint, muscle, or tendon pain or rupture, nerve pain (burning, electrical sensations, tingling), muscle weakness, thinking or memory problems, heart palpitations, rapid heart rate, gastric problems, skin rash, or many other unusual physical or psychological symptoms. These reactions can occur quickly and suddenly, and patients should alert their doctors immediately.
Doctors, for their part, must recognize that these symptoms can lead to severe, long-term pain or dysfunction, and should stop the antibiotics immediately if at all possible. Because adverse reactions may increase in severity and duration with each exposure, patients with these reactions should not receive fluoroquinolones again. I'd hoped that my article would accomplish this, just as it prompted the U.S. Centers for Disease Control to alter their guidelines for treating anthrax. But it hasn't had the same impact on the medical system.
"These adverse reactions can occur quickly and severely. Doctors must be better informed."

Most people do fine with these antibiotics. For those who don't, the effects can often be minimized with proper warning and prompt response. Unfortunately, few patients were given any warnings. Again, their rights of informed consent are violated.
On the hopeful side, I have spoken to the FDA about this issue. They are taking a very serious look at the problem. But although the FDA has already received thousands of reports, action is slow. And even if the FDA requires new warnings in package inserts and the PDR, most doctors will never notice them, and because of the unrelenting influence of the drug industry, most doctors will continue to overprescribe these drugs when other, safer, cheaper drugs would do.
So you'd better be informed. Preventing fluoroquinolone reactions is much, much better than trying to treat them, because there is no known, specific treatment. Below is the information that I have sent to people seeking help. I don't know if any of these suggestions is highly effective, but having experienced a severe, long-term disability myself in the mid-1990s and now having improved considerably, I encourage people to keep asking questions and trying things. You can also connect with others enduring similar experiences with fluoroquinolones at the web sites listed at the end of this article.
Information for People with Fluoroquinolone-Related Reactions
I have sent this information to hundreds of people who have contacted me about their reactions following the publication of my paper. I wrote the paper so that people having these types of problems might get accurately diagnosed, because most physicians have no idea how severe some of these fluoroquinolone-related reactions can be.
First, I should explain I am not a neurologist or orthopedist. I am a researcher and my major area of expertise is medication reactions, which you can read about in my medical journal articles and my recent book, Over Dose: The Case Against The Drug Companies (Tarcher/Putnam, info & reviews at amazon.com). I wrote the article about fluoroquinolones because of the reports I received and because no one was paying attention to this serious problem. My knowledge about fluoroquinolones in particular and antibiotics in general is limited to what is contained in the article. I have not conducted any new research on fluoroquinolones since writing my article in the Annals of Pharmacotherapy in December, 2001, so you need to check the medical literature and others sources for updated information.
Regrettably, there are few doctors who are informed about fluoroquinolone-related reactions. You might find information about knowledgeable doctors at some of the fluoroquinolone websites, where people have posted a lot of useful information.
As far as I know, there are no specific treatments for the nerve or tendon/joint/muscle problems associated with Cipro, Floxin, and Levaquin, and other fluoroquinolones. Most of my information is hypothetical or anecdotal; some of these recommendations may help some people, but not others.
Medications such as amitriptyline or other tricyclics, or Neurontin (gabapentin), may be helpful for neuropathic pain (tingling, burning or electrical sensations) or nerve pain. Muscle spasms, twitching, tremors, and seizures may be helped with long-acting benzodiazepines such as clonazepam (Klonopin) or diazepam (Valium). SSRI antidepressants (Zoloft, Paxil, Effexor, Prozac, etc.) are occasionally helpful for depression. Because patients' nervous system are sometimes very sensitive, these drugs should be started at very low doses and increased, if necessary, very gradually.
Magnesium (chelated) in doses of 400-1000 mg/day may be useful for reducing neuropathic pain or muscle spasms in some people. Doses over the U.S. recommended daily amount of 320 for women and 400 for men should always be taken with a doctor's supervision. Seniors, people with kidney disorders, and those taking medications for heart, hypertension, or other vascular or neurological disorders should have medical supervision even for RDA doses of magnesium.
Interestingly, another doctor has also been recommending magnesium, as low doses of milk of magnesia (1 or 2 teaspoons twice-daily), to be taken for several months. The theory is that because of the affinity of minerals for these antibiotics, this might help leech some of the remaining fluoroquinolone molecules from the tissues. Some patients have benefited, but not all. In discussion with this doctor, our sense is that calcium, magnesium, and perhaps other minerals may be beneficial. With magnesium, better absorption is important to get the magnesium into the tissues, so chelated magnesium or a magnesium solution might work best. As with all of these recommendations, there's little solid science, so it's trial and error. (For more information on magnesium, please go to the other magnesium sections of this website.)
B-vitamins have been reported to reduce tingling. One person wrote to me that high doses of lecithin have helped with memory problems. GABA, an amino acid, has some similar qualities to Valium and Klonopin and may be helpful for anxiety, nervousness, or insomnia.
Anti-inflammatory drugs are controversial: some people have written to me that they have helped, especially for muscle/joint/tendon pain; others have written that they have worsened their conditions. If you have benefited from anti-inflammatory drugs, you might obtain additional benefit from high doses of omega-3 oils (fish oils; EPA/DHA). There is considerable literature on this. Omega-3 oils take time to work, but the ultimate result can be better than standard anti-inflammatory drugs (NSAIDs).
Many alternative doctors are knowledgeable about magnesium, GABA, omega-3 oils and, perhaps, about other possibilities.
Corticosteroids (cortisone, etc.) are very controversial. Doctors sometimes prescribe steroids in the hope of reducing the reactions, but many people have written that steroids actually made their cases worse. Steroids should be used with great caution unless there is a specific indication.
Fluoroquinolone-linked reactions can be nasty, and recovery varies from individual to individual, with some reactions resolving quickly and others lasting years. That's why I do not advocate using fluoroquinolones as the first antibiotics for treating minor infections. If we are ever to change the medical-pharmaceutical mindset about this, it will be accomplished by patients. So please submit a Medwatch report. It's easy to do at: www.fda.gov/medwatch/report/consumer/consumer.htm. Or call 800-FDA-1088).
I regret that I cannot give you a more specific, well-proven remedy for these reactions. It is tragic -- and very frustrating -- that the medical-pharmaceutical system frequently fails to recognize these problems and, therefore, doesn't warn patients or doctors. So doctors not only fail to recognize the reactions, but continue to prescribe fluoroquinolones to people who've already shown signs of toxicity previously. It's a terrible situation, but not unlike I've seen and written about with other drugs.
I hope that your condition resolves soon. Sincerely, Jay S. Cohen, M.D.

1. Cohen, JS. Peripheral Neuropathy with Fluoroquinolone Antibiotics. Annals of Pharmacotherapy, Dec. 2001;35(12):1540-47.
Copyright 2003, Jay S. Cohen, M.D. Readers have my permission to copy and disseminate all or part of this newsletter if it is clearly identified as the work of: Jay S. Cohen, M.D., The Free MedicationSense Underground E-Newsletter, July-August 2003, www.MedicationSense.com.
Websites for Information on Fluoroquinolone-Related Reactions
Quinolone Antibiotics Adverse Reaction Forum:
http://www.geocities.com/quinolones/

Discussion Group Website of the Quinolone Forum: Case Reports, Updated Reports, Information, Support, and More
http://groups.yahoo.com/group/quinolones/messages/?threaded=1

DrugVictims.Org: Information, Articles, Studies, Personal Reports of Reactions to Quinolones
http://www.drugvictims.org/

RxList Website: Levaquin Case Reports
http://www.rxlist.com/rxboard/levaquin.pl

Medications.com: Levaquin Case Reports
http://medications.com/index.php?act=se&drug=Levaquin

Fluoroquinolone Adverse Effects Research & Recovery Forum:
http://groups.yahoo.com/group/fq_research




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