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Fluoroquinolone Antibiotics and Tendonitis


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Here is something to watch out for. My apologies if it has aready been covered. I did search.

 

There is a class of antibiotics prescribed by doctors to fight infections called fluoroquinolones, some of which have a side effect that is particularly bad for climbers. They can cause "pain, inflammation and rupture of a tendon". Both Tequin (gatifloxacin) and Levaquin (levofloxacin) have this as a COMMON side effect.

 

My wife took Levaquin for an infection and immediately developed painful tendons in her hands. My understanding is that the drug causes the tendons to shorten and become brittle. The pain went away a few weeks after she discontinued the medication.

 

If you should ever see a doctor about an infection, be sure to ask him if the medicine has any side effects relating to tendons. If so, ask him if he can substitute a different antibiotic that doesn't have this side-effect.

 

Oh, lest I be called a plagarist. I got the idea for this post from a thread on RockClimbing.com.

Edited by catbirdseat
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So far as I know, the fluoroquinolones are the only class of antibiotics to have this side effect. I have no idea what the mechanism is. This effect on connective tissue is also why they are contraindicated for children. I spent a summer researching the activity of Cipro against certain bacteria, before it was licensed, and I remember learning that in animal studies the drug was found to cause cartilage dysplasia in beagle puppies. (Thank God for animal research! snaf.gifshocked.gif) They're slowly edging into using it on children in cases where other drugs aren't working, such as advanced cystic fibrosis. So far as I know, it hasn't caused this in human beings. Still, though it's otherwise a very effective and well tolerated drug, there is almost always a cheaper alternative. The main drugs in this group are: Cipro, Levaquin, Tequin, and Avelox. There are a few others as well, whose names I forget just now.

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So is it the case that every known fluoroquinolone has this side effect?

 

Apparently, the answer is yes, but some are worse than others:

 

"We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin." Source: [/url] Pub Med

 

There were a whole bunch of articles on "spontaneous achilles tendon ruptures" associated with the use of fluoroquinolones. Yikes!

 

So what is the mechanism? No one knows for sure, but they are closing in on the answer. Some think that fluoroquinolones stimulate enzymes that digest cartilage, the "matrix metalloproteinases". Abstract

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Al_Pine said:

Fuck CBS are you kidding? Tell that to your doctor and they'll most likely say, "What's a tendon?" Then look at you like you're a bug or something.

 

Look out for yourself out there.

 

Extremely constructive comment. Thank you.

 

Here is some info from micromedex (probably the most used online resource for doctors and pharmacists):

 

Ciprofloxacin-induced tendonitis, an unusual adverse drug effect, can be unilateral or bilateral appearing between 3 and 30 days after initiating therapy. Prognosis is usually favorable and symptoms resolve within the first week after antibiotic discontinuation with persistent symptoms occurring for several weeks in some patients. The mechanism for tendon damage is unknown. Tendon necrosis related to ischemic processes in areas of deficient blood supply has been suggested (Carrasco, et al, 1997).

 

As of October 1994, the FDA's Postmarketing Spontaneous Reporting System has received 25 case reports of TENDON RUPTURE thought to be associated with fluoriquinolone therapy (Szarfman et al, 1995). A majority of the cases occurred outside the United States. The patients were 33 to 85 years of age with most of the ruptures (n=17) occurring bilaterally or unilaterally in the Achilles tendon. Tendon rupture was reported to occur 2 to 42 days after the start of fluoroquinolone therapy. Most patients allegedly received therapeutic doses; however, in 7 patients the dosage may have been higher than recommended. Of the 25 cases, 16 had risk factors for tendon rupture (eg, concomitant corticosteroids, advanced age, long-term dialysis). Other sources have stated that more than 40 cases of Achilles tendonitis and rupture have been associated with the fluoroquinolone antibiotics (Huston, 1994).

 

A retrospective review of outpatient prescriptions for ciprofloxacin (n=2,122) within a naval medical center over a one year period was conducted. International Classification of Diseases (ICD9) codes for admission for ACHILLES TENDON RUPTURE were identified among the ciprofloxacin prescriptions. None of the 24 admissions for Achilles tendon rupture received ciprofloxacin. The result was not statistically significant and clinic visits (non-admission visits) were not apparently analyzed. The authors concluded that prospective studies are needed to quantify relative risk of Achilles tendon rupture in patients treated with ciprofloxacin and other quinolones (Shinohara et al, 1997).

 

 

 

Cipro is one of the most frequently prescribed medications in the world. It is one of the safest antibiotics with a very low rate of cross reaction with other drugs and adverse drug reactions, but as with all medications there is some finite risk.

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mneagle said:

Al_Pine said:

Fuck CBS are you kidding? Tell that to your doctor and they'll most likely say, "What's a tendon?" Then look at you like you're a bug or something.

 

Look out for yourself out there.

 

Extremely constructive comment. Thank you.

 

[cut and paste websurfing stuff snipped, but can be read above]

 

Your welcome Doc. Actually, I was probably wrong about what I wrote. Most doctors will never admit to not knowing something (I believe they are trained to act "decisively". Bad bedside manner to appear mortal.) Some, like CBS's doc, will promise to look into it. Some will just lie through their teeth, pretend they actually know what a tendon is, and move on to the next patient. I have seen both.

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I agree, watch out! Medicine is a very complicated field. Do not believe the hype that your doctor knows all the answers. He/she probably knows more than you, but that doesn't mean you shouldn't be able to press them on why they recommend something to do or put into your body.

 

Try taking this challenge. If your doctor recommends something that you are unsure about, for example, using a fluoroquinalone AB, ask him/her why they recommend this. See if they get all flustered and/or start treating you like a child, or if they attempt to explain their reasoning to you in a respectful way.

 

You are paying a lot of money for a few minutes of their time. I believe that entitles you to ask a few questions (in a respectful manner) and get some answers.

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  • 3 months later...

I have been looking into this more. There are many case reports available in PubMed about fluoroquinolone-induced tendonitis and tendon rupture. Mostly the people are old who get the tendon rupture, but apparently it is suspected that the effects could be intensified by steroid use, and NSAID use, both medications commonly used to treat tendon problems.

 

In some cases the symptoms persisted 6 months after the patient discontinued the drug.

 

 

There is currently a class-action lawsuit going on by a lot of the people who took a bunch of Cipro (probably preventive vs Anthrax) and are having tendon problems. The basis of the suit is that Bayer deceptitvely markets the drug and downplays the side effects. Apparently doctors are not always aware of the contraindications for Cipro and NSAIDS.

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From this link. Truth in Advertising: it's a law firm that's currently working on the above-mentioned class-action.

 

"Compounding the problem is that there are numerous drugs which should not be taken in combination with fluoroquinolones. There are increased risks of injury when fluoroquinolones are taken in combination with corticosteriods (e.g.: Prednisone, Flovent, Nasarel, Azmacort, Advair Disku, Methylprednisolone Dospak, Elocon Cream, Desoximetasone Cream, and Sterapred) and when taken in combinations with non-steroidal anti-inflamatory drugs (NSAIDs) (e.g.: Motrin, Pamprin, Aleve, Advil, and Ibuprofen, among others). Physicians are frequently not aware of these contraindications and prescribe dangerous combinations of drugs which cause severe injuries to their patients. Physicians may also not be able to identify that their patient is suffering an adverse reaction and instruct them to continue to take more fluoroquinolones resulting in very serious and perhaps preventable injuries."

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Of course a law firm is going to run with any minimal evidence supporting a potential lawsuit!...

 

Before believing someone who has millions of dollars to score when they say that "dangerous" combinations are causing "severe" injury it may be a good idea to look for independent data, and check out the FDA's prescribing info:

FDA info

 

This document only mentions NSAID's once:

 

"In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones."

 

I did not see NSAID's contraindicated anywhere in the document.

 

Tendon rupture is mentioned as a potential, rare side-effect. Every drug has lots of potential, rare side effects.

 

Some other rare, partially unsubstantiated side effects of Cipro include agitation, agranulocytosis, albuminuria, anaphylactic reactions, anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, flatulence, glucose elevation (blood), hemolytic anemia, hepatic necrosis, hypotension (postural), jaundice, methemoglobinemia, myalgia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis, phenytoin alteration (serum), potassium elevation (serum), prothrombin time prolongation, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal calculi, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, toxic epidermal necrolysis, triglyceride elevation (serum),

vaginal candidiasis, and vasculitis.

 

There are also 50-75 “common” side effects listed.

 

If you expect your physician to know all of this offhand, you have some pretty high expectations of others.

 

And if you experience one of these many symptoms in conjunction with weak data or meaningless “case reports” you have the potential to sue your doctor and make a bunch of money!

 

Plus if one of the common side effects is experienced, eg nausea (5.2%), diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache (1.2%), restlessness (1.1%), or rash (1.1%), it would be pretty difficult to know that the drug is causing it.

 

I bet a lot of people have had a headache recently, even without taking Cipro! Should a patient with a “potential” drug interaction be switched to a less effective medication if that may increase the risk of serious complications from an infection? This is not a straightforward issue.

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Of course a law firm is going to run with any minimal evidence supporting a potential lawsuit!...

 

Before believing someone who has millions of dollars to score when they say that "dangerous" combinations are causing "severe" injury it may be a good idea to look for independent data, and check out the FDA's prescribing info:

FDA info

 

Colt,

Agreed that one should be wary of "advice" from a law firm in this case, that is why I clearly marked where the info was from. Two comments though.

 

First do you think that a legal firm would print this stuff on a webpage, potentially impugning huge rich corporations, if there was a chance they could be successfully sued for slander or libel or whatever the relevant crime would be in this case if they just made this stuff up.

 

Second, before impugning the motives of lawyers for the reason of potential to make millions, you better think about the drug companies and how much they stand to make. That argument definitely cuts both ways.

 

Here's the abstract of a review article abstract from Pub-Med. Mentions NSAID's interactions with respect to seizures (not tendinitis I guess).

 

Here's a full article in the British Medical Journal (BMJ. 2002 Jun 1;324(7349):1306-7) presenting the results of a case-control study investigating the fluoroquinolone tendinopathy connection. I'm not sure this article is fully available to everyone so here's the summary ("comment" section)

 

"Current exposure to fluoroquinolones increases the risk of Achilles tendon disorders. This finding is in agreement with a smaller study, in which we found an association between tendinitis and fluoroquinolones. Our results indicate that this adverse effect is relatively rare, with an overall excess risk of 3.2 cases per 1000 patient years. The effect seems to be restricted to people aged 60 or over, and within this group concomitant use of corticosteroids increased the risk substantially. The proportion of Achilles tendon disorders among patients with both risk factors that is attributable to their interaction was 87%. Although the mechanism is unknown, the sudden onset of some tendinopathies, occasionally after a single dose of a fluoroquinolone, suggests a direct toxic effect on collagen fibres. Prescribers should be aware of this risk, especially in elderly people taking corticosteroids."

 

Guess maybe that one was too recent for MNeagle's micromedex. You'd think that something important like that, that many many doctors use as their only source of information about drugs, would have a reference to a well-done case-control study done a year ago in a reputable journal. Funny.

 

 

 

This document only mentions NSAID's once:

 

"In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones."

 

I did not see NSAID's contraindicated anywhere in the document.

 

I believe your quote may indicate that caution with regard to seizures is advised. Doc's please correct me if I'm wrong.

 

 

And if you experience one of these many symptoms in conjunction with weak data or meaningless “case reports” you have the potential to sue your doctor and make a bunch of money!

 

What makes a case report meaningless? Don't expect the drug companies to fund long-term studies to investigate and announce all harmful effects. The only way negative information is going to get out is via case reports. Do a search in PubMed for fluoroquinolones & tendon, you will find a wealth of "meaningless" case reports in peer-reviewed journals.

 

 

I bet a lot of people have had a headache recently, even without taking Cipro! Should a patient with a “potential” drug interaction be switched to a less effective medication if that may increase the risk of serious complications from an infection? This is not a straightforward issue.

 

You are correct here. This is not a straightforward issue. Don't expect your doctor to know everything. Especially don't expect the drug companies to volunteer negative information about their drugs.

 

As a climber, I put a huge strain on my tendons. They are banged up enough as it is. You may think you are young and it won't affect you, then go ahead, make Bayer's day! There is a case report out there about some guy (on a fluoroquinolone concommitant with a steroid I think) who ruptured BOTH achilles tendons bending down to change his VCR tape! You being a climber are probably not as disheveled as this guy, but you are putting a much greater strain on your tendons too.

 

I think it's food for thought. I don't think it can be easily dismissed by saying "all drugs have side effects".

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I may have misinterpreted what you meant by case reports--I thought you were referring to separate reports of individual patient experiences (esentially anecdotal evidence).

 

For example here is an abstract of a peer reviewed article that is NOT particularly informative:

---------------------

J Am Podiatr Med Assoc. 2003 Jul-Aug;93(4):333-5

 

Fluoroquinolones have been associated with tendinopathies. The authors present three cases of Achilles tendinopathy in which the patients' symptoms were preceded by treatment for unrelated bacterial infections with ciprofloxacin. Although the exact mechanism of the relationship is not understood, those who engage in sports or exercise should be advised of the risk of quinolone-induced tendinopathy.

-----------------------

Given the large number of people who have been given Cipro you could pick almost ANY random symptom/outcome and find three people who experienced it. You could probably find three case reports of climbers who redpointed their first 5.13 while taking Cipro, and draw the conclusion that Cipro enhances climbing ability.

 

Drug companies do carry out large, expensive studies before a medication is approved for use. Of course post-marketing surveillance via case reports is important to pick up rare side effects, but it is important to have a reasonable number of cases and hopefully some sort of control population.

 

And while the lawyer web site may not be lying outright, they are definitely giving a slanted view of the data.

 

Regarding the British Medical Journal article you cited: the study found ZERO correlation between fluoroquinolone use and tendon injury for people under 60 years of age. For a person over age 60, the risk appears real but quite small. However it is also worth noting that their choice of control population is questionable: the controls were randomly selected from the provider's practices, instead of being patients who are on an unrelated antibiotic for a similar condition. Consequently they are comparing a group of people KNOWN to have health issue(s) (by virtue of being on an antibiotic) to a group of other people--MANY of whom may have been healthy.

 

Note also that few details are provided on the mechanism of rupture, and that they do not specify statistics regarding the variables going into the "adjusted relative risk" category. All they did was query a database and look for associations (which certainly can give good information). The entire study is just two pages long! For these reasons this study is not necessarily "well done" as you stated. These may be some of the reasons that the provider information has not been modified on the basis of this single database query & statistical analysis.

 

And while the drug companies comprise the most profitable industry in America, they are heavily regulated by the government.

 

In any case it seems like climbers should be aware of these issues. The important thing in my opinion is to keep any such risk in perspective, and look to data for information rather than going with isolated case reports or rumors.

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Also here is the specific use/warning information from Micromedex that a care provider would see. It looks like tendonitis and tendon rupture are on the "short list" of potential causes for concern:

 

Indications

FDA labeled indications

Susceptible infections due to E. coli, K. pneumoniae, E. cloacae, P. mirabilis, P. vulgaris, P aeruginosa, H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus (methicillin susceptible), S. epidermidis, S. pyogenes

Susceptible infections due to Campylobacter jejuni, Shigella species, Salmonella typhi

Anthrax, inhalational - treatment/postexposure prophylaxis

Bone and joint infections

Febrile neutropenia, empiric therapy

Infectious diarrhea

Intra-abdominal infections

Lower respiratory tract infections

Nosocomial pneumonia

Prostatitis, chronic bacterial

Sinusitis

Skin/skin structure infections

Typhoid fever

Urinary tract infections

 

Contraindications

hypersensitivity to ciprofloxacin or other quinolones

 

Precautions

alkalinized urine; may result in crystalluria

concurrent administration of ciprofloxacin and theophylline; cardiac arrest, seizure, status epilepticus and respiratory failure have occurred

elevations in liver function tests

excessive sunlight; may cause phototoxicity

intracranial pressure elevations

known or suspected CNS disorders; may predispose to seizures or lowering seizure threshold

neurotoxicity; risk factors include renal failure, underlying CNS disease, and increased CNS penetration of the drug

tendonitis; risk factors include patients over 60 years of age, renal failure, dialysis, concomitant corticosteroid therapy, and dyslipidemia

 

Adverse Effects

COMMON

dizziness, headache, restlessness

diarrhea, nausea

rash

SERIOUS

convulsions, increased intracranial pressure, toxic psychosis (rare)

serious hypersensitivity reactions (rare)

tendon rupture (rare)

 

Drug Interactions

aluminum carbonate, basic

aluminum hydroxide

aluminum phosphate

antidiabetic agents

azlocillin

calcium

corticosteroids

cyclosporine

didanosine

dihydroxyaluminum aminoacetate

dihydroxyaluminum sodium carbonate

dutasteride

fennel seed

fosphenytoin

iron

magaldrate

magnesium carbonate

magnesium hydroxide

magnesium oxide

magnesium trisilicate

phenytoin

probenecid

rifapentine

ropivacaine

sucralfate

theophylline

warfarin

zinc

 

Pregnancy Category

C

 

Breast Feeding

controversial

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Because NSAID's are also under discussion, here is the analagous information for Ibuprofen. Note that neither Cirpo nor Ibuprofen lists the other as having a known interaction (in contrast to what is stated as a "dangerous" combination with "serious" side effects on the law group's website):

 

Indications

FDA labeled indications

Fever, self-medication of

Juvenile rheumatoid arthritis

Osteoarthritis

Pain, mild to moderate

Pain, self-medication of minor

Primary dysmenorrhea

Rheumatoid arthritis

 

Contraindications

hypersensitivity to ibuprofen

allergic-type reactions, including asthma or urticaria, to aspirin or nonsteroidal antiinflammatory agents

 

Precautions

history of liver dysfunction

history of renal disease

avoid in late pregnancy

hypertension or CHF

history of GI ulceration, bleeding or perforation

dehydration

preexisting anemia

history of coagulation defects

asthma

 

Adverse Effects

COMMON

abdominal pain, constipation, diarrhea, dyspepsia

heartburn, nausea, stomatitis, vomiting

dizziness, drowsiness, headache

edema

tinnitus

rash

 

SERIOUS

liver function test abnormalities (<1%), hepatitis (<1%), jaundice (<1%)

GI bleeding (<1%), GI perforation (<1%), melena (<1%), pancreatitis (<1%)

acute renal failure (<1%), azotemia (<1%), hematuria (<1%)

agranulocytosis (<1%), anemia (<1%), thrombocytopenia (<1%), neutropenia (<1%)

hypertension (<1%), CHF (<1%)

anaphylaxis (<1%)

depression (<1%), insomnia (<1%), confusion (<1%), aseptic meningitis (rare)

erythema multiforme (<1%), Stevens-Johnson syndrome (<1%)

hearing loss (<1%), amblyopia (<1%)

 

Drug Interactions

aspirin

chaparral

clopidogrel

comfrey

cyclosporine

danaparoid

eptifibatide

fosphenytoin

germander

ginkgo

jin bu huan

kava

ketorolac

levofloxacin

lithium

loop diuretics

low molecular weight heparins

meadowsweet

methotrexate

pennyroyal

phenytoin

warfarin

 

Pregnancy Category

D

 

Breast Feeding

safe

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Hmm...I just looked at that study again after your comments and it wasn't a case-control like I thought. You are right, the control group is kinda screwy. Makes it hard to rule out the illnesses prompting the AB's being the culprit.

 

All those people who got preventive Cipro after the anthrax deal might be a pretty good cohort to test this question. If those people have a higher rate of tendonopathies than the general population, you'd have to believe it because they are almost a random sample. Well, maybe not, they're all postal workers probably. Maybe this will "show" Cipro causes you to work really damn slow laugh.gif.

 

 

You could probably find three case reports of climbers who redpointed their first 5.13 while taking Cipro, and draw the conclusion that Cipro enhances climbing ability.

 

Ten bucks says you've overextended your hyperbole there chief! yellaf.gif

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You could probably find three case reports of climbers who redpointed their first 5.13 while taking Cipro, and draw the conclusion that Cipro enhances climbing ability.

 

Ten bucks says you've overextended your hyperbole there chief! yellaf.gif

 

hmm, I agree.....what if we make it 5.11? That would be at least somewhat plausible! cool.gif

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This is actually quite helpful. I'm on Levaquin right now, supposed to refill in a day or 2....I think I'll call the doc and arrange a suitable substitute.

 

Another side effect of the Levaquin is halucinations and sleep disorders. Combining the two, it has made for some interesting nights lately....

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  • 4 weeks later...

I went to the doc on Friday about a sinus infection. She prescribed Alelox. They cost $7 a pill, but she happened to have a bunch of free samples that she gave me. Got home and noticed that the generic name is moxifloxacin. Turns out it is a fluoroquinolone. Egads! Now I have to decide what to do. Monday, I'll call her and ask if she can switch me to something else. I suppose we can try good old amoxacillin. It didn't work for the last sinus infection I had.

 

Thinker, did you end up on a different antibiotic? If so what was it? I haven't had any hallucinations, but I did sleep rather poorly last night.

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The author of the third article has some misconceptions about the fluoroquinolones. He attributes their side effects to "fluoride" ion. The fluoroquinolones all contain fluorine, but it is a very strong carbon-fluorine bond and the fluorine is not liberated as fluoride ion by the body. That is not to say that fluoroquinolones are not toxic, just that the mechanism is not attributable to fluoride ion.

 

It seems to me that while these drugs are not as toxic as chloramphenicol (causes aplastic anemia in 1:25,000), they should only be used in life threatening infections. It is highly unlikely that my minor sinus infection is life-threatening. Certainly, anthrax is life threatening, but there are a whole host of older, cheaper and safer drugs that can be used to treat it.

 

Anthrax has not been subject to the constant selection pressures that organisms such as pseudomonas, strep and staph have been and therefore there is little or no drug resistence to the older drugs. It has been marketing pressure on doctors that explains the use of fluoroquinolones as first line antibiotics.

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I went to the doc on Friday about a sinus infection. She prescribed Alelox. They cost $7 a pill, but she happened to have a bunch of free samples that she gave me. Got home and noticed that the generic name is moxifloxacin. Turns out it is a fluoroquinolone. Egads! Now I have to decide what to do. Monday, I'll call her and ask if she can switch me to something else. I suppose we can try good old amoxacillin. It didn't work for the last sinus infection I had.

 

Thinker, did you end up on a different antibiotic? If so what was it? I haven't had any hallucinations, but I did sleep rather poorly last night.

 

I was switched to Rifampin oral antibiotic, which I've finished...no lasting side effects that I can detect. The first dose is typically a double dose, and that gave me some pretty severe intestinal cramps. A nurse at the hospital said that's not uncommon for Rifampin.

 

I'm also still on intraveneous Vancomycin 2x/day for another 10 days.

 

My last check up on Friday indicated continued progress, no severe scaring in my lung, and no significant amounts of fluid in my lung.. I did 11 flights of stairs on Friday...getting stronger every day!

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