Connecting the dots: Reasons why fluoroquinolones such as Levaquin destroy connective tissue matrices found in tendons all over the body

Armand Rossetti

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Sometimes searching for information has to occur outside the box. For example, who would have thought that a scholarly paper about eye drops would contain information central to understanding how fluoroquinolones (floxacins) like Levaquin, can negatively affect the connective tissue scaffolding found in tendons all over the body?

Recently the FDA issued a boxed warning for fluoroquinolones. If you have not seen the video that I posted yesterday about the extent of fluoroquinolone toxicity, you may want to take a few minutes and view it.

The following information about Levaquin appears online at Wikipedia:

“Levofloxacin is a third-generation fluoroquinolone antibiotic, marketed by Ortho-McNeil under the trade name Levaquin in the United States. In Europe, it is marketed by Sanofi-Aventis under the trade name Tavanic, in Chile as Gatigol by Alpes Selection, in India under the trade name Lebact marketed by Nicolas Piramal and in Asia it is marketed by Xeno Pharmaceuticals as Terlev and by Daiichi under the trade names Cravit and Levox. Generics are also widely available in most countries; other manufacturers include Novell Pharmaceutical Laboratories (Levores).”

In its July 2008 fluoroquinolone news release, the FDA stated the following concerning boxed warnings:

…"Fluoroquinolones are effective in treating certain bacterial infections, but health care professionals and patients need to be aware of the increased risk associated with the use of these drugs of developing tendinitis and tendon rupture, particularly for certain patient populations," said Edward Cox, M.D., director, Office of Antimicrobial Products, Center for Drug Evaluation and Research. "The FDA believes it is important to highlight and strengthen information regarding possible side effects of fluoroquinolones because it may affect decisions about the relative risks and benefits associated with these products….

The medications involved in this action are: Cipro and generic ciprofloxacin, Cipro XR and Proquin XR (ciprofloxacin extended release), Factive (gemifloxacin), Levaquin (levofloxacin), Avelox (moxifloxacin), Noroxin (norfloxacin), and Floxin and generic ofloxacin.”

Questions:

· What is the reason why the fluoroquinolone family of drugs is linked with tendon destruction all over the body?

· Why is the Achilles tendon, the largest tendon in the body, the site of the most dramatic tendon shearing?

Let’s address the second question first.

· Why is the Achilles tendon most prominently affected?

The Achilles tendon lifts the entire body’s weight against an incredible adverse leverage ratio. That is why it is the largest, toughest and strongest tendon in the body. Therefore, the Achilles tendon takes the most stress and does it often. If the largest tendon should become internally compromised by connective tissue degradation, then it will be the first to shear during repeated, heavy duty use. Nevertheless, the Achilles tendon may be dramatic in its manifestation, but toe flexor and posterior tibial tendons are the ones that people complain about most often.

However, Levaquin affects all tendons in the body. Most of the may not shear. Patients taking Levaquin, especially those who use Levaquin for extended periods, will experience tendonitis and tendinopathy to one degree or another. The extent to which tendinopathy occurs might also depend in part on whether a patient has an active or less active lifestyle.

· Why are fluoroquinolones linked with tendon destruction all over the body?

The answer seems to be connected with metalloproteinases (also called metalloproteases). I happened to find a paper that appeared in the October 6, 2003 edition of BNC Ophthalmology entitled, Effect of topical fluoroquinolones on the expression of matrix metallproteinases in the cornea. The following excerpt from that paper seems to shed light on the way that the use of fluoroquinolone eye drops predisposes the cornea to perforation (it’s a little techie, but worth the read):

“The metalloproteinases [MMPs] are potent enzymes that are capable of degrading a wide range of extracellular matrix components. Numerous studies have documented the important role of matrix metalloproteinases in the corneal wound healing process. The perturbation of the normal regulation of degradative processes may result in the accelerated breakdown of connective tissues and may lead to conditions such as ulcerative keratolysis. There is increasing experimental and clinical evidence that during corneal injury and inflammation, MMPs play a major role in the proteolytic processes, which can predispose the cornea to perforation. Thus, this study focuses on evaluating the expression of MMPs after the use of commercially available fluoroquinolone eye drops in order to elucidate a relationship between keratolysis, corneal perforation and the use of ophthalmic fluoroquinolone drugs as reported in previous clinical studies.” [Emphasis added].

I really do not want to spend more time defining esoteric acronyms; you can read the linked papers and get the idea on your own. Nevertheless, the main words of interest are “matrix metalloproteinases” or MMPs and “accelerated breakdown of connective tissues.” Tendons are mainly formed from connective tissue. This brings us to the need to make a connection between MMPs affecting the eye (cornea and other sites), and whether MMPs affect tendons as well.

In 2005, the British Journal of Sports Medicine published a paper entitled Matrix metalloproteases: a role in overuse tendinopathies (M Magra and N Maffulli; Br. J. Sports Med. 2005;39;789-791 {second paper in the linked website}). The author concluded the following:

“Tendon matrix is not static; it is constantly remodelled, with higher rates of turnover at sites exposed to high level strain. MMPs and their inhibitors are crucial to the [extracellular matrix] ECM remodelling, and a balance exists between them in normal tendons. Alteration of MMP and [tissue inhibiters of metallproteinases] TIMP expression from basal levels leads to alteration of tendon homoeostasis. Tendinopathic tendons have an increased rate of matrix remodelling, leading to a mechanically less stable tendon which is more susceptible to damage.”

What all of this means is that when a drug like Levaquin affects the expression of MMPs, which creates an MMP-TIMP imbalance. That imbalance affects the tendon’s ability to remodel the tissue matrix effectively, and ineffective remodelling creates tissue weakness. That is the reason why the often used and heavily loaded Achilles tendons in patients who take fluoroquinolones such as Levaquin, will shear in many instances.

There is one last question:

If this information discussed above is available by reading the scientific literature, what is taking the FDA so long to suggest either a recall of all fluoroquinolones, or at least a restriction on fluoroquinolone use?

For example, the FDA might require that fluoroquinolone use be limited to hospital in-patients. The FDA might also require special training for physicians who prescribe fluoroquinolones and a mandatory extensive review of patient medical history, and specified laboratory testing, before, during and after fluoroquinolone administration. If the benefit of administering fluoroquinolones is to outweigh the risk, it will be due to those types of requirements.

A word about the availability of fluoroquinolone related scientific literature:

I was astonished to learn just how much scientific literature is available on the subject of fluoroquinolones. The Fluoroquinolone Toxicity Research Foundation has posted several hundred research papers that discuss fluoroquinolone toxicity; many of those papers are studies on tendinopathy. One French study addressed adverse events involving 100 patients with Achilles tendon disorders. The 1994 French paper reported that 31 of the 100 patients with tendinopathy had experienced tendon ruptures (Royer, R. J.; Pierfitte, C.; and Netter, P.: Features of tendon disorders with fluoroquinolones. Therapie, 49: 75-76, 1994.).

This means that the FDA has been (or should have been) awash, for at least a decade, in a sea of information that exposes the grave dangers of fluoroquinolone treatment. Yet, the FDA waited until July of 2008 before requiring boxed warnings for several fluoroquinolone preparations.

“There are those who look at things the way they are, and ask why... I dream of things that never were, and ask why not?” [Robert F. Kennedy]. I guess that under the above circumstances, asking the FDA and fluoroquinolone manufacturers either question, might help.