Elena Vietti e Caterina Vassallo
Fluoriquinolones (FQs) are one of the most common antibiotics, because of their excellent gastrointestinal absorption and their wide distribution in most of the tissues. Since they don't bind blood carriers, they have a high bioavailability (over 50%) and can reach easily and fast organs such as kidney, lung and prostate. For this reasons they are widely used to treat urinary infections, community-acquired pneumonia and prostatis.
Their main target is the bacterial DNA gyrase, a topoisomerase II involved in DNA replication so it is considered a bacteriostatic antibiotic, because it arrests cell proliferation.
Although FQs normally are well tolerated, they can cause adverse events such as: gastrointestinal and neurological symptoms (respectively in 1-7% and 0.1-0.3% of cases) and cutaneous eruption (0.5-2.5%) . Another possible side effect (caused especially by cyprofloxacin), that has been observed recently, is a predisposition to tendinopathy or even a tendon rupture, especially of the Achilles tendon.
The incidence is estimated to be 0.14-0.4%, but there are some risk factors that can increase the percentage of patients developing tendinopathy. The major risk factor is the age of the patient: it has been reported that the rupture of the tendon is more common in patients over 64 years. Other factors are corticosteroid therapy, renal failure and diabetes mellitus.
Tendinopathy is a common orthopedic condition characterized by damage to the tendons, the collagenous connective tissues that link muscles to bones.
The diagnosys of tendinopathy is usually clinical and can be confirmed by magnetic resonance imaging (MRI) and leads to the discontinuation of FQ therapy, use of analgesics, physical therapy and, in extreme situations, even surgery.
Normally the prodromes of tendinopathy (swelling, tenderness and erythema) appear a few weeks after the administration of FQs therapy due to the direct toxicity of the drug to collagen.
The damage of the tissue is caused by three main factors:
- Inhibition of tenocytes proliferation
- Reduction tenocytes cell to cell and cell-matrix adhesion
- Alteration of the ECM structure
Inhibition of tenocytes proliferation
Starting from the first point, it has been demonstrated that FQs reduce the expression of and Cyclin dependent kinase 1, that normally allow the continuation of cell cycle from G2 to M. For this reason the drug arrests the cycle and inhibits tenocytes proliferation.
Moreover, FQ, through the chelation of divalent cations, inhibit the MAPK signaling pathway (which is involved in cell differentiation and survival), both directly and by blocking the integrins function (Mg2+ participate to the regulation of this activity). Integrins, in particular Integrin-B1, are not only involved in MAPK activation, but also in cell-matrix adhesion. The loss of these interactions and the inhibition of the mitogenic pathway lead the cells to apoptosis.
Fluoroquinolone-associated Tendinopathy, 2011
Reduction of adhesion
Secondly, FQs reduce the phosphorylation of Focal adhesion kinase, , responsable of the contacts between cells and ECM. In addition, it decreases the expression of and connexin 43 (), that are involved respectively in adherence junctions and gap junctions. FQs chelate divalent and trivalent cations, such as Ca2+, that participates in the activity of cadherins, so they inhibit these proteins.
The drug even affects the tendon stability and the tissue homeostasys since the cells are not able to communicate and respond appropriately to mechanical loading. However no alterations of the actyn cytoscheleton, intermediate filaments or microtubules has been reported, so the mechanotransduction system of the tendon isn't affected by FQs.
Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the athletic population, 2011
Alteration of the ECM structure
Finally all the researches highlighted higher levels of matrix metalloproteinases, that is caused both by the direct up-regulation of the gene and by a lower expression of Tissue inhibitor of MMPs, , that usually bounds the MMPs in order to reduce their breakdown of the collagen. Even if MMPs activation is higher, there is no trigger of expression, a matrix glycoprotein that is involved in the proliferation of tenocytes associated to MMPs activity during tendon repair and modelling. Moreover the FQs down-regulate the expression Long lysyl hydroxylase 2, ,an enzyme involved in the creation of cross-links between the newly synthesized collagen.
Furthermore it has also been demonstrated that FQs affect the process of tendon healing, because the drug decreases especially the expression of type III collagen, that is used as a mold for the deposition of type I collagen in early phase of tendon repair.
New insights in extracellular matrix remodeling and collagen turnover related pathways in cultured human tenocytes after ciprofloxacin administration
Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen, 2010
The main risk factor realted to tendinopathy is the age, beacuse some studies demonstrated an inibition of type III collagen in elderly patients and a change in the structure of collagen, whose diameter increases. Moreover fibrotic changes related to aging cause a weakening of the tendons and a reduction in ultimate strain, ultimate load and in the modulus of elasticity.
Another important risk is the corticosteroid treatment. Glucocorticoids, such as cortisol or corticosteroids, are normally released in stressfull situations to increase catabolism through the stimulation of MMPs, so they strenghten the effects of FQs. In addition, this therapy also causes the differentiation of the tenocytes precursors in adipocytes instead of tenocytes. This side effect decreases the probability of succes of surgical repair of broken tendons. Beside this adverse effect, corticosteroids are still the most common treatment for tendinopathy.
Tendon ruptures are very common in body builders because they use anabolic-androgenic steroids (such as testosterone) to increase their muscular masses. This substances bind to androgen receptors and inhibit MMPs, reducing the turnover of tendon matrix, making the tendon stiffer and less able to remodel in response to mechanical demand.
Diabete is also an important risk factor, since it has been demonstrated that high glucose levels can increase the expression of MMP's mRNA making the effects of FQs more devastating. In addition, advanced glycation end products (AGEs) accumulate in the connective tissue and can modify the synthesis of ECM by signaling through cell surface receptors.
The effect of aging on migration, proliferation, and collagen expression of tenocytes in response to ciprofloxacin, 2011
Androgenic-Anabolic Steroids Associated with Mechanical Loading Inhibit Matrix metallopeptidase Activity and Affect the remodeling of the Achilles Tendon in rats, 2006
High glucose concentration up-regulates the expression of matrix metalloproteinase-9 and -13 in tendon cells
The effects of enrofloxacin on canine tendon cells and chondrocytes proliferation in vitro. 2007