What is the mechanism behind fluoroquinolone-induced Achilles tendon rupture?/nBackground: A 68-yea

Fråga: What is the mechanism behind fluoroquinolone-induced Achilles tendon rupture? Background: A 68-year-old-man with diabetes, kidney failure (requiring hemodialysis), and extensive impairment of peripheral arterial blood flow, developed an ulcer on his foot. Treatment with ciprofloxacin 500 mg x2 and flucloxacillin 1.5 g x2 was then started. However, after two weeks the patient´s Achilles tendon spontaneously ruptured and ciprofloxacin was cessated. In addition to flucloxacillin, the patient is currently treated with omeprazole, citalopram, sodium bicarbonate, oral ketobemidone, erythropoietin, calcium carbonate, sodium polystyrenesulphonate.

Sammanfattning: The mechanism involved in fluoroquinolone-associated tendinopathy remains unclear.

In the present case, the impairment of peripheral arterial blood flow, renal failure, ageing, the concomitant use of corticosteroids and fluoroquinolones are probably contributing factors to the development of spontaneous tendon rupture.

We recommend that doctors be more aware of Achilles tendon ruptures associated with fluoroquinolone antibiotic treatment, especially in elderly patients, and patients with other high risk factors.

Svar: Fluoroquinolone-associated disruption of tendons has been estimated to occur at a rate of approximately 15 to 20 per 100000 patients (1). The mechanism involved in fluoroquinolone-associated tendinopathy remains unclear (2-4). Reports on histopathological changes in tendons exposed to fluoroquinolones are sparse. However, cystic degeneration, changes in cellular function which are associated with increased glycosaminoglycans of the tendon (5), ischaemia and mechanical forces (3), renal failure, the concomitant use of corticosteroids and fluoroquinolones (2), an increase in protease activity and the inhibition of both cell proliferation and the synthesis of matrix ground substance (6) are thought to be the likely contributory factors.

First, most tendinous ruptures are located at sites of deficient blood supply, leading to the possibility of an ischemic process. Several clinicians described Achilles´ tendon rupture 2 to 3 cm above the calcaneal insertion, which is relatively avascular (7) (2).

Second, spontaneous rupture, a classic but rare complication of renal disease, is probably due to an accelerated degeneration of collagen fibers associated with hyperparathyroidism and long-term steroid therapy (7). The concomitant use of corticosteroids and fluoroquinolones is recognised as a risk factor for developing tendinopathy (2). Vitro studies on cultivated tendon cells ( human, animals) showed also that cytotoxic response was distinctly increased by combined treatment with fluoroquinolone and corticosteriod (8). Fluroquinolones are in part excreted by the kidney and renal failure prolongs elimination of these compounds (2).

Third, mechanical stress probably plays a part as well in fluoroquinolone-associated tendinopathy. High load-bearing tendons, such as Achilles, quadriceps, and rotator cuff tendons, are frequently described in the literature as being involved in tendinopathy (2,3).

Fourth, an alteration of cell function may be involved. In one case with microscopic evaluation, histopathological examination showed irregular collagen fiber arrangement, hypercellularity, and increased interfibrillar glycosaminoglycans, which are also seen in tendon overuse injuries in athletes (5). A recent study by Williams et al (6) demonstrates that ciprofloxacin stimulates matrix-degrading protease activity from fibroblasts and exerts an inhibitory effect on fibroblast metabolism.

Fifth, an age dependency of the effect of fluoroquinolones on the cartilage is observed. Juvenile animals are more sensitive to the drug than adults (8). Patients over 60 years old and undergoing corticosteroid therapy showed a high incidence of fluoroquinolone-induced tendinitis or tendon rupture. The altered kinetics of fluoroquinolones caused by ageing, underlying disease, period of therapies with other drugs, may contribute to the development of the tendon disorders in human (4,8).

The files of SADRAC (The Swedish Adverse Drug Reactions Advisory Committee) contain 5 cases of ciprofloxacin-associated tendon rupture, 3 cases of other fluoroquinolones-associated tendon rupture, and 14 cases of fluroquinolones-associated tendinitis. We suggest this case be reported to SADRAC.