Fluoroquinolones and Tendinopathies

Abstract & Commentary

Synopsis: The excess risk of Achilles tendon disorders attributable to fluoroquinolone use was estimated to be 3.2 cases per 1000 patient-years, with most of that increase accounted for by patients 60 years of age and older who concomitantly receive corticosteroids.

Source: van der Linden PD, et al. Fluoroquinolones and risk of Achilles tendon disorders: Case-control study. BMJ. 2002; 324:1306-1307.

The IMS database containing information from UK general practices covering 1 million to 2 million inhabitants was queried in order to perform a nested case control study designed to examine risk factors for the development of Achilles tendon disorders (ATD) related to fluoroquinolone use. The cohort included 47,776 adults who had received a flu-oroquinolone, of whom 704 (1.4%) had Achilles ten-donitis and 38 (.08%) had Achilles tendon rupture. This represented an overall excess risk of 3.2 cases per 1000 patient-years. The adjusted relative risk (RR) of ATD was 1.9 (95% CI, 1.3-2.6) for current fluoroquinolone use; there was no increased risk associated with recent (but not current) or remote past use. While there was no increased risk associated with current use among those younger than 60 years of age, for those 60 years of age or older, the RR was 3.2 (2.1-4.9) and for those in this latter age group who were also receiving corticosteroids, the RR was 6.2 (3.0-12.8). Those with both risk factors, age older than 60 years and corticosteroid use, accounted for 87% of cases of ATD.

Comment by Stan Deresinski, MD, FACP

A large increase in both fluoroquinolone use and non-traumatic tendon ruptures was observed in The Netherlands between 1991 and 1996.1 It was concluded, however, that less than 7% of the increase in tendon ruptures could be attributed to the increase in fluoroquinolone use. Nonetheless, the epidemiologic and laboratory evidence demonstrates a strong causal relationship.

Fluoroquinolones are known to cause cartilaginous abnormalities in immature animals, such as beagle pups. Histologic changes in tenocytes of experimental animals exposed to fluoroquinolones include vacuolation of tenocytes and decrease in fibril diameter with an increase in the distance between individual collagenous fibrils. In vitro experiments indicate that fluoroquinolones stimulate matrix-degrading protease activity of fibroblasts while inhibiting fibroblast metabolism.

Much evidence supports the hypothesis that tendinopathy is the consequence of chelation of magnesium ions by fluoroquinolones—a class effect and the reason why simultaneous oral administration of magnesium-containing antacids and fluoroquinolones results in markedly impaired gastrointestinal absorption of the latter. Thus, both magnesium deficiency and ciprofloxacin administration can each cause similar biochemical changes in the Achilles tendons of immature dogs.

Fluoroquinolones remain highly effective antibiotics in most regions. The low incidence of tendon disorders should not preclude their use, especially when only a tiny fraction of these complications involve actual tendon rupture. Nonetheless, the recognition that patients older than age 60, especially those receiving corticosteroids, comprise those at significant risk should alert the clinician. An evaluation in The Netherlands in 1998 found that the median time from initiation of fluoroquinolone use to onset of tendon symptoms was 6 days.2 It is unfortunate, of course, that these risk factors describe a large number of patients with underlying chronic obstructive lung disease who are at risk of acute bacterial exacerbations and who might benefit, on occasion, from fluoroquinolone therapy. Thus, if a fluoroquinolone is the treatment of choice in such a patient, it might be beneficial, albeit unproven, to correct any magnesium deficiency that might be present, with the hope that this would reduce the potential for development of a tendinopathy.

References

1. van der Linden PD, et al. Fluoroquinolone use and the change in incidence of tendon ruptures in The Netherlands. Pharm World Sci. 2001;23:89-92.

2. van der Linden PD, et al. Tendon disorders attributed to fluoroquinolones: A study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum. 2001;45:235-239.

Dr. Deresinski is a Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.