The Fluoroquinolone Toxicity Research Foundation

 
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Fluoroquinolones and Risk of Achilles Tendon Disorders: Case-Control Study [van der Linden PD et al. BMJ 2002;324:1306]: This is a study of Achilles tendon disorders from a large UK general practice database including 46,776 with fluoroquinolone exposures compared to 10,000 randomly selected control patients. Among the 46,776 fluoroquinolone users, 704 had Achilles tendonitis and 38 (0.1%) had Achilles tendon rupture. The mean age was 56 years. The greatest risk for tendon rupture was age over 60 years and concurrent use of corticosteroids. The authors conclude that this adverse effect is relatively rare with an excess risk of 3.2 cases per 1,000 patient-years.

>Comment: Tendon rupture has long been recognized as an adverse effect of fluoroquinolones, although the mechanism is unclear and the data are almost entirely anecdotal. This report represents the largest systematic evaluation, confirms the low incidence, and adds age over 60 years plus corticosteroids as major risk factors.
By John G. Bartlett, M.D., posted 06-24-2002

Below From BMJ (British Medical Journal archives)

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Electronic responses to:
CLINICAL REVIEW
Lesson of the week: Spontaneous rupture of Achilles tendon: missed presentation of Cushing's syndrome
Abdusalam Mousa, Steve Jones, Anthony Toft, and Petros Perros
BMJ 1999; 319: 560-561 [Full text] Rapid Responses: Submit a response to this article


Electronic letters published:

rder=0> Spontaneous rupture of Achilles tendon and fluoroquinolones
Hari Polenakovik (23 September 1999)

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Spontaneous rupture of Achilles tendon and fluoroquinolones 23 September 1999
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Hari Polenakovik,
Clinical Instructor
Wright State University - Department of Medicine

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Re: Spontaneous rupture of Achilles tendon and fluoroquinolones


Email Hari Polenakovik:
hpolenakovik@pol.net

EDITOR:

The article by Abdusalam Mousa et al on spontaneous rupture of Achilles tendon: missed presentation of Cushing’s syndrome, failed to mention tendon rupture as a complication of fluoroquinolone (FQ) use.1

FQ are synthetic antibiotics with good efficacy against infections caused by gram -positive and gram negative organisms.2 Musculoskeletal side effects (arthralgias, arthropathy, tendinitis and tendon rupture) are rare but well documented complications of FQ therapy.2-5 There have been over 200 reported cases in the literature of FQ associated tendinitis and tendon rupture, mostly involving the Achilles tendon.2,5 Pefloxacin and enoxacin are most common offending agents, but cases implicating newer FQ (ciprofloxacin and levofloxacin) can also be found in the literature.2-5

Tendon rupture can occur from 2 to 42 days after the start of therapy.3 Relevant risk factors include concomitant corticosteroid use (in close to half of the reported cases), chronic renal failure and advanced age. 2-5 The latter two probably reflect decreased clearance of these drugs.

Magnetic resonance imaging is helpful in diagnosing suspected FQ induced tendinitis and tendon rupture and may allow planning of therapy.2,4 Therapy includes withdrawal of the FQ and rest of the affected extremity, use of splints, occasional bellow-the-knee casting, and rarely surgical repair of the tendon.2,3 Patients presenting with new onset tendon discomfort or swelling should be questioned about recent use of FQ along with evaluation for symptoms and signs of systemic diseases (Cushing's disease, rheumatoid arthritis systemic lupus erythematosus, gout etc) associated with tendon rupture.

1/ Mousa A, Jones S, Toft A, Perros P. Spontaneous rupture of Achilles tendon: missed presentation of Cushing’s syndrome. BMJ 1999; 319:560-561.

2/ Harrel RM. Fluoroquinolone-induced tendinopathy: what do we know? South Med J 1999; 92:622-625,1999.

3/ Szarfman A, Chen M, Blum M. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med 1995; 332: 193.

4/ Pierfitte C, Gillet P, Royer RJ. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med 1995; 332: 193.

5/ Lewis JR, Gums JG, Dickensheets DL. Levofloxacin-induced bilateral Achilles tendinits. Ann Pharmacother 1999; 33:792-795.

Hari Polenakovik, MD
Clinical Instructor
Wright State University – Department of Medicine, 128 East Apple Street, CHE 2nd floor, Dayton, OH 45419 USA
Email: hpolenakovik@pol.net

Sylvia Polenakovik, MD
Clinical Instructor
Wright State University – Department of Medicine, 128 East Apple Street, CHE 2nd floor, Dayton, OH 45419 USA

We have no competing interests.

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Electronic responses to:
PAPERS
Fluoroquinolones and risk of Achilles tendon disorders: case-control study
P D van der Linden, M C J M Sturkenboom, R M C Herings, H G M Leufkens, and B H Ch Stricker
BMJ 2002; 324: 1306-1307 [Full text] Rapid Responses: Submit a response to this article



Electronic letters published:

Tendinopathy by Quinolones
Javier Rodriguez-Vera (3 June 2002)
Clarification needed on population studied
Michael T. Koller, Milo A. Puhan (4 June 2002)
Were old and young patients really different?
Adam Jacobs (9 June 2002)

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Tendinopathy by Quinolones 3 June 2002

Javier Rodriguez-Vera
Hospital do Barlavento Algarvio. Sitio do Poço Seco 8500. Portimao. Portugal

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Re: Tendinopathy by Quinolones


Email Javier Rodriguez-Vera:
frodriguezv14@hotmail.com

The quinolone related tendinopathy is an uncommon side effect of this family of drugs, that generally implies the withdrawal of the quinolone and not giving any other drug of this kind because it high frequency of class effect of this collateral effect. Although the most common place of presentation is the Aquilles tendon, it may be located in other places (1). In this basis, the incidence of the total percentage of the quinolone tendinopathies may be higher than the registered in the study. By the other way, it would be of great interest knowing if any kind of quinolone was specially related to the incidence of tendinopathy because in a recent study carried out, Ofloxacin was found to be the most common quinolone associated with tendinopathy(2) and was also related to the most severe presentation of the condition. Although the physiopathology of the side effect is not known, it seems to be an inflammatory response. In that basis, we treated a patient with colchicine in a n=1 randomized controlled trial with successs (3). Finally, we would like to add that despite the class effect of this drugs, the new quinolones, like Levofloxacin and Moxifloxacin, seems not to have this characteristic (3), that would allow the clinician giving this kind of drugs if necessary. References 1.Casparian JM, Luchi M, Moffat RE, Hinthorn D. Quinolones and tendon ruptures. South Med J 2000;93:488-491. 2.Van der Linden PD, Van de Lei J, Nab HW, Knol A, Striker BH. Achilles tendinitis associated with fluorquinolones. Br J Pharmacol 1999;48:433-7. 3. Rodriguez-Vera FJ,Pereira Vega A, Pujol de la Llave E. Tendinopathy by quinolones: treatment and class effect in two new cases. Rev Clin Esp (in press)


Clarification needed on population studied 4 June 2002
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Michael T. Koller,
Research fellow
Horten-Zentrum, Universitätsspital Zürich, 8091 Zürich,
Milo A. Puhan

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Re: Clarification needed on population studied


Email Michael T. Koller, et al.:
michael.koller@dim.usz.ch

The study by Van der Linden et al. raises several questions. First, in the publication it was mentioned, that the base cohort was defined by subjects aged older than 18 years who had received a fluoroquinolone (46776 subjects). Cases and Controls were identified out of this base cohort. Further in both groups four categories of exposure were defined. But one category is labelled as “no use”, which contradicts the defined characteristics of the base cohort. Therefore the origin of the “no use” subjects in the cases as well in the controls is obscure (see table). As the “no use” subjects serve as reference to calculate the relative risks, the origin of this group should have been stated clearly. Since the aim of the study was to identify an association of fluorochinolones with Achilles tendon disorders, it does not make sense to include only subjects who have this risk factor anyway. Therefore it is not obvious which criteria were applied to include subjects in the study cohort beside the use of fluorochinolones.

Second, we missed diagnostic criteria to differentiate between the Achilles tendon disorders. From a practical point of view we see no reason why to make a distinction between Achilles tendon disorders and tendinitis.

Third, we missed a description of how cases were identified in a database containing 1-2 million inhabitants.

Kind regards

Michael Koller 1 Milo Puhan 1

1 Horten-Zentrum für praxisorientierte Forschung und Wissenstransfer Universitätsspital Zürich Bolleystrasse 40 8091 Zürich Switzerland


Were old and young patients really different? 9 June 2002

Adam Jacobs,
Director
Dianthus Medical Limited, London SW19 3TZ

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Re: Were old and young patients really different?


Email Adam Jacobs:
ajacobs@dianthus.co.uk

In assessing the relationship between fluoroquinolones and tendon disorders, van der Linden et al conclude that 'The effect seems to be restricted to people aged 60 or over'. I am not convinced. We are not told the rationale for comparing a subgroup of elderly patients with younger patients: was it a prespecified hypothesis that old and young patients would be different, or was this subgroup analysis done after the authors had already noticed a difference between elderly and young patients in their dataset? Why was the cutoff of 60 years chosen? Because of a prespecified hypothesis, or because this was the cutoff that made the difference between elderly and young patients look most impressive?

It is almost always possible to find a difference between subgroups if you look at enough subgroups, especially if you are prepared to dichotomise in a post-hoc manner. The finding of a difference between elderly and young patients in this dataset is not compelling evidence of a genuine age difference, if the presentation of results was driven by the data.

Furthermore, van der Linden et al do not present the results of an interaction test between fluoroquinolone use and age, so we have not been told the magnitude of the age difference or its confidence interval.