Case report

Rupture of multiple tendons after levofloxacin therapy

Denis Braun a, Nadine Petitpain b, Françoise Cosserat b, Damien Loeuille c, Suleiman Bitar d,Pierre Gillet b,c, Philippe Trechot b,*

a Pneumology Department, Maillot Hospital, 54150 Briey, Franceb Regional Pharmacovigilance Center, Central Hospital—CHU de Nancy, 29, avenue du Maréchal de Lattre de Tassigny, 54035 Nancy cedex, France

c Rheumatology Department, Nancy Brabois Teaching Hospital, 54511 Vandœuvre, Franced Orthopedic Surgery Department, Maillot Hospital, 54150 Briey, France

Received 10 June 2003; accepted 15 October 2003

Available online 31 December 2003

Abstract

An 80-year-old man treated by levofloxacin developed multiple tendon ruptures. His symptoms resolved over 9 months after levofloxacindiscontinuation. Nasal corticosteroid therapy, aging and chronic respiratory insufficiency were probably predisposing factors in this patient.© 2003 Elsevier SAS. All rights reserved.

Keywords: Levofloxacin; Fluoroquinolones; Tendon rupture

1. Introduction

Tendinopathy is a well-documented but uncommon classeffect of fluoroquinolone therapy. The Achilles tendon is afrequent site of involvement, and both sides may be affected.Multiple tendinopathy with diffuse joint and muscle pain asdescribed by Schwald and Debray-Meignan [1] in 1999 israre. Fluoroquinolone-induced tendinopathy should be diag-nosed and treated promptly to avoid tendon rupture, which isthe main complication. Levofloxacin, the levo-rotating iso-form of the racemic mixture ofloxacin (Tavanic®), was intro-duced on the French market in 2000. Levofloxacin can in-duce tendinopathy [2] yet is often used in patients with riskfactors, as illustrated by the case described below.

2. Case report

In April 2002, this 80-year-old man with a negative smok-ing history experienced an episode of bronchitis, for whichhe was given a 5-day course of levofloxacin (Tavanic®

500 mg, one tablet in the morning), methylprednisolone(Medrol® 16 mg, three tablets in the morning), and car-bocisteine (Carbocisteine RPG®, 15 ml tid). He continued

his usual treatment, with inhaled budesonide (Pulmicort200® twice daily in the morning, verapamil (Isoptine®,120 mg, one tablet per day), vinburnine (Cervoxan®, 60 mg,one tablet per day), an antiplatelet agent (Asasantine LP®

200 mg, one tablet bid), and an ocular hypotensive agent(Xalatan®, one drop per day in each eye). He reported aremote history of lung tuberculosis with residual bron-chiectasis, as well as microinvasive epidermoid carcinoma ofthe lung treated with cryotherapy 2 years earlier. In June2002, a further episode of lower respiratory tract infectionwas again treated with levofloxacin (Tavanic® 500 mg, onetablet per day), flunisolide nasal solution (Nasalide®, twoactuations bid), and carbocisteine. After the third daily levo-floxacin dose, he suddenly experienced pain in the left anklethen in both upper limbs. On the next day, he had majorfunctional impairment with symptoms typical for rupture ofthe left Achilles tendon, left long biceps tendon, and rightrotator cuff tendons. Several orthopedic surgeons consideredthe diagnosis clinically unequivocal and, consequently, nei-ther ultrasonography nor magnetic resonance imaging wasperformed. The ankle was immobilized in a cast and thepatient advised to rest in an armchair. A program of physicaltherapy was started. Laboratory tests showed only mild in-flammation and only minimal renal dysfunction (serum crea-tinine, 11–12 mg/l on several occasions, and corrected crea-tinine clearance calculated using Cockroft and Gault’sformula, 78 ml/min). The pain in the ankle and shoulders

* Corresponding author.E-mail address: crpv@chu-nancy.fr (P. Trechot).

Joint Bone Spine 71 (2004) 586–587

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qresolved within 3 months, and after 9 months the patientwas again self-sufficient.

Pefloxacin has often been reported to cause iatrogenictendinopathy, an effect ascribed to the excellent tissue diffu-sion of this drug. However, all commercially available fluo-roquinolones including levofloxacin [3] can induce tendin-opathy. Although focal involvement is the rule, with theAchilles tendon being a common target [4], severe formswith involvement of multiple tendons have been reported [1].Multiple tendon rupture is exceedingly rare [5]. In agreementwith the marketing authorization, levofloxacin is often usedto treat flares of lower respiratory tract infection in patientswith chronic obstructive pulmonary disease. These patientsoften have a combination of risk factors for tendinopathy,such as hypoxemia, older age, renal failure, and concomitantshort- or long-term glucocorticoid therapy (which is a riskfactor even via the inhaled route) [6].

3. Discussion

Risk factors identified in our patient were advanced age,chronic respiratory failure, and inhaled glucocorticoidtherapy. Because his renal function was normal, he receivedthe full dosage of levofloxacin. The time to onset was consis-tent with earlier reports [4,7]. The possibility of progressionto tendon rupture (30% of reported cases of tendinopathy [8])is mentioned in the Summary of Product Characteristics.Furthermore, although the Achilles tendon is the most com-mon target, involvement of the biceps [9] and rotator cuff [1]has been reported at the beginning, at discontinuation, orsome time after fluoroquinolone treatment. Finally, apartfrom an inhaled glucocorticoid, no other drugs known toinduce tendinopathy [10] were used concomitantly in thispatient, and there were no intercurrent factors associatedwith fragility of the tendons (e.g. hyperparathyroidism orhemodialysis). A causal relation with levofloxacin seemsplausible according to the French method for causality as-sessment (chronology score, 2, and semiology score, 2, clas-sifying intrinsic causality as I2) [11].

The pathogenesis of fluoroquinolone-induced tendinopa-thy remains unknown. Local overproduction of free radicalsas part of an ischemia-reperfusion response within the tendonhas been suggested. An alternative hypothesis is enhancedcytokine or metalloprotease activity in the tendons [12].Concomitant use of glucocorticoids, which have direct toxiceffects on collagen fibers and other tissue components, may

increase the risk of fluoroquinolone-induced tendinopathy.The tendon toxicity of fluoroquinolones per se is dose-dependent in rats [13] but in humans can occur at any timeduring the treatment, even after a single dose [6].

As underlined in the prescribing information for levof-loxacin published on December 17, 2001 and available on theAFSSAPS site [8], a careful evaluation of the risk/benefitratio and close attention to symptoms alerting to possibletendon involvement are in order in patients with multiple riskfactors (age older than 65 years, concomitant glucocorticoidtherapy even by the inhaled route, possible renal dysfunc-tion).

References

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[8] Informations importantes de pharmacovigilance concernantTAVANIC (lévofloxacine). Available from: http://agmed.sante.gouv.fr/htm/10/filltrpsc/levoflo.pdf.

[9] Guerin B, Grateau G, Quartier G, Durand H. Rupture of the longbiceps tendon following ingestion of fluoroquinolone. Ann MedInterne 1996;147:69.

[10] Hayem G. Tendinopathies induites par les médicaments. Rev Rhum[Ed Fr] 2002;69:406–10.

[11] Bégaud B, Evreux JC, Jouglard J, Lagier G. Imputabilité des effetsinattendus ou toxiques des medicaments. Therapie 1985;40:11–4.

[12] Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B.Pefloxacin-induced Achilles tendon toxicity in rodents: biochemicalchanges in proteoglycan synthesis and oxidative damage to collagen.Antimicrob Agents Chemother 2000;44:867–72.

[13] Kashida Y, Kato M. Characterization of fluoroquinolone-inducedAchilles tendon toxicity in rats: comparison of toxicities of 10 fluoro-quinolones and effects of anti-inflammatory compounds. AntimicrobAgents Chemother 1997;41:2389–93.

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