Department of Microbiology, University Hospital Lewisham, Lewisham High Street, London SE13 6LH, UK
Keywords: levofloxacin, tendinopathy
Sir,
Levofloxacin is recommended for the management of community-acquired pneumonia. As its use increases, it is important that doctors are aware of its relatively uncommon adverse effects. Achilles tendinitis (incidence: 0.10.01%) and tendon rupture (incidence: < 0.01%) are well recognized but rare adverse effects of levofloxacin and other fluoroquinolones.15
In this paper, we describe four cases illustrating tendinopathy of the Achilles tendon associated with levofloxacin treatment.
Case 1
A 78-year-old female patient with a background of ischaemic heart disease, chronic heart failure and osteoarthritis developed hospital-acquired pneumonia while under investigation for an unrelated problem. She was treated for 5 days with oral levofloxacin 500 mg twice a day. She had not previously received quinolone antibiotics. Three days after stopping the antibiotic, during assessment of the patients mobility, both patient and physiotherapist heard a snap and the session had to be ended due to pain in the left leg. She had not reported pain in her legs prior to this incident. An orthopaedic surgeon made a clinical diagnosis of rupture of the left Achilles tendon. A plaster cast was applied and the patient required the aid of a frame and further rehabilitation. The tendon injury delayed discharge from hospital by 3 weeks.
Case 2
A 67-year-old man was admitted with an infectious exacerbation of chronic obstructive pulmonary disease (COPD). He was treated with oral prednisolone 40 mg daily and levofloxacin 500 mg twice daily for 5 days, and was discharged from hospital after a further 5 days of treatment. However, 3 days after discharge, he developed bilateral swollen, painful Achilles tendons, as well as an acute confused state. Despite rest and simple analgesia, symptoms of tendinitis continued for 5 months.
Case 3
A 71-year-old woman was admitted with a suspected lower respiratory tract infection and was treated with oral levofloxacin 500 mg twice daily. The diagnosis was reviewed and the antibiotic stopped after two doses. The next day she felt pain in both Achilles tendons, impairing her ability to walk. There was localized tenderness at this site. She was treated with non-steroidal anti-inflammatory drugs intermittently for 4 months. Although she had a history of pain in her cervical and lumbar regions, these symptoms were most likely due to degenerative disease and unrelated to her tendinitis.
Case 4
A 67-year-old man with an exacerbation of COPD was treated with levofloxacin 500 mg twice a day for 5 days. He had a history of hypertension. Three days into treatment (a total of five doses), he developed widespread muscle pains, most severe in his Achilles tendons, so that he was unable to walk. He was advised to stop the antibiotic and the pain settled after 2 weeks, without treatment.
The four patients described were originally enrolled into a study of levofloxacin treatment of lower respiratory tract infection. This study included 489 patients treated with levofloxacin, a total of 3217 treatment days. Tendinopathy was not measured as an outcome in the study. These cases suggest an approximate incidence of levofloxacin-associated tendinopathy of 1%, higher than previously reported in the Hoechst Marion Roussel summary of product characteristics (SPC). There may be a greater propensity for levofloxacin to cause tendon lesions than other quinolones. Published data suggest that pefloxacin and ofloxacin have the highest incidence of this side effect, but the reasons for differences between quinolones are unknown.5,6
None of the four patients described had a history of tendinitis, or any systemic disease known to cause an enthesopathy (such as psoriasis, inflammatory bowel disease, ankylosing spondylitis or spondyloarthropathy). All were over 65, two had poor cardiac function, two had chronic lung disease and one was on corticosteroids. None had raised serum creatinine at the time of treatment. The patients described received levofloxacin 500 mg twice daily for between 1 and 10 days. Levofloxacin is licensed in the UK for treatment of community-acquired pneumonia in doses of 500 mg once or twice daily.
Risk factors for tendinopathy include old age, chronic lung disease, steroid treatment and impaired renal function. Concomitant treatment with corticosteroids may be a predisposing factor for tendinitis, but this is not a consistent finding.1,2
The pathological mechanism of tendinitis due to fluoroquinolones is unknown. Histological studies have identified ultrastructural abnormalities in tenocytes and the presence of giant cells, the features being similar to those of overuse injuries.2,6
Animal studies have suggested that chelation of magnesium and free radical formation result in oxidative stress, leading to a direct toxic effect on collagen.3,6 The association with renal disease is thought to be due to the accelerated degeneration of collagen in hyperparathyroidism.2
Achilles tendinitis and rupture may be more common adverse effects of levofloxacin than previously thought. Particular caution should be exercised in prescribing levofloxacin in high doses, and to elderly patients, especially those on corticosteroids.
Acknowledgements
Aventis Pharma Ltd supported the study on the incidence of Clostridium difficile-associated diarrhoea in patients treated with levofloxacin.
Footnotes
* Corresponding author. Tel: +44-20-8333-3264; Fax: +44-20-8690-8891; E-mail: gopal.rao{at}uhl.nhs.uk
References
1
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Lewis, J. R., Gums, J. G. & Dickensheets, D. L. (1999). Levofloxacin-induced bilateral Achilles tendonitis. Annals of Pharmacotherapy 33, 7925.
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3
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Simonin, M. A., Gegout-Pottie, P., Minn, A., Gillet, P., Netter, P. & Terlain, B. (2000). Pefloxacin-induced Achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen. Antimicrobial Agents and Chemotherapy 44, 86772.
4 . Ribard, P., Audisio, F., Kahn, M. F., De Bandt, M., Jorgensen, C., Hayem, G. et al. (1992). Seven Achilles tendinitis including three complicated by rupture during fluoroquinolone therapy. Journal of Rheumatology 19, 147981.[ISI][Medline]
5 . Kashida, Y. & Kato, M. (1997). Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of 10 fluoroquinolones and effects of anti-inflammatory compounds. Antimicrobial Agents and Chemotherapy 41, 238993.[Abstract]
6 . Casparian, J. M., Luchi, M., Moffat, R. E. & Hinthorn, D. (2000). Quinolones and tendon ruptures. Southern Medical Journal 93, 48891.[ISI][Medline]