Medical Hypotheses 77 (2011) 696–697
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Can oral levofloxacin cause of flexor digitorum profundus rupture? Tolga Turker ⇑, Joseph E. Kutz Christine M. Kleinert Institute for Hand and Micro Surgery, United States
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Article history: Received 5 April 2011 Accepted 7 July 2011
a b s t r a c t Fluoroquinolones are broad-spectrum antibacterial agents. Reports of Achilles tendon rupture as a possible side effect of the quinolones have been previously presented but mechanism of the side effect of the medication is still unknown. Tendon rupture in the forearm associated with fluoroquinolone use has not been reported. We present a patient who underwent levofloxacin treatment for skin infections and subsequently developed left small finger flexor digitorum profundus rupture. We propose that this rupture may be related to the side effect of the medication. If it is, clinicians have to be aware of possible tendon ruptures in the upper extremity due to side effects of quinolones and patients have to be informed about it. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Fluoroquinolones are antibiotics commonly used to treat a broad range of bacterial infections, including respiratory, urinary tract, skin, soft tissue, bone and joint infections. The common adverse effects of fluoroquinolones are gastrointestinal, central nervous system and myocardial toxicity, as well as disrupted glucose metabolism. Other important adverse effects of fluoroquinolones are tendon and joint toxicity. Even though possible levofloxacin-related tendon ruptures have been previously reported, these ruptures only reported in the Achilles tendon. Tendon rupture in the forearm related to fluoroquinolones has not been published [1–3]. We present the case of a patient who developed left small finger flexor digitorum profundus rupture. A 71 year-old male patient complained of not being able to bend his left small fingertip for over six weeks. He developed forearm pain and subsequently could not bend his left small finger. Levofloxacin 500 mg p.o. every 12 h was prescribed for five days due to a skin infection seven days prior to the rupture. Patient was seen by his doctor and referred to our clinic. The patient’s past medical and surgical history was not significant and there was no family history of spontaneous tendon rupture. The patient’s examination revealed no skin changes, no atrophy, and normal skin turgor. His capillary refill was less than 2 s and his two point discrimination was less than 5 mm. All joints were soft, and full passive range of motion was observed by examiners. The cascade of fingers was disrupted at the small finger, where the fingertip remained extended. Motor examination showed that the patient was ⇑ Corresponding author. Address: Christine M. Kleinert Institute, 225 Abraham Flexner Way, Suite 850, Louisville, KY 40202, United States. Tel.: +1 502 299 8634; fax: +1 502 562 0326. E-mail addresses:
[email protected],
[email protected] (T. Turker). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.07.020
able to flex his metacarpophalangeal joint and proximal interphalangeal joint of the left small finger without any difficulty. However, he was unable to flex the distal interphalangeal (DIP) joint. There was no active extension problem (Fig. 1). There was no evidence such as hamate fracture on the patient’s X-ray offering explanation for the mechanism of tendon rupture. The patient was given all treatment options, including tendon primary repair, tendon repair with a tendon graft, and DIP joint arthrodesis. After discussion, the patient chose not to undergo surgical treatment. We propose that this rupture may be secondary to levofloxacin treatment for skin infections. Hypotheses Even thought there is no basic science study in humans that shows tendon ruptures with quinolones use, numerous studies claim that there is a relationship between the medication and the tendon ruptures. Reports of Achilles tendon rupture as a possible side effect of the quinolones have been previously claimed but mechanism of the side effect of the medication is still unknown. We propose that quinolones may cause not only lower extremity tendon ruptures, but also they may cause upper extremity tendon ruptures such as flexor tendons of the hand. It is important because the hand performs very complex tasks and any tendon rupture in the hand may cause severe morbidity. Especially musician patients may lose their talents. Discussion Fluoroquinolones are broad-spectrum antibacterial agents that are well-tolerated and have a relatively low incidence of serious
T. Turker, J.E. Kutz / Medical Hypotheses 77 (2011) 696–697
Fig. 1. The rupture of the FDP of the left small finger.
side effects [4]. However, they have musculoskeletal side effects that may manifest as tendon ruptures. The most common tendon rupture reported is in the Achilles tendon [1–3]. Even though several clinical studies claim that quinolones might cause tendon rupture, readers might question whether these claims are merely coincidences. There are few basic science studies that offer validation for the clinical claims. Kashida et al. demonstrated the toxic potentials of fluoroquinolones in the muscle, tendon, synovial membrane and articular cartilage [5]. They showed that local vascular hyperpermeability may contribute to the development of tendon ruptures. Williams et al. performed in vitro administration of quinolones, which resulted in significantly decreased collagen and proteoglycan synthesis within three days [6]. The exact mechanism of the side effect of quinolones is still unknown [7,8]. However, Medrano San Ildefonso described how mechanical stress, direct toxicity on the tendon fibers, local ischemia, and preexisting abnormalities could be possible mechanisms for quinolones’ damage to tendons [9]. Simonin et al. administered pefloxacin to rats and showed that oxidative damage might be the mechanism causing tendon rupture. They also showed that such damage might be prevented using N-acetylcysteine [10]. We reviewed our patient’s medical history which was absent of medical problems or predispositions toward tendon rupture. We therefore ruled out the possibility that pre-existing abnormalities caused the rupture and concluded that the only logical explanation of the rupture was the previous administration of levofloxacin. The timing between rupture of tendon and administration of the medicine is variable. Luthje et al., Gold et al. and van der Linden reported tendon rupture occurring within a few hours to 6 months after initial quinolone administration, Gottschalk et al. reported a tendon rupture 1 month after starting treatment and Vyas et al. reported an Achilles tendon rupture one week after starting treatment [1,3,11–13]. Again, Williams et al.’s basic science might help to better understand the latency period [6]. In their study, ciprofloxacin was administered to fibroblasts that were obtained from Achilles tendon, Achilles paratenon, and shoulder capsule. Collagen and proteoglycan synthesis significantly decreased three days after fluoroquinolone treatment. Compared with unstimulated control fibroblasts, culture media from Achilles tendon, paratenon, and shoulder capsule cells that were exposed to ciprofloxacin demonstrated statistically significant increases in matrix-degrading
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proteolytic activity after 72 h in culture. Our patient’s tendon rupture occurred one week after the administration of levofloxacin, which shows consistency with the rest of the publications [1,2,6,7,11,12,14]. Patients who undergo fluoroquinolone treatment should be informed that tendon rupture may occur even 6 months after the medication is discontinued. If a tendon rupture occurs, we believe that surgical treatment for ruptured tendon should not be different from normal tendon repair. However, when the tendon rupture is neglected as in our patient, hand surgeons might consider secondary tendon repairs and salvage procedures as the ideal repair method. Because our patient refused medical intervention, we could not perform any radiological imaging such as MRI or CT scan. We could not take tissue from the tendon for biopsy to investigate the possible relation of the medicine and the tendon rupture either. Tendon ruptures in upper extremity are more important because they cause more morbidity due to functions of the upper extremity. We propose that levofloxacin use may cause upper extremity tendon ruptures. But even the Achilles tendon rupture as a possible side effect of the quinolones has not been proven scientifically. Our hypotheses has to be proven nevertheless we strongly recommend that before prescribing quinolone antibiotics, information describing potential side effects should be given to all patients. Conflict of interest None declared. References [1] Gottschalk AW, Bachman JW. Death following bilateral complete Achilles tendon rupture in a patient on fluoroquinolone therapy: a case report. J Med Case Rep 2009;3:1. [2] Kowatari K, Nakashima K, Ono A, Yoshihara M, Amano M, Toh S. Levofloxacininduced bilateral Achilles tendon rupture: a case report and review of the literature. J Orthop Sci 2004;9:186–90. [3] Vyas H, Krishnaswamy G. Images in clinical medicine. Quinolone-associated rupture of the Achilles’ tendon. N Engl J Med 2007;357:2067. [4] Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging 2010;27:193–209. [5] Kashida Y, Kato M. Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats. Toxicol Pathol 1997;25:635–43. [6] Williams 3rd RJ, Attia E, Wickiewicz TL, Hannafin JA, et al. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. Am J Sports Med 2000;28:364–9. [7] Braun D, Petitpain N, Cosserat F, Loeuille D, Bitar S, Gillet P, et al. Rupture of multiple tendons after levofloxacin therapy. Joint Bone Spine 2004;71:586–7. [8] Liu HH. Safety profile of the fluoroquinolones: focus on levofloxacin. Drug Saf 2010;33:353–69. [9] Medrano San Ildefonso M, Mauri Llerda JA, Bruscas Izu C. [Fluoroquinoloneinduced tendon diseases]. An Med Interna 2007;24:227–30. [10] Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B. Pefloxacininduced Achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen. Antimicrob Agents Chemother 2000;44:867–72. [11] Gold L, Igra H. Levofloxacin-induced tendon rupture: a case report and review of the literature. J Am Board Fam Pract 2003;16:458–60. [12] Luthje P, Nurmi I, Nyyssonen T. Missed Achilles tendon rupture due to oral levofloxacin: surgical treatment and result. Arch Orthop Trauma Surg 2005;125:124–6. [13] van der Linden PD, van Puijenbroek EP, Feenstra J, Veld BA, Sturkenboom MC, Herings RM, et al. Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum 2001;45:235–9. [14] Haddow LJ, Chandra Sekhar M, Hajela V, Gopal Rao G. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. J Antimicrob Chemother 2003;51:747–8.