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Fluoroquinolone-Induced Tendinopathy: What Do We Know?
Richard M. Harrell, MD, Department of Emergency Medicine, Louisiana State University School of Medicine, Shreveport.

[South Med J 92(6):622-625, 1999. (c) 1999 Southern Medical Association]

Abstract
Fluoroquinolones are relatively safe, effective antibiotics. As their use becomes more frequent, so will the adverse side effects. I highlight a rare but debilitating adverse reaction -- fluoroquinolone-induced tendinopathy. Case reports and letters from 1987 to 1998 were identified by using Grateful Med and PubMed Internet accesses to the National Library of Medicine. Articles were reviewed for clinical practicality. There are few articles on fluoroquinolone-induced tendinopathy in the US literature targeting primary care physicians. This entity has been described in many case reports, but little has been done to isolate the causative agents. Incidence of this side effect is difficult to estimate, since no prospective studies are available for review or calculation of risk. Fluoroquinolone-induced tendinopathy appears more commonly in tendons under high stress. The cause is probably multifactorial. Risk factors for the development of fluoroquinolone-induced tendinopathy are age, renal failure, corticosteroid use, and previous tendinopathy from fluoroquinolones.

Introduction
Fluoroquinolones are synthetic antibiotics that inhibit bacterial DNA gyrase, which is necessary for the synthesis of bacterial DNA.[1] Fluoroquinolones have in vitro activity against a wide range of gram-negative and gram-positive organisms and have been shown to be relatively safe. Pharmaceutical companies are developing fluoroquinolones with longer half-lives for once daily dosing. For these reasons, these drugs are being used more often than ever before. Fluoroquinolone-induced tendinopathy is well described in France and, to a much lesser extent, by US rheumatologic and orthopaedic journals, but there is scant information in primary care literature. Fluoroquinolone-induced tendinopathy is underreported, both in the literature and to the Food and Drug Administration (FDA). With greater penetration of managed care into our practices, primary care physicians in the United States are more apt to see and be expected to treat this medication complication. The following is a presentation of a case of fluoroquinolone-induced tendinitis and a current literature review of tendinopathy associated with fluoroquinolones.

Case Report
A 28-year-old white woman came to her primary care physician's office complaining of a 3- to 4-day history of left heel pain. She denied any history of trauma or exercise over the week before presentation. Pain was worse with walking but not completely relieved with rest. She denied any radiation of the pain. Her medical history was pertinent for chronic sinusitis but negative for diabetes, hypertension, or renal disease. She denied any corticosteroid use. She had had sinus surgery for chronic pansinusitis 4 weeks earlier. Ciprofloxacin was prescribed post-operatively for 2 weeks, and her symptoms began 3 days after completing the ciprofloxacin. Her examination was remarkable for the following. Temperature was 98.1°F. She was a well-developed, well-nourished female who weighed 124 pounds. Left lower extremity examination revealed a normal appearing calf, ankle, and foot. However, she complained of extreme tenderness with light palpation of the Achilles' tendon along its entire length from the calcaneal insertion to the distal gastrocnemius. This was accentuated with plantar flexion. Thompson's sign was negative. The tendon did not appear to be ruptured; tendon swelling was palpable. Proximal calf and popliteal fossa tenderness was absent. There were no palpable venous cords. She was diagnosed with tendinitis due to ciprofloxacin. She was prescribed non-weight-bearing activity and nabumetone (500 mg BID) for 4 weeks. On repeat examination 6 weeks later, she was asymptomatic.

Incidence
Fluoroquinolones are antibacterial agents with an exceptional record of accomplishment regarding safety and efficacy. Generally, they are well tolerated with a minimum of side effects. During clinical trials of ciprofloxacin, the drug was discontinued in only 3.5% of patients tested. The most frequently reported events were nausea (5.2%), diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache (1.2%), restlessness (1.1%), and rash (1.1%). Adverse events considered likely to be drug related occurred in 7.3% of patients treated and possibly related in 9.2%.[2] Tendinopathy related to fluoroquinolone treatment has been reported but is an infrequent occurrence compared with the incidence of arthralgia and myalgia. Although the exact incidence is not known, some authors have estimated the incidence of fluoroquinolone-induced tendinopathy to be 15 to 20/100,000 treated patients.[3,4] However, to date, there are no prospective studies that will allow direct calculation of the relative risk of tendinopathy in patients treated with fluoroquinolones. Fluoroquinolones were first associated with Achilles' tendinitis in 1983.[5] The first case of tendon rupture by ciprofloxacin was reported to the Committee on Safety of Medicines in 1987.[6] Although there were 84 reported cases of fluoroquinolone-associated tendinitis or tendon rupture by 1995, the FDA did not issue a Report of Adverse Events until October 1996.[7,8] There are more than 200 reported cases of fluoroquinolone associated tendinitis, mostly in European medical journals and many associated with pefloxacin (not marketed in the United States). Tendinitis by other agents such as ofloxacin, norfloxacin, enoxacin, lomefloxacin, and ciprofloxacin has been reported, but incidence appears to be much lower. From 1987 to July 1997, the FDA had received 201 reported cases of tendon disorders associated with fluoroquinolones. This did not include the foreign cases associated with pefloxacin. The breakdown by event, drug, and location (United States or foreign) are listed in Table 1.

Pathophysiology and Predisposing Factors
The etiology of these lesions remains unknown and probably multifactorial. Drug-induced arthropathy has been described in various juvenile animal species after long-term, high-dose administration of fluoroquinolones. The diarthrodial, synovial, weight-bearing joints of juvenile dogs appear most susceptible to the effects of fluoroquinolones.[9] The lesions are characterized as macroscopic cartilaginous erosions and result in symptomatic arthralgia. The lesions in dog cartilage have caused regulatory concern that similar effects might be seen in children. A voluntary moratorium on human childhood use has operated for the last 13 years, but compassionate use has occurred for children with severe infections. Although arthralgia has been reported with fluoroquinolones,[10] arthritis has not been described in children before adolescence.[11] The sudden onset of some tendinopathies, occasionally after a single dose of a fluoroquinolone, suggests the possibility of direct toxicity.[4] Few histologic studies exist. Jorgensen et al[12] reported necrosis with neovascularization, interstitial edema, and degenerative lesions with fissures but without inflammatory cell infiltrate or angiitis. They proposed that tendon rupture might be due to vascular phenomenon leading to ischemia. Most tendon ruptures are at a site of deficient blood supply, lending to the possibility of an ischemic process. Several clinicians have described Achilles' tendon rupture 2 to 3 cm above the calcaneal insertion, which is relatively avascular.[13,14] LeHuec et al[4] found a few macrophages and giant cells peripheral to the injured tendon. Usually giant cells indicate a reaction to a foreign body. A 1997 study by Movin et al[15] revealed irregular collagen fiber arrangement, hypercellularity, and increased interfibrillar glycosaminoglycans. These findings are present in tendon overuse injuries in athletes as well.[16]

The concomitant use of corticosteroids and fluoroquinolones is recognized as a risk factor for developing tendinopathy. Forty-one percent of the reported cases reviewed were associated with corticosteroids. Some patients had been taking oral corticosteroids long-term, while others were given an injection of corticosteroids within the past 72 hours.[3,4,6,8,13,15,17-21] End stage renal disease has been implicated, since 12% were associated with renal disease alone.[4,6,8,15,18,19,21,22] This may be due in part to decreased renal excretion of the drugs, but spontaneous rupture of tendons has been described as a classic but rare complication of renal disease. This has been presumably due to accelerated degeneration of collagen fibers associated with hyperparathyroidism and chronic steroid use.[22] Mechanical stress probably plays a part as well. High load-bearing tendons, such as the Achilles, quadriceps,[23] and rotator cuff tendons,[24,25] are frequently described in the literature as being involved in tendinopathy. Age is also thought to be a risk factor.

Diagnosis and Diagnostic Studies
The history and physical examination are the cornerstones in making this diagnosis. Patients with symptoms of tendinitis should be questioned regarding the use of antibiotics in the preceding 90 days. Most patients presented within 2 weeks from initiation of therapy, but others ranged from 1 day to 3 months. Fluoroquinolone-induced tendinitis differs from other forms of tendinitis by its acute onset and sharp pain that occurs while using the associated extremity and with palpation. Usually, there is marked swelling of the tendon, and involvement is frequently bilateral. Tendon rupture is usually preceded by pain, and then the pain decreases with rupture. Thompson's test (loss of plantar flexion when the calf is squeezed by the examiner) accompanies Achilles' tendon rupture. Although the Achilles' tendon is more frequently reported, fluoroquinolone-induced tendinitis and rupture must be considered with any patient with tendon complaints and recent history of fluoroquinolone use. Other tendons reported to be involved are the quadriceps,[22] extensor pollicis longus,[26] peroneus brevis,[12] rotator cuff,[24,25] and epicondylitis.[4] Fluoroquinolones have even been reported to mimic de Quervain's disease.[20]

Magnetic resonance imaging (MRI) helps in the diagnosis. Gillet et al[19] reported features typical of intratendinous changes, longitudinal or transversal, detected on T1- or T2-weighted sequences. They believe MRI is an accurate method of identifying and classifying tendinitis and detecting a risk of rupture. Tendinous involvement has been classified in five stages using MRI (Table 2).[27]

These MRI findings are not exclusive to the Achilles' tendon, since similar findings have been described with tendinopathy in rotator cuff tears.[25]

Ultrasonography is useful, since it can show tendon abnormalities such as tendon ruptures and surrounding edema.[3,4,15]

Treatment and Prognosis
Treatment consists of immediate discontinuance of the fluoroquinolone and placing the tendons at rest. If tendinitis is suspected to be mild and the patient reliable, non-weight-bearing activity for 2 to 6 weeks should be sufficient. However, more often than not, splints and crutches are needed. If tendon rupture is suspected or potential risk for rupture is present (per MRI), the patient needs to be referred to orthopedics for below-the-knee casting. Surgery is rarely done on the Achilles' tendon ruptures, and there is scant information regarding this. Elderly patients seem to do particularly poorly with surgery because the local involvement renders the repair unreliable.[3,23]

Even with early diagnosis and management, tendinitis heals slowly. I found that tendon rupture occurred in 30% of reported tendinitis cases, despite appropriate care. This is probably biased for two reasons. (1) Patients with tendon rupture are more likely to have complaints; (2) rupture is a more severe consequence than tendinitis, and physicians are more likely to report ruptures than tendinitis. The mean recovery time reported is from 3 weeks for tendinitis to 3 months for a tendon rupture. Of the patients with ruptures, temporary incapacity was present 44% of the time. Complete recovery should be expected if rupture is not present. Patients should not be rechallenged with any fluoroquinolone.

Conclusion
Fluoroquinolones are safe, effective, tolerable, and convenient antibiotics. With once-a-day dosing becoming more common with the newest drugs, physicians will use them more frequently. Nevertheless, their indications should be strictly followed; they should not be used as single-drug, empirical therapy or in nosocomial infections alone. Resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa have already appeared. These antibiotics should be avoided, if possible, in patients with renal disease, elderly patients, and patients receiving concomitant corticosteroids. The diagnosis should be suspected in a patient on a fluoroquinolone, who has a sudden onset of tendon swelling and pain. Management consists of immediately discontinuing the drug and placing the tendon at rest. Corticosteroids, either orally or parenterally, should not be used to treat tendinitis if fluoroquinolones were prescribed within the previous 3 months. These patients should not be considered future candidates for fluoroquinolone therapy. As primary care medicine assumes a larger role in caring for all patients, we will see more of the associated side effects of these drugs. Primary care providers should be aware of this potentially debilitating adverse reaction when using these medications.

Reprint requests to Richard M. Harrell, MD, 1455 E Bert Kouns Industrial Loop, Shreveport, LA 71105.

References
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