A 57-year-old male retired Army Colonel living in Virginia presented to Bethesda Naval Hospital for evaluation of a 4-day history of swelling and pain in both ankles. Swelling initially began in the left ankle and progressed to involve the right ankle and mid-foot region. Aggravating factors included dorsiflexion of the foot and weight bearing. His recent past medical history was significant for prostatitis that was diagnosed 2 months earlier. Other chronic medical problems included hypertension, benign prostatic hypertrophy, and gastroesophageal reflux. he was taking omeprazole, lisinopril, enteric coated aspirin, tamsulosin, and levofloxacin. The patient recalls a single episode of fevers and chills 1 day prior to the onset of the foot and ankle pain.

1. The most important diagnosis to initially rule out in this patient is:

a. Acute polyarticular gout

b. Reactive arthritis

c. Septic arthritis

d. Viral arthritis

e. Initial presentation of a systemic rheumatic disease (i.e., rheumatoid arthritis, systemic lupus erythematosus)

The goal of making an early diagnosis for any inflammatory arthritis is to institute the appropriate therapy so that joint damage can be minimized. Acute polyarticular gout involving the lower extremity can include the knees, ankles, heels, mid-foot region, and small joints of the toes. Even if untreated, however, most early attacks of gout would be expected to resolve in 7 to 10 days without significant joint damage. Reactive arthritis is typically associated with enteric or urogenital infections, is sterile, and can also cause inflammation along tendons or at the attachment of tendons or ligaments to bone. This may result in heel pain or plantar fascial pain depending upon its location. Early diagnosis of a septic arthritis, in comparison to the other options listed, is essential due to the potential for significant joint damage if left untreated. Polyarticular septic arthritis is relatively uncommon. In a report from one hospital, this diagnosis accounted for 16.6% of all septic arthritis with the majority (80%) caused by Staphylococcus aureus.1 Fifty-two percent had underlying rheumatoid arthritis and 36% had immunosuppression caused by drugs or concurrent illness. Viral arthritis, in comparison to bacterial arthritis, more typically occurs in a symmetric, small joint distribution and is nonerosive. An acute presentation of rheumatoid arthritis or other inflammatory connective tissue diseases would not be high on the differential diagnosis at this time due to the brief duration of symptoms.

On examination, the patient had a blood pressure of 128/74 mm Hg, a heart rate of 78 beats per minute, a respiratory rate of 14 breaths per minute, and a temperature of 99.0°F. He was well developed and well nourished and in no acute distress. He had male pattern hair loss and no evidence of facial rash or oral ulcers. Cardiopulmonary examination was normal. No lymphadenopathy was noted in the cervical, axillary, or inguinal areas. He had moderate swelling of both ankles with limited visualization of both the medial and lateral malleoli, fullness of the Achilles tendons, and pitting edema of the foot which extended to just above the ankle. The ankle joint itself was tender to palpation bilaterally; however, the most significant tenderness occurred with palpation of the Achilles tendons. Both Achilles tendon regions were diffusely swollen and without nodularity. Subtalar and plantar flexion of the ankle was normal; however, the patient was unable to dorsiflex beyond a neutral position because of pain. Other joints, including the mid-foot, first metatarsal phalangeal joints, and toes were without warmth, erythema, or swelling.

2. Physical examination features associated with Achilles tendonitis include all qf the following EXCEPT:

a. A palpable calf bulge

b. Tenderness along the length of the Achilles tendon

c. Swelling or warmth of the posterior ankle

d. Pain with passive dorsiflexion of the foot

e. Pain localized to the heel or back of the leg

A thorough physical examination of the involved joints and periarticular areas is essential in coming to the appropriate diagnosis. Careful evaluation of the Achilles tendon may reveal some nodularity; however, a calf bulge would not be expected in uncomplicated tendonitis. This finding would indicate some degree of tendonous rupture. Achilles tendonitis is associated with pain along the length of the tendon, most commonly several centimeters proximal to the calcaneus.

Because of the associated inflammation, the area may appear swollen and warm with fullness noted in the ankle region posteriorly. Pain would be expected to occur with active and passive dorsiflexion of the foot due to tension on the tendon. In some cases, pain may be described in the heel or more proximally in the calf.2

The patient was admitted to the hospital for pain management and further work-up of his ankle swelling. Radiographs of both ankles showed diffuse soft tissue swelling without fracture or degenerative changes. Laboratories were significant for a white blood cell count of 12,500/mm^sup 3^ (4,000-11,000/mm^sup 3^) with 69% neutrophils (51-67%) and 14% lymphocytes (21-35%), normal serum chemistry, erythrocyte sedimentation rate of 50 mm/hour (0-15 mm/hour), C-reactive protein of 9.87 mg/dL (10.0800 mg/dL), negative anti-nuclear antibody, negative rheumatoid factor, uric acid of 4.1 mg/dL (3.3-8.4 mg/dL), and unremarkable urinalysis. Five milliliters of blood-tinged fluid was aspirated from the right ankle shortly after admission revealing no crystals and a negative Gram stain. An automated cell count showed 333 red blood cells/mm^sup 3^ and 75 white blood cells/mm^sup 3^ (56% neutrophils, 16% lymphocytes, 28% monocytes).

3. The right ankle aspiration would best be described as:

a. Inflammatory

b. Noninflammatory

c. Indicative of a hemarthrosis

d. Consistent with a septic joint

e. Uninterpretable without also measuring synovial fluid glucose and protein levels

One of the most helpful additional studies available in evaluation of an acutely swollen joint is needle aspiration. Synovial fluid analysis helps to further clarify the nature of the arthropathy. Tests routinely ordered for synovial fluid would include a Gram stain, cell count, culture, and polarized microscopy for crystalline disease. Synovial fluid that is inflammatory may appear cloudy and typically has a white blood cell (WBC) count ranging from 3,000 to more than 100,000 cells/ mm3.3 A noninflammatory fluid without a significant amount of blood would appear clear. A simple test that can be performed at the time of the procedure is placing the vial of fluid in front of a book or newspaper. If the fluid is clear enough to allow the observer to easily read the text, the fluid is most likely noninflammatory. Although the fluid specimen obtained in this patient had more red blood cells than WBCs, it is not indicative of a hemarthrosis. WBC counts in septic joints are typically (but not always) highly inflammatory and can exceed 100,000 cells/mm3. These aspirates typically show organisms on Gram stain and culture except in the case of gonococcal arthritis which is often culture negative. Tests such as glucose and protein add little to the diagnostic work-up of synovial fluid and should not be ordered.

Because of the patient's unusual presentation, further information was obtained regarding the recent history of prostatitis. He recalled that it was diagnosed 2 months before admission based on painful urination, an elevated WBC count, and discomfort when his prostate gland was examined. No organism was cultured from the urine; however, he was treated empirically with amoxicillin and clavulanate for 14 days. Urinary symptoms improved for approximately 1 month but then recurred. Levofloxacin was initiated 7 days before the ankle swelling occurred.

4. Based on the history, laboratory results, and examination features noted previously, the most appropriate assessment at this time woutd be:

a. Reactive arthritis

b. Bilateral Achlles tendonitis with noninflammatory ankle effusions

c. Acute ankle strain/sprain

d. Gouty arthritis

e. Lower extremity edema

Although many of the history and examination features in this case lead one to a diagnosis of reactive arthritis (prostatitis, Achilles tendon involvement, and oligoarthritis), synovial fluid would be expected to be inflammatory with WBC counts ranging from 5,000 to 50,000 cells/mm3 with a polymorphonuclear predominance on differential.4 When left with a situation such as this, descriptive assessments are the most accurate. This patient definitely has two conditions, bilateral Achilles tendonitis and noninflammatory ankle effusions. An acute ankle sprain or strain seems unlikely without any history of injury. Gouty arthritis would also be extremely unlikely in the setting of a low uric acid, noninflammatory ankle aspirate, and negative synovial fluid crystal examination. Simple lower extremity edema does not adequately explain the patient's pain and examination findings.

Synovial fluid cultures from the patient's ankle remained without growth over the next week. A diagnosis of levofloxacin-induced bilateral Achilles tendonitis was subsequently made based on the temporal association of the ankle and Achilles tendon swelling and exclusion of the other aforementioned arthritides. He was treated conservatively with nonsteroidal anti-inflammatory agents, rest, and discontinuation of the levofloxacin.

5. If this condition had occurred in an active duty troop, the appropriate initial management of this patient would include all of the following EXCEPT:

a. Fitting with an ankle immobilier

b. Injection of the Achilles tendon region to decrease inflammation

c. Limited weight bearing

d. Use of nonsteroidal anti-inflammatory medication

e. Evaluation by an orthopedist/or any concern of tendon rupture

Appropriate initial management for fluoroquinolone-associated Achilles tendonitis focuses on conservative measures to decrease inflammation and limit the likelihood of progression to tendon rupture. Ankle immobilization, either through casting or a brace, has been used in some case series.5 Injection of the Achilles tendon as an initial treatment modality would be discouraged due to the concern for Achilles tendon rupture, especially if deposited within the tendon itself. Decreased activity, use of cold packs, and administration of anti-inflammatory medications would all be reasonable treatment options. If there is a concern that tendon rupture has occurred, evaluation by an orthopedist is indicated.

Discussion

Fluoroquinolones are a class of antibiotics that are commonly prescribed because of their broad spectrum of activity, high degree of bioavailability after oral administration, and efficacy against many different types of infections. Fluoroquinolones are currently used in the treatment of urinary tract infections, prostatitis, complicated skin and soft tissue infections, sexually transmitted diseases, and community acquired pneumonias.6 In 2002, a total of 370,824 prescriptions were filled at military medical treatment facilities throughout the world (Fig. 1).

Fluoroquinolone-associated tendonitis is an unusual but important complication to identify and treat due to the potential progression to complete rupture. With prescription-event monitoring, a frequency rate of 2.4 per 10,000 patients was found for tendonitis and 1.2 per 10,000 for tendon ruptures.7 A review of ICD-9 diagnostic codes for the fiscal year 2002 for active duty soldiers in TRICARE Region 1 revealed 63 cases of Achilles tendonitis within 1 month of taking a fluoroquinolone antibiotic. Individual cases were not reviewed to determine whether there was a direct association between the two; however, the number is impressive considering the limited population examined. Ninety percent of cases involve the Achilles tendons; however, other tendons reported to be affected include the tendons of the rotator cuff, epicondyles, and quadriceps femoris.8 The Achilles tendon is thought to be most commonly affected due to its weight-bearing role. In some cases a concurrent arthritis of the ankle may be present which is sterile and non-inflammatory.9 The average latency period between starting fluoroquinolone treatment and the appearance of symptoms is 6 days, with 93% of cases occurring within 1 month. Patients over the age of 60 are at most risk, especially those who are on concurrent steroids or who have renal failure. Other risk factors such as sports activities and diabetes may also play a role in determining overall risk.8

If patients develop an Achilles tendonitis while on a fluoroquinolone antibiotic, they should be counseled to stop the medication, limit physical activity, and see their medical provider. Appropriate work-up includes a thorough history to evaluate for other potential causes of tendonitis. With discontinuation of the fluoroquinolone antibiotic, most patients will recover within 2 months; however, some will continue to have longer term pain and disability.5,8,9

In conclusion, fluoroquinolone-associated tendonitis is an uncommon, but likely underappreciated complication which needs to be considered if it should develop during or within 1 month of the antibiotic regimen.

Acknowledgments

We thank MAJ Travis Watson and Ms Beth Spearman for their help in obtaining military prescribing data for this article.

Answers

1. c; 2. a; 3. b; 4. b; 5. b

References

1. Dubost JJ, Fis I. Denis P, et al: Polyarticular septic arthritis. Medicine 1993; 72: 296-310.

2. Vogelgesang S: Regional musculoskeletal disorders. In: Rheumatology Secrets, Ed 2, p 446. Edited by West S. Philadelphia, Hanley & Belfus, 2002.

3. McCarty DJ: Synovial fluid. In: Arthritis and Allied Conditions, Ed 14, pp 83-8. Edited by Koopman WJ. Philadelphia, Lippincott Williams & Wilkins, 2001.

4. Arnett FC: Seronegative spondyloarthropathies: reactive arthritis and enteropathic arthritis. In: Primer on the Rheumatic Diseases, Ed 12, pp 247-8. Atlanta, Arthritis Foundation, 2001.

5. Lewis RL, Gums JG, Dickensheets DL: Levofloxacin-induced bilateral Achilles tenclonitis. Ann Pharmacother 1999; 33: 792-4.

6. Karchmer AW: Antibacterial therapy. In: Cecil Textbook of Medicine, Ed 21, p 1599. Edited by Goldman L. Philadelphia, W. B. Saunders Co, 2000, 1599.

7. Wilton LV, Pearce GL, Mann RD: A comparison of ciproiloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J CHn Pharmacol 1996; 41: 277-84.

8. Van der Linden PD, Van Puijenbroek EP, Feenstra J, et al: Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Care Res 2001; 45: 235-9.

9. Ribard P, Audisio F, Kahn MF, et al: Seven Achilles tendonitis including three complicated by rupture during fluoroquinolone therapy. J Rheumatol 1992; 19: 1479-81.

Guarantor: LTC Robert J. Oglesby, MC USA

Contributors: CPT Brian T. McKinley, MC USA; LTC Robert J. Oglesby, MC USA

Department of Medicine and Rheumatology Service, Walter Reed Army Medical Center, Building 2, Ward 77, Washington, DC 20307-5001; e-mail: Robert.Oglesby@ NA.AMEDD.ARMY.MIL.

The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

This manuscript was received for review in June 2003 and accepted for publication in July 2003.

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