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Physical Therapist Management of Fluoroquinolone-Induced Achilles Tendinopathy

BL Greene, PT, PhD, OCS, is Assistant Professor, Division of Physical Therapy, Department of Rehabilitation Medicine, School of Medicine, Emory University, 1441 Clifton Rd, Rm 160, Atlanta, GA 30322 (USA) (bgree02{at}emory.edu)

Address all correspondence to Dr Greene at Emory University

Submitted November 7, 2001; Accepted June 30, 2002

	Abstract

 
Background and Purpose. Use of fluoroquinolone antibiotics is reported to be a cause of adverse musculoskeletal effects, such as tendinopathies and tendon ruptures. The purpose of this case report is to describe the management and outcomes of a patient with bilateral Achilles tendinopathy secondary to fluoroquinolone antibiotic use. Case Description. The patient was a 41-year-old man who developed bilateral Achilles tendon pain on the third day of levofloxacin use. The physical therapy intervention consisted of an initial phase to reduce stress on the tendon through the use of crutches and orthoses and a second phase to progressively stress the tendon through exercise and functional activities. Outcomes. After 11 weeks of physical therapy (14 treatments), the patient's pain decreased from 3/10 to 1/10 on a visual analog scale and his Lower Extremity Functional Scale score increased from 28/80 to 71/80. Discussion. An overlapping 2-phased intervention approach based on connective tissue remodeling principles may be effective in elimination of pain and restoration of function following fluoroquinolone-induced Achilles tendinopathy.

Key Words: Achilles tendon • Fluoroquinolons • Lower extremity • Musculoskeletal disorders • Physical therapy

	Introduction

Top Abstract Introduction Case Description Outcomes Discussion Conclusions References

 
Achilles tendon disorders encompass a variety of medical diagnoses, such as tendon rupture, tendinitis, and tendinopathy. In the past decade, the medical literature has increasingly reported the onset of tendinopathy and Achilles tendon ruptures secondary to fluoroquinolone antibiotic use.^1–4 A recent increase in the prescription of Ciprofloxacin,^* a fluoroquinolone antibiotic, has resulted from the increased exposure of US citizens to anthrax. With increased fluoroquinolone use, the potential exists for greater incidence of adverse effects, such as Achilles tendinopathy.

Fluoroquinolones are antibacterial agents that hinder bacterial nucleic acid replication by inhibiting the DNA-gyrase enzyme.⁵ Fluoroquinolones have become more popular since the 1980s when a longer half-life was achieved, allowing once-daily doses and improved effectiveness against a broad spectrum of gram-negative and gram-positive bacteria.^4,6 The fluoroquinolone antibiotics are indicated for infections of the upper and lower respiratory tract, urinary tract, and skin.⁶ The most frequently reported adverse effects of fluoroquinolone antibiotics are gastrointestinal distress, skin reaction, headache, and dizziness,⁵ although adverse effects also are known to occur in the hepatic, renal, and musculoskeletal systems.⁶ Tendinopathy and rupture have been reported as infrequent adverse reactions that occur most often in the Achilles tendon. The exact incidence of tendinopathy is unknown, but it has been estimated to be 15 to 20 cases per 100,000 medicated people.⁴ In 1995, the Food and Drug Administration (FDA) updated the warning label for fluoroquinolones to include a warning about tendon pathology and possible rupture. The warning label recommends discontinuing fluoroquinolone use at the first sign of tendon pain or inflammation and refraining from exercise until the problem is diagnosed.⁷

The pathophysiology of drug-induced tendinopathy and rupture is poorly understood. The sudden onset of symptoms after a single dose, in some cases, suggests a direct toxic effect of fluoroquinolones on the cells and fibers of the tendon.⁸ Movin and colleagues³ found histological evidence of abnormal collagen fiber structure and arrangement, and altered fibril to matrix ratio with a resultant increase in the extracellular matrix. One hypothesis of the etiology is that the histological changes result in decreased tensile loading capacity of the tendon such that normal functional activities overload the tendon.⁹ The literature does not explain why drug-induced tendinopathy and rupture occur more frequently in the Achilles tendon, but the rapid and immense tendon loading during weight-bearing activities, such as walking and running, may make the Achilles tendon more vulnerable than other tendons.¹⁰ Risk factors believed to be associated with Achilles tendinopathy and rupture are use of corticosteroids, increasing age (over age 60 years), chronic renal disease, and rheumatoid arthritis.^8,9

The purpose of this case report is to describe the management and outcomes of a patient with bilateral Achilles tendinopathy secondary to fluoroquinolone antibiotic use. A problem-solving approach was used to classify and manage a patient with an unfamiliar condition. As physical therapists become a point of entry into the health care system, awareness of fluoroquinolone-induced tendon disorders is important.

	Case Description

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Patient Description

The patient was a 41-year-old man who was being treated for acute maxillary sinusitis with the antibiotic medication Ceftin. After taking the medication for 18 days, his sinusitis symptoms persisted, and his physician discontinued Ceftin and prescribed levofloxacin (500 mg 1 time per day), a fluoroquinolone antibiotic. On the third day of taking the prescribed dose of levofloxacin, he reported soreness around both Achilles tendons to his physician's office. He described a feeling "as if something was rubbing against my sneakers." On the fifth day, he reported severe pain with walking, and he was advised by his physician's office to discontinue the antibiotic medication. Independently, he began taking 9 Advil (200 mg) per day for the pain.

Two days later, while out of town, he went to the emergency department due to severe pain with standing and an inability to walk. Two days later, he was seen by a physiatrist, who diagnosed his condition as bilateral Achilles tendinopathy. At that time, he was referred for physical therapy.

The following day, 5 days after discontinuing the levofloxacin, he began physical therapy with his first physical therapist. He attended a total of 10 physical therapy sessions over the next 4 weeks. According to the patient and the office staff, the first 7 physical therapy sessions consisted of an initial evaluation, a combination of ultrasound and low-voltage electrical stimulation applied to the tendon, Achilles tendon stretching, and ice. He was instructed in a home exercise program that consisted of Achilles tendon stretching, plantar-flexion strengthening, and 10 minutes of walking twice daily. The Achilles tendon pain did not subside. The last 3 visits consisted of only the exercises. On the 10th visit, the exercise program was expanded to include 10 minutes of walking on a treadmill.

After 10 treatments, the patient discontinued physical therapy because he believed he was not improving. His physiatrist prescribed axillary crutches and then referred him to an orthopedist specializing in foot and ankle disorders. He received heel lifts from the orthopedist and underwent a magnetic resonance imaging (MRI) scan of the ankles and hematological studies. The MRI results were normal, indicating no tendon rupture or degeneration. His hematology results were normal for electrolyte levels, sedimentation rate, hematocrit, hemoglobin, and platelet levels. He discontinued all medications except Klonopin, a benzodiazepine, which he was taking prior to his Achilles tendinopathy for an unrelated disorder. He had no history of acute trauma or cumulative trauma, and he had no risk factors associated with fluoroquinolone-induced tendinopathy prior to his diagnosis. He had no history of similar conditions in the past, although he did report an incidence of plantar fasciitis more than 20 years ago. Prior to his diagnosis, he was very active, walking and bicycling 4.8 to 8 km (3–5 miles) per week. Nine weeks after he discontinued the levofloxacin, he consulted me.

Examination: Tests and Measures

Pain.
On a numeric pain rating scale from 0 ("no pain") to 10 ("worst pain imaginable"), the patient reported 1/10 pain bilaterally in the Achilles tendon region at rest and 3/10 pain after weight-bearing activity of short duration (5 minutes or less) The test-retest reliability for the 11-point numeric pain scale is .67 to .96.¹¹ The reported Pearson correlation coefficient between the numeric pain scale and the visual analog scale is r=.80.¹¹

Posture.
Observation of standing posture revealed that the left calcaneus was positioned in 4 degrees of varus as measured by a goniometer with one arm aligned to a line bisecting the calcaneus and the other arm parallel to the floor (calcaneal-to-vertical angle). The calcaneal-to-vertical angle was 0 degrees on the right. Intraclass correlation coefficients (ICCs) for intrarater reliability have been reported to be .91 to .92 for this measurement in patients with diabetes mellitus.¹² Both feet appeared to have a high medial longitudinal arch. These findings are indicative of a supinated subtalar joint position.¹³

Range of motion.
Active range of motion was measured with a standard goniometer; the results are presented in Table 1. Other researchers^14,15 have found the ICCs for intrarater reliability of goniometric measurements of ankle dorsiflexion and plantar flexion to be .86 to .90.

Gait.
The patient ambulated with axillary crutches and a swing-through gait pattern. He was able to ambulate without the crutches for the gait analysis. The patient walked with short steps and had decreased plantar flexion at both ankle joints during the late stance phase. He also had a bilateral lack of calcaneal eversion beyond neutral during early stance phase, indicative of decreased subtalar joint pronation. Although observational gait analysis is a common and convenient examination procedure, the intrarater reliability is moderate to poor.¹⁷

Muscle strength.
Using manual muscle testing,¹⁸ the tibialis anterior and tibialis posterior muscle strength were 5/5 bilaterally. With the weight-bearing muscle test for the gastrocnemius and soleus muscles, strength was 4/5 on the right and 5/5 on the left. The patient reported no pain during muscle testing, but he did note a mild pulling sensation in each Achilles tendon during muscle testing. According to Lamb,¹⁹ reliability of manual muscle testing has not been well established, but appears to have face and content validity.

Palpation.
No ankle joint effusion or soft tissue edema was palpable. The gastrocnemius/soleus muscle bellies, musculotendinous junction, Achilles tendon belly, and Achilles tendon insertion were not tender to palpation.

Work, community, and leisure integration.
The Lower Extremity Functional Scale (LEFS)²⁰ was used to measure his functional status. The LEFS is a relatively new questionnaire consisting of 20 items rated on a 0 to 4 scale; a higher score indicates greater functional ability. Based on a sample of 98 patients referred for physical therapy with any lower-extremity musculoskeletal condition, the reported correlation coefficient for test-retest reliability within a 24- to 48-hour period was r=.86.²⁰ The correlation between the LEFS scores and scores on the physical function subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), as determined by a Pearson correlation coefficient, was .80. The patient's initial score was 26/80, indicating a low functional level.

Patient response to the examination.
The patient had no notable increase in symptoms during the examination, although he reported a mild pulling sensation in each Achilles tendon during muscle testing of the calf. Twenty-four hours after the initial examination, he reported 3/10 level pain that was present at rest and during activity. The pain was located in the Achilles tendon region bilaterally, particularly near the insertion. The patient's pain level took several days to return to the pre-examination level of 1/10.

Evaluation

Evaluation of the examination findings formed the basis for the hypothesis that the patient's decreased functional level was due to the decreased capacity of the Achilles tendon to accept normal loading forces. Based on the pathophysiology of drug-induced tendinopathies, I believed that the fluoroquinolone antibiotic had altered the microscopic structure of the tendon and the ability of the collagen to resist tensile forces during normal weight-bearing activities. Based on the signs and symptoms, the patient did not appear to have a primary inflammatory problem; however, an inflammatory response was induced after mechanical overloading. I determined that the patient had impaired motor function and muscle performance associated with connective tissue dysfunction of the Achilles tendons. The physical therapist diagnostic classification was Pattern 4D, "Impaired Joint Mobility, Motor Function, Muscle Performance, and Range of Motion Associated with Connective Tissue Dysfunction."²¹

Little literature exists to guide intervention planning and the formulation of a prognosis. The prognosis for full functional recovery without physical therapy is highly variable.^8,10 Case reports indicate that recovery generally occurs within 2 months after the cessation of antibiotic use^8,10; however, continued pain and disability in up to 26% of the cases has been reported.^3,8 Tendon rupture reportedly occurs in 24% to 30% of the cases up to 90 days after the cessation of antibiotic use.^4,8 The prognosis for full functional recovery with physical therapy has not previously been reported for tendinopathy secondary to fluoroquinolone use.

Intervention and Re-evaluation

I took an overlapping 2-phased intervention approach. The first phase consisted of techniques to protect the tendon from overload stresses, and the second phase consisted of graduated loading of the tendon and muscle. Based on the patient's response to the initial physical therapy program and my initial examination, the tendon appeared to overload easily, causing inflammation. To protect the tendon from overloading forces, techniques were used to "unload" the tendon during weight-bearing activities. The patient was advised to continue using axillary crutches and the heel lifts for the purpose of decreasing tendon loading. Although he was instructed in a 2-point gait with the crutches because it is a more natural pattern, the patient reported that he often continued to use the swing-through gait pattern. During the third week of therapy, I recommended use of a counterforce Achilles tendon brace^|| (Figure) during functional weight-bearing activities, excluding exercises. The counterforce brace for the Achilles tendon is a nonelastic constraint with a tension strap that crosses the Achilles tendon. Empirical evidence supports the use of counterforce bracing in the upper extremity for decreasing pain in patients^22,23 and decreasing muscular activity in people who are asymptomatic^24,25; however, contradictory evidence also exists.²⁶ The underlying mechanisms proposed to explain the effects of counterforce bracing are that the pressure from the tension strap either broadens the musculotendinous attachment or limits muscle expansion at the time of contraction resulting in decreased stress within the tendon.²³

View larger version (127K): [in this window] [in a new window]   Figure. Counterforce Achilles tendon brace.

I designed a progressive exercise program (Tab. 2) to address the hypothesis that graduated loading of the tendon and muscle would improve the tendon's ability to withstand tensile forces through the process of connective tissue remodeling. As a result of remodeling, the patient's functional ability was expected to improve.

The patient was seen 2 times a week for the first 3 weeks and then 1 time per week for the next 8 weeks (except for his vacation) to monitor his progress and revise his home program. Across the 11 weeks of physical therapy, resistance of the lower-extremity exercises was gradually increased, as noted in Table 2. By the sixth week, the patient was standing and walking for 5 minutes without crutches but with the counterforce braces. During week 11, crutch use was discontinued. After 11 weeks of physical therapy (14 visits), he continued with a home exercise program for an additional 3 weeks. After 3 weeks of home exercises, he was seen for one more follow-up visit to reassess his progress and adjust his home exercise program. During the final visit, the home exercise program was adjusted to include plyometric exercise consisting of a partial squat on the Total Gym machine with acceleration during the extension phase of the exercise and controlled flexion back to the squat position, 10 repetitions, jogging in place for 2 to 3 minutes, and jumping up a step with one foot, 5 repetitions each foot, once per day. Plyometric exercise attempts to reproduce the stretch-shortening cycle found in functional activities and is proposed to improve muscular performance through both mechanical and neurophysiologic mechanisms.²⁷

	Outcomes

Top Abstract Introduction Case Description Outcomes Discussion Conclusions References

 
After 11 weeks of physical therapy (14 visits), the goal of an improved functional level was achieved, and a follow-up visit 3 weeks later indicated continued functional improvement. The increase in the patient's LEFS scores, shown in Table 3, corresponded to his exercise tolerance. For the first 6 weeks, he tolerated minimal exercise progression, but during the last 5 weeks his exercise tolerance markedly improved, and his LEFS scores increased.

	Discussion

Top Abstract Introduction Case Description Outcomes Discussion Conclusions References

 
This case report described a patient whose Achilles tendinopathy was an adverse side effect of short-term antibiotic use. It illustrates the importance of awareness of relationships between adverse drug effects and musculoskeletal conditions. This case report also describes a patient's recovery from fluoroquinolone-induced tendinopathy. Decreased load-bearing ability of the tendon suggests that the first phase of rehabilitation should be a protective one. During the first month of rehabilitation with his first physical therapist, this patient's tendon was not protected and his symptoms worsened. Later, the heel lifts, counterforce bracing, and crutch use were all intervention strategies designed to decrease the tensile load transmitted to the Achilles tendon during walking. Although little is known about connective tissue healing subsequent to drug-induced toxicity, the literature does provide insight into connective tissue mutability and response to mechanical stress, in general. Too great a load results in microfailure and potentially macrofailure of the connective tissue,²⁸ but lack of loading results in connective tissue atrophy and weakness.²⁹ For this reason, it was necessary to find a balance between loading and unloading the tendon and to progressively stress the tendon over time in an attempt to increase the tendon's ability to tolerate greater stresses. The progressive exercise program was designed to gradually load the Achilles tendon in a controlled fashion. During the first 6 weeks, the patient was able to tolerate minimal progression of the exercise program, but during the last 5 weeks, his ability to resist loading increased weekly.

This case report also demonstrates the use of a problem-solving approach to synthesize the examination findings and classify a patient with a condition unfamiliar to me. The treatment plan was based on the judgment that the patient's decreased functional status was due to an alteration in the connective tissue due to the antibiotic use. By understanding the nature of connective tissue remodeling, the intervention was designed to first protect the tendon and then to progressively load the tendon. During the initial 6 weeks of protection, however, when the tendon was structurally and mechanically altered from the toxic effects of the fluoroquinolone antibiotic, the progression was slow in comparison with the relatively faster initial recovery from acute overuse injuries that I have observed. The patient's improvement was nonlinear in that he made little progress in the first 7 weeks and made rapid progress in the last 4 weeks. In fluoroquinolone-induced tendinopathy, the tendon has the potential to rupture even after the cessation of medication usage.⁶ Adequate protection of the healing tendon, which lasts until the tendon regains its tension-bearing capacity, probably is important. The time frame for this patient's recovery was consistent with the range stated in Pattern 4D of the Guide to Physical Therapist Practice—2 weeks to 6 months and 3 to 36 visits.²¹ His entire recovery process took 5 months and a total of 24 physical therapy visits. He had 10 visits with his first physical therapist and 14 visits with me.

Case reports are a good approach to describe relatively infrequent pathologies, such as Achilles tendinopathy secondary to fluoroquinolone antibiotic use. However, due to the lack of controls in case reports, the experiences with this patient may not be generalizable to other patients and the patient's recovery could have resulted from factors other than the physical therapy intervention.

	Conclusions

Top Abstract Introduction Case Description Outcomes Discussion Conclusions References

 
Achilles tendinopathy is a relatively infrequent adverse effect of fluoroquinolone antibiotic use. The pathophysiology is poorly understood, but the toxic effects of the drug are believed to alter the structure and biomechanical properties of the connective tissue. By applying principles of connective tissue biomechanics, a balance between initial protection of weakened connective tissue and progressive tendon loading was sought. Further documentation of other cases would be helpful to establish a typical course of recovery, and research is needed to determine the effectiveness of the 2-phase approach described in this case report.

	Footnotes

 
The author thanks Jill Sitlinger, PT, MPT, Cert MDT, OCS, for her consultation on the case, and she thanks Bruce Greenfield, PT, MMSc, OCS, and Marie Johanson, PT, MS, OCS, for their thoughtful comments.

^* Bayer Corp, 400 Morgan Ln, West Haven, CT 06516.

Glaxo Wellcome Inc, Five Moore Dr, Research Triangle Park, NC 27709.

Wyeth Consumer Health Care International Inc, Five Giralda Farms, Madison, NJ 07940.

Roche Pharmaceuticals, Roche Laboratories Inc, 340 Kingsland St, Nutley, NJ 07110-1199.

^|| Cho-Pat Inc, PO Box 293, Hainesport, NJ 08036.

^# Engineering Fitness International Inc, 7755 Arjons Dr, San Diego, CA 92126.

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Top Abstract Introduction Case Description Outcomes Discussion Conclusions References

 

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when Rapid Responses are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Greene, B. L Search for Related Content PubMed PubMed Citation Articles by Greene, B. L