- Email: [email protected]
An elderly patient with fluoroquinolone-associated achilles tendinitis
The American Journal of Geriatric Pharmacotherapy
E. Damuth et al.
Case Report
An Elderly Patient with Fluoroquinolone-Associated Achilles Tendinitis Emily Damuth} MD1; Joel Heidelbaugh} MD1,2; Preeti N. Malani} MD3-6; and Sandra K. (inti} MD3,5 University of Michigan Medical School, University of Michigan Health System, Ann Arbor, Michigan; 2Department of Family Medicine, University of Michigan Health System, Ann Arbor, Michigan; 3Department of Internal Medicine, Division of Infectious Disease, University of Michigan Health System, Ann Arbor, Michigan; 4Department of Internal Medicine, Division of Geriatric Medicine, University of Michigan Health System, Ann Arbor, Michigan; 5Vetemns Affairs Ann Arbor Healthcare System, University of Michigan Health System, Ann Arbor, Michigan; and 6Geriatric Research Education and Clinical Center (GRECC), University of Michigan Health System, Ann Arbor, Michigan 1
ABSTRACT Background: Due to their broad-spectrum activity and oral bioavailability, fluoroquinolone antibiotics are commonly prescribed to adults aged >60 years for many common community-acquired infections. The association between fluoroquinolone use and Achilles tendinitis is well established but sometimes missed in clinical practice. Older patients and patients with renal dysfunction are at particularly increased risk for this complication. Case summary: We present a case of Achilles tendinitis in a 77-year-old patient with renal dysfunction and a urinary tract infection (UTI) treated with ciprofloxacin 250 mg PO QD. Tendinitis developed within several days of the start of treatment and improved within 2 days of treatment cessation, without the need for intervention. The likelihood of ciprofloxacin having caused this reaction was probable (Naranjo score, 7). Early diagnosis and treatment cessation might have prevented tendon rupture, and the tendinitis resolved completely with subsequent physical therapy. Conclusion: Based on this outcome in this patient with UTI, fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age and renal dysfunction. (Am] Geriatr Pharmacother. 2008;6:264-268) © 2008 Excerpta Medica Inc. Key words: Achilles tendinitis, fluoroquinolone, ciprofloxacin, tendinitis. Accepted for publicatIOn July 23, 2008. © 2008 Excerpta Medica Inc. All rights reserved.
264
I December 2008 I
Volume 6 • Number 5
doi:l0.l016/j.amjopharm.2008.11.002 1543-5946/$32.00
E. Damuth et al.
INTRODUCTION Fluoroquinolones provide broad-spectrum antibacterial coverage and are generally well tolerated among older adults. 1 Adverse effects mainly include gastrointestinal disturbance (overall prevalence, 2%-5%), skin reactions (1%), and central nervous system disorders (1%).1,2 An association between fluoroquinolones and Achilles tendinitis, defined as redness and pain along one or both Achilles tendons, was first reported in the 1980s. 3 The number of clinical reports has subsequently increased, prompting the US Food and Drug Administration (FDA) to recommend that the labeling for all fluoroquinolones include a black-box warning indicating an increased risk for tendon rupture. 4 There has also been an increase in the use of fluoroquinolones in elderly inpatients and outpatients. 3 Older adults are at a 1.5- to 3-fold higher risk for fluoroquinolone-associated tendinitis. 3 Although tendinitis is a well-established adverse effect associated with fluoroquinolone use, the association is sometimes missed, with Achilles tendinitis being attributed to a different inflammatory condition (eg, gout).5 We present a case of Achilles tendinitis in an older adult patient with a urinary tract infection (UTI) treated with ciprofloxacin. We also review the literature found in a search of PubMed (key terms: fluoroquinolonesand Achilles tendinitis; years: 1966-2006). CASE SUMMARY A 77-year-old man weighing 68 kg with a history of benign prostatic hypertrophy (BPH), chronic obstructive pulmonary disease (COPD), coronary artery disease, and hypertension presented to the Veterans Mfairs Ann Arbor Hospital System in Michigan. The patient had dysuria, flank pain, incomplete bladder emptying, and hesitancy 3 weeks after the completion of a 7-day course of ciprofloxacin (250 mg PO QD) for UTI with Escherichia coli. On hospital admission, physical examination was remarkable for right-sided costovertebral angle tenderness. Laboratory tests were notable for a white blood cell (WEe) count of 12.8 x 10 3 cells/rL (normal range, 4-10 x 10 3 cells/rL); hemoglobin, 12.8 g/dL (12-16 g/dL); blood urea nitrogen (BUN), 26 mg/dL (8-20 mg/dL); and creatinine, 1.7 mg/dL (baseline, 1.2 mg/dL) (normal range, 0.5-1.0 mg/dL). Urinalysis found cloudiness with trace protein (normal, no protein), negative nitrites, 3+ leukocyte esterase (normal, no leukocyte esterase), WECs too numerous to count (normal, 0-5 WECs per high-powered field [HPF]), and 10 to 25 red blood cells (RBCs) per HPF (normal, 0-5 RBC/HPF). Postvoid residual volume was 800 mL. Ciprofloxacin 250 mg/d PO was initiated
The American Journal of Geriatric Pharmacotherapy
for the treatment of presumed complicated UTI (renal dysfunction). Concurrent medications, which included albuterol administered by metered dose inhaler (2 puffs q4h PRN), furosemide 40 mg PO QD, lovastatin 20 mg PO QD, metoprololl00 mg PO QD, omeprazole 20 mg PO QD, and aspirin 80 mg PO QD, had not been changed. The patient had not received any corticosteroids for the treatment of COPD in the previous month. On hospital day 2, multiple blood cultures showed no growth, but urinary culture again grew ciprofloxacinsensitive E coli. WEC count increased to 17.5 x 10 3 cells/ rL; creatinine concentration decreased to 1.5 mg/dL with hydration. Renal sonography found no calculi or hydronephrosis. Treatment with terazosin 1 mg PO at night was started for BPH. On hospital day 3, the patient noted a sudden onset of severe left heel pain and increased pain with ambulation. A palpable nodule with swelling and erythema along the left Achilles tendon was found on physical examination (Figure). The area was tender on palpation, and the patient experienced pain on passive and active dorsiflexion. This was the first episode of Achilles tendinitis in this patient. The patient had been treated with a fluoroquinolone on several occasions in the previous few years, without any reported adverse events. Because ciprofloxacin use was considered a possible cause of the Achilles tendinitis, treatment with that drug was discontinued and amoxicillin/clavulanate 875/125 mg/d PO was substituted. Weight-bearing activity on the left leg was restricted, and a pneumatic boot was provided for immobilization. With treatment with NSAIDs, the patient's Achilles tendon pain improved over the next day. Mter resolution of UTI and improvement in tendinitis, on day 8 of hospitalization, the patient was discharged. BUN was 21 mg/dL; creatinine, 1.4 mg/dL. Eleven days after hospital discharge, the patient was seen for follow-up in the Infectious Disease Clinic. The erythema and swelling of the left Achilles tendon had largely resolved, but a nontender knot was noted on palpation. The patient was referred for physical therapy. One week later, he was able to ambulate using a rolling walker and the pneumatic boot. He was instructed to complete a home exercise program and continue to restrict weight-bearing activity until cessation of the pain. Previous to hospitalization, the patient had been fully ambulatory without the use of adaptive devices.
DISCUSSION Achilles tendinitis is an uncommon adverse effect associated with fluoroquinolone agents, occurring in
265
The American Journal of Geriatric Pharmacotherapy
E. Damuth et al.
Figure. Swelling and erythema along the left Achilles tendon in a patient receiving a fluoroquinolone.
case of fluoroquinolone-associated Achilles tendinitis based on a Naranjo score of 7. In a review of 98 cases of fluoroquinolone-associated tendon injury reported in the literature between 1961 and 2001, Khaliq and Zhanel6 found that pefloxacin was the fluoroquinolone most commonly implicated (37%), followed by ciprofloxacin (25.5%). The most common tendon injury was Achilles tendinitis (89.8%); 44% of cases were bilateral. Other sites included the triceps epicondyle, flexor tendon sheath, patellar tendon, quadriceps muscle, rotator cuff, subscapularis terrea, supraspinal tendon, and thumb. Onset of tendon injury occurred from 2 hours after initiation of fluoroquinolone treatment to 6 months after discontinuation, with a median duration of 8 days. (The patient in the present report presented with unilateral tendinitis 3 days after initiation of ciprofloxacin treatment of UTI.) Forty-one percent of patients experienced Achilles tendon rupture, which was reported after therapy was discontinued. 6,7 A case-control study by Corrao et aI3 compared 22,194 patients with tendon disorders (tendinitis, tenosynovitis) admitted with 101,953 age-, sex-, and municipality of residence-matched patients randomly selected from the regional archive. That study found that fluoroquinolone use was associated with an increased risk for tendon injury (odds ratio, 1.7; 95% CI, 1.4-2.0), with 1 case per 5958 patients treated. Although the prevalence of fluoroquinolone-induced tendon injury is low in the general population (0.14%-0.4%), risk is significantly increased (1.5- to 3.0fold higher) in association with age >60 years, chronic renal failure, hemodialysis, and corticosteroid thera-
266
py.3,6-10 Corrao et aI3 found that in patients 260 years of age who recently (1-30 days prior) were treated with a fluoroquinolone, tendon disorders were 1.5-fold more likely to develop, and Achilles tendon rupture was 2.7-fold more likely to develop, than in patients who were <60 years of age. In the same study, in patients who were using corticosteroids concurrently, the risk for tendon rupture was 46-fold that in age-matched patients who were not. Important risk factors in the present case included advanced age and acute renal dysfunction. Although chronic renal failure has been associated with fluoroquinolone-induced Achilles tendon injury, fewer cases have been reported in patients with acute renal failure. 3,6-9 Whether specific fluoroquinolones are more likely to be associated with Achilles tendinitis remains unclear. In a review of 36 studies in a total of98 patients with tendon injurywho were receiving fluoroquinolones,6 use of ciprofloxacin (26%) and pefloxacin (37%) was most commonly associated with tendon injury, but these 2 drugs were more commonly used. However, in a retrospective cohort study in 1841 patients who were receiving fluoroquinolones,2 the relative risk for Achilles tendinitis in patients who were receiving ofloxacin was 10.1 (95% CI, 2.2--46.0) compared with 3.7 (95% CI, 0.9-15.1) for all fluoroquinolones; there was no association found with ciprofloxacin or norfloxacin. The exact mechanism of fluoroquinolone-induced tendinopathy remains elusive; however, experimental evidence in animals suggests that fluoroquinolones may impede collagen matrix proliferation and promote collagen degradation. 6,s,1l,12 Other studies suggest a role of ischemia in tendinitis, with histopathologic evidence of edema and constricted vasculature. 6,7 It has also been
E. Damuth et al.
suggested that decreased clearance of fluoroquinolones may playa role in predisposing patients with renal dysfunction to tendinitis. 6 In juvenile animals, the observation of arthropathy caused by inhibition of mitochondrial DNA replication in immature chondrocytes has led to limited use of fluoroquinolones in the pediatric population, although most (no number given) of the musculoskeletal adverse events reported were reversible following immobilization and discontinuation of treatment. 12 ,13 The only arthropathies reported in children receiving fluoroquinolones have been mild to moderate arthralgias in adolescent patients (1.5%).12 Full recovery from Achilles tendinitis generally occurs within 3 months after discontinuation of fluoroquinolone therapy and may require physical therapy and protection of the affected Achilles tendon?,ll Although the patient reported here had immediate improvement in pain and erythema after discontinuation of ciprofloxacin and treatment with NSAIDs, he was still ambulating with a walker 1 month later. To help prevent Achilles tendon rupture when tendinitis is suspected, treatment with the fluoroquinolone should be promptly discontinued, the patient should be placed in an immobilization boot, steroids should be avoided or discontinued, and treatment with analgesics and physical therapy should be initiated. 6 - 8 ,1l Because rupture can occur even late in the course of treatment or after discontinuation, patients receiving fluoroquinolones should be counseled to seek medical attention immediately if symptoms of tendinitis, such as redness, pain, swelling, and stiffness, develop .14 In July 2008, the FDA recommended that the labeling of all fluoroquinolones include a black-box warning indicating an increased risk for tendon rupture. 4 Patients with a history of Achilles tendinitis with fluoroquinolone use should not be prescribed this class of drugs, as recurrences have been reported. 15 Finally, it is unclear why Achilles tendinitis developed in the patient in the present report only after his second course of ciprofloxacin treatment. He was not receiving any other medications that might increase this risk (eg, corticosteroids). It is possible that renal dysfunction was more profound with the second UTI, which necessitated admission. Fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age, corticosteroid use, and/or acute or chronic renal dysfunction. The tendinitis may be misdiagnosed as gouty flare or infection, leading to unnecessary testing and treatment. Achilles tendinitis can be debilitating and may lead to rupture.
The American Journal of Geriatric Pharmacotherapy
CONCLUSION Based on this outcome in this patient with UTI, fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age and renal dysfunction. ACKNOWLEDGMENT Dr. Heidelbaugh is a member of the scientific advisory board at Takeda Pharmaceuticals. REFERENCES 1. StaWmann R, Lode H. Fluoroquinolones in the elderly: Safety considerations. Drugs Aging. 2003;20:289302. 2. van der Linden PD, van de Lei J, Nab HW, et al. Achilles tendinitis associated with fluoroquinolones. Br ] Clin Pharmacol. 1999;48:433--437. 3. Corrao G, Zambon A, Bertu L, et al. Evidence oftendinitis provoked by fluoroquinolone treatment: A casecontrol study. Drug Saf 2006;29:889-896. 4. US Food and Drug Administration (FDA). FDA News. FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs: Seeks to Strengthen Warnings Concerning Increased Risk of Tendinitis and Tendon Rupture [FDAWeb site]. http://www.fda.govjbbs/topicsjNEWS/ 2008/NEW01858.html. Accessed July 15,2008. 5. Mahoney PG, James PD, Howell CJ, Swannell AJ. Spontaneous rupture of the Achilles tendon in a patient with gout. Ann Rheum Dis. 1981;40:416--418. 6. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: A critical review of the literature. Clin Infect Dis. 2003;36:1404-1410. 7. Yu C, Giuffre BM. Achilles tendinopathy after treatment with fluoroquinolone. Australas Radiol. 2005;49:407410. 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 Rheum. 2001;45:235-239. 9. Marti HP, Stoller R, Frey FJ. Fluoroquinolones as a cause of tendon disorders in patients with renal failure/renal transplants. Br ] Rheumatol. 1998;37:343-344. 10. Haddow LJ, Chandra Sekhar M, Hajela V, Gopal Rao G. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. ] Antimicrob Chemother. 2003;51:747748. 11. Mathis AS, Chan V, Gryszkiewicz M, et al. Levofloxacinassociated Achilles tendon rupture. Ann Pharmacother. 2003;37:1014-1017. 12. Leibovitz E. The use of fluoroquinolones in children. Curr Opin Pediatr. 2006;18:64-70.
267
The American Journal of Geriatric Pharmacotherapy
E. Damuth et al.
13. The American Academy of Pediatrics. The use of systemic fluoroquinolones. Pediatrics. 2006;118: 1287-1292. 14. Shortt P, Wilson R, Erskine 1. Tendinitis: The Achilles heel of quinolones! Emer;g MedJ. 2006;23:e63.
15. Muzi F, Gravante G, Tati E, Tati G. Fluoroquinolonesinduced tendonitis and tendon rupture in kidney transplant recipients: 2 Cases and a review of the literature. Transplant Proc. 2007;39:1673-1675.
Address correspondence to: Sandro K. Cinti, MD, Veterans Mfairs Ann Arbor Healthcare System, 2215 Fuller Road, Ill-I, 8th Floor, Ann Arbor, MI 48105. E-mail: [email protected]
268
E. Damuth et al.
Case Report
An Elderly Patient with Fluoroquinolone-Associated Achilles Tendinitis Emily Damuth} MD1; Joel Heidelbaugh} MD1,2; Preeti N. Malani} MD3-6; and Sandra K. (inti} MD3,5 University of Michigan Medical School, University of Michigan Health System, Ann Arbor, Michigan; 2Department of Family Medicine, University of Michigan Health System, Ann Arbor, Michigan; 3Department of Internal Medicine, Division of Infectious Disease, University of Michigan Health System, Ann Arbor, Michigan; 4Department of Internal Medicine, Division of Geriatric Medicine, University of Michigan Health System, Ann Arbor, Michigan; 5Vetemns Affairs Ann Arbor Healthcare System, University of Michigan Health System, Ann Arbor, Michigan; and 6Geriatric Research Education and Clinical Center (GRECC), University of Michigan Health System, Ann Arbor, Michigan 1
ABSTRACT Background: Due to their broad-spectrum activity and oral bioavailability, fluoroquinolone antibiotics are commonly prescribed to adults aged >60 years for many common community-acquired infections. The association between fluoroquinolone use and Achilles tendinitis is well established but sometimes missed in clinical practice. Older patients and patients with renal dysfunction are at particularly increased risk for this complication. Case summary: We present a case of Achilles tendinitis in a 77-year-old patient with renal dysfunction and a urinary tract infection (UTI) treated with ciprofloxacin 250 mg PO QD. Tendinitis developed within several days of the start of treatment and improved within 2 days of treatment cessation, without the need for intervention. The likelihood of ciprofloxacin having caused this reaction was probable (Naranjo score, 7). Early diagnosis and treatment cessation might have prevented tendon rupture, and the tendinitis resolved completely with subsequent physical therapy. Conclusion: Based on this outcome in this patient with UTI, fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age and renal dysfunction. (Am] Geriatr Pharmacother. 2008;6:264-268) © 2008 Excerpta Medica Inc. Key words: Achilles tendinitis, fluoroquinolone, ciprofloxacin, tendinitis. Accepted for publicatIOn July 23, 2008. © 2008 Excerpta Medica Inc. All rights reserved.
264
I December 2008 I
Volume 6 • Number 5
doi:l0.l016/j.amjopharm.2008.11.002 1543-5946/$32.00
E. Damuth et al.
INTRODUCTION Fluoroquinolones provide broad-spectrum antibacterial coverage and are generally well tolerated among older adults. 1 Adverse effects mainly include gastrointestinal disturbance (overall prevalence, 2%-5%), skin reactions (1%), and central nervous system disorders (1%).1,2 An association between fluoroquinolones and Achilles tendinitis, defined as redness and pain along one or both Achilles tendons, was first reported in the 1980s. 3 The number of clinical reports has subsequently increased, prompting the US Food and Drug Administration (FDA) to recommend that the labeling for all fluoroquinolones include a black-box warning indicating an increased risk for tendon rupture. 4 There has also been an increase in the use of fluoroquinolones in elderly inpatients and outpatients. 3 Older adults are at a 1.5- to 3-fold higher risk for fluoroquinolone-associated tendinitis. 3 Although tendinitis is a well-established adverse effect associated with fluoroquinolone use, the association is sometimes missed, with Achilles tendinitis being attributed to a different inflammatory condition (eg, gout).5 We present a case of Achilles tendinitis in an older adult patient with a urinary tract infection (UTI) treated with ciprofloxacin. We also review the literature found in a search of PubMed (key terms: fluoroquinolonesand Achilles tendinitis; years: 1966-2006). CASE SUMMARY A 77-year-old man weighing 68 kg with a history of benign prostatic hypertrophy (BPH), chronic obstructive pulmonary disease (COPD), coronary artery disease, and hypertension presented to the Veterans Mfairs Ann Arbor Hospital System in Michigan. The patient had dysuria, flank pain, incomplete bladder emptying, and hesitancy 3 weeks after the completion of a 7-day course of ciprofloxacin (250 mg PO QD) for UTI with Escherichia coli. On hospital admission, physical examination was remarkable for right-sided costovertebral angle tenderness. Laboratory tests were notable for a white blood cell (WEe) count of 12.8 x 10 3 cells/rL (normal range, 4-10 x 10 3 cells/rL); hemoglobin, 12.8 g/dL (12-16 g/dL); blood urea nitrogen (BUN), 26 mg/dL (8-20 mg/dL); and creatinine, 1.7 mg/dL (baseline, 1.2 mg/dL) (normal range, 0.5-1.0 mg/dL). Urinalysis found cloudiness with trace protein (normal, no protein), negative nitrites, 3+ leukocyte esterase (normal, no leukocyte esterase), WECs too numerous to count (normal, 0-5 WECs per high-powered field [HPF]), and 10 to 25 red blood cells (RBCs) per HPF (normal, 0-5 RBC/HPF). Postvoid residual volume was 800 mL. Ciprofloxacin 250 mg/d PO was initiated
The American Journal of Geriatric Pharmacotherapy
for the treatment of presumed complicated UTI (renal dysfunction). Concurrent medications, which included albuterol administered by metered dose inhaler (2 puffs q4h PRN), furosemide 40 mg PO QD, lovastatin 20 mg PO QD, metoprololl00 mg PO QD, omeprazole 20 mg PO QD, and aspirin 80 mg PO QD, had not been changed. The patient had not received any corticosteroids for the treatment of COPD in the previous month. On hospital day 2, multiple blood cultures showed no growth, but urinary culture again grew ciprofloxacinsensitive E coli. WEC count increased to 17.5 x 10 3 cells/ rL; creatinine concentration decreased to 1.5 mg/dL with hydration. Renal sonography found no calculi or hydronephrosis. Treatment with terazosin 1 mg PO at night was started for BPH. On hospital day 3, the patient noted a sudden onset of severe left heel pain and increased pain with ambulation. A palpable nodule with swelling and erythema along the left Achilles tendon was found on physical examination (Figure). The area was tender on palpation, and the patient experienced pain on passive and active dorsiflexion. This was the first episode of Achilles tendinitis in this patient. The patient had been treated with a fluoroquinolone on several occasions in the previous few years, without any reported adverse events. Because ciprofloxacin use was considered a possible cause of the Achilles tendinitis, treatment with that drug was discontinued and amoxicillin/clavulanate 875/125 mg/d PO was substituted. Weight-bearing activity on the left leg was restricted, and a pneumatic boot was provided for immobilization. With treatment with NSAIDs, the patient's Achilles tendon pain improved over the next day. Mter resolution of UTI and improvement in tendinitis, on day 8 of hospitalization, the patient was discharged. BUN was 21 mg/dL; creatinine, 1.4 mg/dL. Eleven days after hospital discharge, the patient was seen for follow-up in the Infectious Disease Clinic. The erythema and swelling of the left Achilles tendon had largely resolved, but a nontender knot was noted on palpation. The patient was referred for physical therapy. One week later, he was able to ambulate using a rolling walker and the pneumatic boot. He was instructed to complete a home exercise program and continue to restrict weight-bearing activity until cessation of the pain. Previous to hospitalization, the patient had been fully ambulatory without the use of adaptive devices.
DISCUSSION Achilles tendinitis is an uncommon adverse effect associated with fluoroquinolone agents, occurring in
265
The American Journal of Geriatric Pharmacotherapy
E. Damuth et al.
Figure. Swelling and erythema along the left Achilles tendon in a patient receiving a fluoroquinolone.
case of fluoroquinolone-associated Achilles tendinitis based on a Naranjo score of 7. In a review of 98 cases of fluoroquinolone-associated tendon injury reported in the literature between 1961 and 2001, Khaliq and Zhanel6 found that pefloxacin was the fluoroquinolone most commonly implicated (37%), followed by ciprofloxacin (25.5%). The most common tendon injury was Achilles tendinitis (89.8%); 44% of cases were bilateral. Other sites included the triceps epicondyle, flexor tendon sheath, patellar tendon, quadriceps muscle, rotator cuff, subscapularis terrea, supraspinal tendon, and thumb. Onset of tendon injury occurred from 2 hours after initiation of fluoroquinolone treatment to 6 months after discontinuation, with a median duration of 8 days. (The patient in the present report presented with unilateral tendinitis 3 days after initiation of ciprofloxacin treatment of UTI.) Forty-one percent of patients experienced Achilles tendon rupture, which was reported after therapy was discontinued. 6,7 A case-control study by Corrao et aI3 compared 22,194 patients with tendon disorders (tendinitis, tenosynovitis) admitted with 101,953 age-, sex-, and municipality of residence-matched patients randomly selected from the regional archive. That study found that fluoroquinolone use was associated with an increased risk for tendon injury (odds ratio, 1.7; 95% CI, 1.4-2.0), with 1 case per 5958 patients treated. Although the prevalence of fluoroquinolone-induced tendon injury is low in the general population (0.14%-0.4%), risk is significantly increased (1.5- to 3.0fold higher) in association with age >60 years, chronic renal failure, hemodialysis, and corticosteroid thera-
266
py.3,6-10 Corrao et aI3 found that in patients 260 years of age who recently (1-30 days prior) were treated with a fluoroquinolone, tendon disorders were 1.5-fold more likely to develop, and Achilles tendon rupture was 2.7-fold more likely to develop, than in patients who were <60 years of age. In the same study, in patients who were using corticosteroids concurrently, the risk for tendon rupture was 46-fold that in age-matched patients who were not. Important risk factors in the present case included advanced age and acute renal dysfunction. Although chronic renal failure has been associated with fluoroquinolone-induced Achilles tendon injury, fewer cases have been reported in patients with acute renal failure. 3,6-9 Whether specific fluoroquinolones are more likely to be associated with Achilles tendinitis remains unclear. In a review of 36 studies in a total of98 patients with tendon injurywho were receiving fluoroquinolones,6 use of ciprofloxacin (26%) and pefloxacin (37%) was most commonly associated with tendon injury, but these 2 drugs were more commonly used. However, in a retrospective cohort study in 1841 patients who were receiving fluoroquinolones,2 the relative risk for Achilles tendinitis in patients who were receiving ofloxacin was 10.1 (95% CI, 2.2--46.0) compared with 3.7 (95% CI, 0.9-15.1) for all fluoroquinolones; there was no association found with ciprofloxacin or norfloxacin. The exact mechanism of fluoroquinolone-induced tendinopathy remains elusive; however, experimental evidence in animals suggests that fluoroquinolones may impede collagen matrix proliferation and promote collagen degradation. 6,s,1l,12 Other studies suggest a role of ischemia in tendinitis, with histopathologic evidence of edema and constricted vasculature. 6,7 It has also been
E. Damuth et al.
suggested that decreased clearance of fluoroquinolones may playa role in predisposing patients with renal dysfunction to tendinitis. 6 In juvenile animals, the observation of arthropathy caused by inhibition of mitochondrial DNA replication in immature chondrocytes has led to limited use of fluoroquinolones in the pediatric population, although most (no number given) of the musculoskeletal adverse events reported were reversible following immobilization and discontinuation of treatment. 12 ,13 The only arthropathies reported in children receiving fluoroquinolones have been mild to moderate arthralgias in adolescent patients (1.5%).12 Full recovery from Achilles tendinitis generally occurs within 3 months after discontinuation of fluoroquinolone therapy and may require physical therapy and protection of the affected Achilles tendon?,ll Although the patient reported here had immediate improvement in pain and erythema after discontinuation of ciprofloxacin and treatment with NSAIDs, he was still ambulating with a walker 1 month later. To help prevent Achilles tendon rupture when tendinitis is suspected, treatment with the fluoroquinolone should be promptly discontinued, the patient should be placed in an immobilization boot, steroids should be avoided or discontinued, and treatment with analgesics and physical therapy should be initiated. 6 - 8 ,1l Because rupture can occur even late in the course of treatment or after discontinuation, patients receiving fluoroquinolones should be counseled to seek medical attention immediately if symptoms of tendinitis, such as redness, pain, swelling, and stiffness, develop .14 In July 2008, the FDA recommended that the labeling of all fluoroquinolones include a black-box warning indicating an increased risk for tendon rupture. 4 Patients with a history of Achilles tendinitis with fluoroquinolone use should not be prescribed this class of drugs, as recurrences have been reported. 15 Finally, it is unclear why Achilles tendinitis developed in the patient in the present report only after his second course of ciprofloxacin treatment. He was not receiving any other medications that might increase this risk (eg, corticosteroids). It is possible that renal dysfunction was more profound with the second UTI, which necessitated admission. Fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age, corticosteroid use, and/or acute or chronic renal dysfunction. The tendinitis may be misdiagnosed as gouty flare or infection, leading to unnecessary testing and treatment. Achilles tendinitis can be debilitating and may lead to rupture.
The American Journal of Geriatric Pharmacotherapy
CONCLUSION Based on this outcome in this patient with UTI, fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age and renal dysfunction. ACKNOWLEDGMENT Dr. Heidelbaugh is a member of the scientific advisory board at Takeda Pharmaceuticals. REFERENCES 1. StaWmann R, Lode H. Fluoroquinolones in the elderly: Safety considerations. Drugs Aging. 2003;20:289302. 2. van der Linden PD, van de Lei J, Nab HW, et al. Achilles tendinitis associated with fluoroquinolones. Br ] Clin Pharmacol. 1999;48:433--437. 3. Corrao G, Zambon A, Bertu L, et al. Evidence oftendinitis provoked by fluoroquinolone treatment: A casecontrol study. Drug Saf 2006;29:889-896. 4. US Food and Drug Administration (FDA). FDA News. FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs: Seeks to Strengthen Warnings Concerning Increased Risk of Tendinitis and Tendon Rupture [FDAWeb site]. http://www.fda.govjbbs/topicsjNEWS/ 2008/NEW01858.html. Accessed July 15,2008. 5. Mahoney PG, James PD, Howell CJ, Swannell AJ. Spontaneous rupture of the Achilles tendon in a patient with gout. Ann Rheum Dis. 1981;40:416--418. 6. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: A critical review of the literature. Clin Infect Dis. 2003;36:1404-1410. 7. Yu C, Giuffre BM. Achilles tendinopathy after treatment with fluoroquinolone. Australas Radiol. 2005;49:407410. 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 Rheum. 2001;45:235-239. 9. Marti HP, Stoller R, Frey FJ. Fluoroquinolones as a cause of tendon disorders in patients with renal failure/renal transplants. Br ] Rheumatol. 1998;37:343-344. 10. Haddow LJ, Chandra Sekhar M, Hajela V, Gopal Rao G. Spontaneous Achilles tendon rupture in patients treated with levofloxacin. ] Antimicrob Chemother. 2003;51:747748. 11. Mathis AS, Chan V, Gryszkiewicz M, et al. Levofloxacinassociated Achilles tendon rupture. Ann Pharmacother. 2003;37:1014-1017. 12. Leibovitz E. The use of fluoroquinolones in children. Curr Opin Pediatr. 2006;18:64-70.
267
The American Journal of Geriatric Pharmacotherapy
E. Damuth et al.
13. The American Academy of Pediatrics. The use of systemic fluoroquinolones. Pediatrics. 2006;118: 1287-1292. 14. Shortt P, Wilson R, Erskine 1. Tendinitis: The Achilles heel of quinolones! Emer;g MedJ. 2006;23:e63.
15. Muzi F, Gravante G, Tati E, Tati G. Fluoroquinolonesinduced tendonitis and tendon rupture in kidney transplant recipients: 2 Cases and a review of the literature. Transplant Proc. 2007;39:1673-1675.
Address correspondence to: Sandro K. Cinti, MD, Veterans Mfairs Ann Arbor Healthcare System, 2215 Fuller Road, Ill-I, 8th Floor, Ann Arbor, MI 48105. E-mail: [email protected]
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