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Three Part Question

In [adult patients receiving fluoroquinolone antibiotics] is there [an increased risk] of [developing tendinopathy]?

Clinical Scenario

You are reviewing urine culture and sensitivity results in your ED. You come across a result growing a germ that is sensitive to ciprofloxacin only. You contact your patient to come and collect a prescription later in the day. Your colleague who has been listening to your phone conversation warns you of the increased risk of tendinopathy in patients taking fluoroquinolones. You wonder if this is just anecdotal. You decide to search and review the current literature to see if any evidence substantiates this risk at all.

Search Strategy

Medline using the OVID interface from 1946 to March 2016.

[(exp Quinolones/) OR (exp 4-Quinolones/) OR (quinolone.mp) OR (fluoroquinolone.mp) OR (exp Fluoroquinolones/)] AND [(tendinopathy.mp) OR (exp Tendinopathy/) OR (exp Tendon Injuries/) OR (tendon rupture.mp) OR (tendinitis.mp)]

The search was limited to adults, humans and English language.

The Cochrane Library was searched using the terms ‘quinolone’ and ‘fluoroquinolone’. No review was found.

The ClinicalTrials.gov site was also searched using the same terms in order to find any ongoing/unpublished trials with no yield.

Search Outcome

One hundred and fifteen results were retrieved with the above-described search strategy. Ten were deemed directly relevant to the clinical question following abstract review. Case reports and series were excluded as deemed to be of low level of evidence.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hori et al, 2012 Japan	Hospital database review in order to determine the risk of tendon disorders that occurred in all patients between the first day of prescription of an oral fluoroquinolone (n=17 147) or cephalosporins as active comparator (n=38 517) to the calculated end date plus 30 days Study conducted during the period 1996–2009 Patients with physical trauma of tendons excluded	Comparative study	Calculated the risk for tendon disorders, risk ratio and their 95% CIs	The risk of tendon disorder in fluoroquinolone-prescribed patients was 0.082% (95% CI 0.049% to 0.137%), and in cephalosporin-prescribed patients (0.013%, and 95% CI 0.006% to 0.030%) The relative risk (RR) of a tendon disorder in fluoroquinolone-prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95% CI 2.27 to 17.46)	Tendon imaging not part of diagnosis Different doses of fluoroquinolones used than in Europe/USA and hospital-based cohort (therefore potential issues around generabilisability)
Sode et al, 2007 Denmark	28 262 first users of fluoroquinolones were analysed during a review of population-based county register over the period 1991–1999 Retrieved data for all Achilles tendon rupture Case-crossover analysis for fluoroquinolones and other antibiotics to control for confounders stable over time	Population-based cohort study	90 days RR, absolute risk and risk difference were calculated with 95% CIs	Standardised incidence ratio was 3.1 (95% CI 1.0 to 7.3) Risk difference to background population n/100 000 was 12.0 (95% CI 0.0 to 35.6) OR for cross-over analysis was 1.8 (95% CI 0.5 to 6.9)	Some confounding factors were not addressed (physical activity, use of steroids, comorbidity and so on) Method for diagnosing Achilles tendon rupture unclear
Seeger et al, 2006 USA	Insurance database review over a period of 4 years 947 cases of tendon rupture were retrieved and studied Controls were randomly assigned persons in a 20:1 ratio	Nested case–control study	OR with 95% CIs were worked out using unconditional logistic regression	OR for association between Achilles tendon rupture and use of fluoroquinolones was 1.2 (95% CI 0.9 to 1.7) Highest cumulative dose associated with higher risk with OR was 1.5 (95% CI 1.0 to 2.3) This was similar to administration of oral corticosteroids or non-fluoroquinolone antibiotics: OR 1.4 (95% CI 1.0 to 1.8) and OR 1.2 (95% CI 1.1 to 1.5), respectively	Patients who were hospitalised and potentially received antibiotics were not included in the study
Van der Linden et al, 2003 UK	1367 cases identified from a review of computerised records from the UK General Practice Research Database over the 1988–1998 period 50 000 patients were used as control	Population-based case–control study	ORs for Achilles tendon rupture with 95% CIs were evaluated Univariate ORs were used for other potential risk factors	ORs for Achilles tendon rupture was 4.3 (95% CI 2.4 to 7.8) for current exposure to quinolones, 2.4 (95% CI 1.5 to 3.7) for recent exposure and 1.4 (95% CI 0.9 to 2.1) for past exposure OR 17.5 (95% CI 5.0 to 60.9) and 18.4 (95% CI 1.4 to 240.2) in patients with current and recent exposure to oral corticosteroids, respectively	Selection bias unlikely but not completely excluded
Van der Linden et al, 2002 UK	46 776 users of fluoroquinolones were identified during a health database review of whom 704 had Achilles tendinitis and 38 cases of rupture Randomly sampled 10 000 patients from control group Excluded patients with chronic tendon disorder, cancer, AIDS, illicit drug use, alcohol misuse or traumatic rupture	Nested case–control study	Adjusted RR with 95% CIs were worked out using unconditional logistic regression analysis	Adjusted RR of Achilles tendon disorders with current use of fluoroquinolones was 1.9 (95% CI 1.3 to 2.6) The RR with current use was 3.2 (95% CI 2.1 to 4.9) among patients aged 60 and over and 0.9 (95% CI 0.5 to 1.6) among patients aged under 60	Unclear diagnoses
Van der Linden et al, 1997 UK	1841 users of fluoroquinolones were identified during a database review of 11, 812 patients records A reference group who used another four types of antibiotics was used (n=9406) Among these, 22 cases of tendonitis (no rupture) were identified Excluded trauma, inadequate diagnosis and chronic tendon disorder were excluded	Retrospective cohort study	Crude and adjusted RRs were calculated with 95% CIs	Adjusted RR for all types of tendinopathy during fluoroquinolones use was 2.1 (95% CI 0.83 to 5.09) Adjusted RR was 3.7 (95% CI 0.93 to 15.14) for Achilles tendinitis Adjusted RR was 1.3 (95% CI 0.36 to 4.71) for other tendinopathies	All confounders not addressed Possible selection bias
Barge-Caballero et al, 2008 Spain	Review of clinical records of 149 heart transplant patients who were given quinolones on 242 occasions over the 1995–2006 period Patients were taught about signs of tendon disorders at point of prescription and instructed to return for assessment if symptomatic	Observational cohort study	Incidence and risk were evaluated Risk factors investigated by multivariate logistic regression	14 patients developed Achilles tendinopathy Individual risk incidence was 5.8% (95% CI 2.8 to 8.7) 8 cases had bilateral symptoms (57.1%) 3 cases had Achilles tendon rupture (21.4%) Median time from start of treatment to symptoms was 2.5 days Independent risk factors for tendinopathy were renal dysfunction (creatinine clearance <60) with p=0.03 and increased time between transplant and treatment with p=0.005	Looked at heart transplant patients only (potential problem with generalisability) Dubious diagnoses (some patients diagnosed clinically and some by use of ultrasound) Close surveillance might have influenced the reported good outcomes on recovery Selection and information bias due to recruitment methodology
Corrao et al, 2006 Italy	Patients' case review from hospital health database for patients admitted with a diagnosis of non-traumatic tendon disorder over the period 2002–2003 (n=22,194 case patients and n=104, 906 controls) Excluded patients with diabetes, cancer, thyroid disease, renal failure and connective tissue disorder Up to five control cases for each patient were randomly selected	Population-based case–control study	ORs with 95% CIs were expressed	OR for tendon disorder associated with current fluoroquinolone use was 1.7 (95% CI 1.4 to 2.0) OR for tendon rupture was 1.3 (95% CI 1.0 to 1.8) OR for rupture of Achilles’ tendon was 4.1 (95% CI 1.8 to 9.6) Number needed to harm NNH was 5958 (95% CI 2148 to 23 085)	Only looked at hospitalised patients (generalisability) Diagnostic procedures unclear
Van Der Linden et al, 2001 UK	Review of Dutch community drug database to identify patients prescribed fluoroquinolones for period 1991–1996 (n=251 000 who experienced 318 000 episodes of fluoroquinolones prescriptions) Annual incidence of non-traumatic tendon ruptures was estimated using a nationwide hospital discharge registry	Population-based nested case–control study	Expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of the antibiotic, the number of non-traumatic rupture and an assumed risk of 1.5–10.0	Assuming a RR of 1.5–10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolones (0.09–1.51% of admitted patients) Only 7% of the observed increased could be attributed to the increased use of the antibiotic	Poor presentation of results All figures extrapolated to wider Dutch population from a local registry No data on in-hospital prescriptions Might have missed patients not presenting to hospitals for signs of tendinopathy Confounders were not addressed appropriately
Donck J et al, 1994 Belgium	90 patients treated with fluoroquinolones (131 treatment episodes) during a review of 230 cases of renal transplant patients database	Nested case–control study	Incidence of tendinopathy expressed in percentage in treated and untreated groups	The incidence of Achilles tendinopathy was 12.2% vs 3.6% in the treated and untreated groups, respectively (p<0.02) In 131 treatment episodes, 8.4% of cases complicated with tendon disorders	Poorly presented results Statistically significant difference on age between the study and control groups Renal transplant patients receiving dialysis so potential issue around generalisability

Comment(s)

Fluoroquinolones as antibacterial drugs have been in clinical use for up to 40 years and are frequently prescribed due to their good tolerability and relative broad activity spectrum. They are mostly prescribed in hospital and in the community for respiratory and urinary infections. Anecdotal case reports have started associating their use with tendinopathies (tendinitis, tendon rupture, tendinosis) shortly after their clinical introduction. This is thought to be due to their chelating and cell apoptosis generating properties. The current review of the medical literature confirms that the use of fluoroquinolones is associated with a broad range of tendon disorders. While the relative risk of tendinopathy was found to be significantly higher with the use of fluoroquinolones, the absolute increase in risk remains relatively low. Tendinopathies are however extremely disabling and complete tendon ruptures can result in the need for surgical repair. Clinicians should therefore be aware of this adverse effect and caution is advised with concomitant corticosteroid use and/or in the elderly patient where alternatives should be sought or they should be started on fluoroquinolones only based on sensitivity results.

Clinical Bottom Line

The use of fluoroquinolones was found to be associated with a broad range of tendon disorders, the risk being higher in the elderly and with concomitant use of corticosteroid.

References

1. Hori K , Yamakawa K , Yoshida N , et al . Detection of fluoroquinolone-induced tendon disorders using a hospital database in Japan. Pharmacoepidemiol Drug Saf 2012;21:886–9.
2. Sode J , Obel N , Hallas J , et al Use of fluoroquinolone and risk of Achilles tendon rupture: a population-based cohort study. Eur J Clin Pharmacol 2007;63:499–503.
3. Seeger JD , West WA , Fife D , et al . Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population. Pharmacoepidemiol Drug Saf 2006;15:784–92.
4. Van der Linden PD , Sturkenboom MC , Herings RM , et al Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med 2003;163:1801–7
5. Van der Linden PD , Sturkenboom MC , Herings RM , et al . Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ 2002;324:1306–7.
6. Van der Linden PD , van de Lei J , Nab HW , et al . Achilles tendinitis associated with fluoroquinolones. Br J Clin Pharmacol 1999;48:433–7.
7. Barge-Caballero E , Crespo-Leiro MG , Paniagua-Martín MJ , et al . Quinolone-related Achilles tendinopathy in heart transplant patients: incidence and risk factors. J Heart Lung Transplant 2008;27:46–51.
8. Corrao G , Zambon A , Bertù L , et al . Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf 2006;29:889–96.
9. Van der Linden PD , Nab HW , Simonian S , et al . Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands. Pharm World Sci 2001;23:89–92.
10. Donck JB , Segaert MF , Vanrenterghem YF Fluoroquinolones and Achilles tendinopathy in renal transplant recipients. Transplantation 1994;58:736–7.