1 Introduction
Fluoroquinolone antibiotics are widely used to treat a broad range of infections, including those of the urinary respiratory and gastrointestinal systems, with variation in the prevalence of prescribing and indications for use within different health systems [
1]. However, fluoroquinolones cause important side effects as listed in their Summary of Product Characteristics (SPC), which include tendon ruptures that are listed as occurring very rarely with a frequency of less than 1 per 10,000 patients [
2,
3]. Tendon ruptures manifest as complete or partial rupture of the tendon and are an important cause of morbidity, affecting both functional ability and quality of life with treatment often involving invasive surgery [
4,
5]. The incidence of tendon rupture in the general population varies according to tendon site, with estimates ranging from 4.7 to 55.2 per 100,000 person-years for Achilles tendon rupture, and 2.6 to 5.4 per 100,000 person-years for biceps tendon rupture [
6‐
8]. The mechanism for fluoroquinolone-induced tendon rupture remains uncertain, but has been linked to changes in collagen fibrils following alterations in the regulation of matric metalloproteinases associated with non-traumatic rupture [
9]. Although some risk factors for tendon rupture have been identified such as increasing age, male gender, obesity, diabetes, corticosteroid therapy and recreational sports [
10‐
12], a further understanding of risk factors is needed to identify at-risk individuals and minimize unintended harm.
In 1995, the US Food and Drug Administration (FDA) updated fluoroquinolone product labelling with a warning about the possibility of tendon rupture, followed by a ‘black box’ warning in 2008 [
13]. In May 2016, the FDA conducted a review of disabling and potentially irreversible serious side effects of fluoroquinolones resulting in a restriction of their use in less severe infections of acute sinusitis, acute bronchitis and uncomplicated urinary tract infections when other treatment options are available [
14]. The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has also recently reviewed the persistence of fluoroquinolones adverse reactions to help determine the need for any restriction in indication, and required further data to characterise the risk of such reactions [
15]. Whilst the risk of tendon rupture is recognized, there is inconsistency in its reported size with relative risk ranging between 1.9- and 5.3-fold increased risk, with limited information on absolute risk [
10,
16‐
21]. The aim of this study was to quantify the relative and absolute risk of tendon rupture with fluoroquinolone exposure, and to investigate factors influencing this risk.
3 Results
The cohort contained 1,351,780 adult patients prescribed ≥ 1 prescription for fluoroquinolone (34.3%) or co-amoxiclav (65.7%) antibiotics (mean age of cohort 52.8 years, 57.0% female). Overall, 4836 tendon rupture events were identified during cohort follow-up (incidence of any tendon rupture 5.9 per 10,000 person-years (pyrs) and of Achilles tendon rupture 1.9 per 10,000 pyrs) that were matched to 18,356 controls (Table
1). Cases and controls were well matched on age, sex and duration of follow-up. The most common types of tendon rupture were: Achilles tendon (32.4%), biceps tendon (27.5%), shoulder tendons (16.6%), hand/wrist tendons (7.4%), hamstring/quadriceps/patellar tendons (7.0%), foot/ankle tendons (0.8%) and triceps tendon (0.5%). Unspecified tendon ruptures accounted for 8.3% of all cases. The mean duration of cumulative fluoroquinolone exposure was 10.6 days (standard deviation, SD 8.9 days) and for co-amoxiclav was 8.6 days (SD 7.4 days).
Table 1
Characteristics of matched cases and controls
Number of individuals | 4836 | 18,356 |
Female sex, no. (%) | 1876 (38.8) | 7164 (39.0) |
Age (years), mean ± SD | 61.6 (15.5) | 61.3 (15.3) |
Years of follow-up, mean ± SD | 5.0 (3.7) | 5.0 (3.7) |
Body mass index, mean ± SD | 28.1 (5.9) | 27.7 (5.7) |
Charlson co-morbidity index, mean ± SD | 1.32 (1.61) | 1.27 (1.64) |
Hypothyroidism, no. (%) | 365 (7.6) | 1296 (7.1) |
Hyperparathyroidism, no. (%) | 17 (0.3) | 61 (0.3) |
Current smokers, no. (%) | 765 (16.1) | 3371 (18.8) |
Oral corticosteroid therapy,a no. (%) | 522 (10.8) | 911 (5.0) |
Injectable corticosteroid therapy,a no. (%) | 43 (0.9) | 32 (0.2) |
Statin therapy,a no. (%) | 326 (20.7) | 1240 (20.6) |
Current fluoroquinolone exposure, no. (%) | 111 (2.3) | 236 (1.3) |
Current co-amoxiclav exposure, no. (%) | 98 (2.0) | 314 (1.7) |
Prior history of tendon rupture, no. (%) | 133 (2.8) | 114 (0.6) |
3.1 Risk of Tendon Rupture with Fluoroquinolone Exposure
The relative incidence of any tendon rupture was significantly elevated with current systemic fluoroquinolone exposure (adjusted IRR [aIRR] 1.61, 95% CI 1.25–2.09). When stratified by type of tendon rupture, current fluoroquinolone exposure was associated with a significantly elevated rate of Achilles tendon rupture (aIRR 3.14, 95% CI 2.11–4.65) but not biceps tendon rupture (aIRR 1.07, 95% CI 0.61–1.89) or other tendon ruptures (aIRR 0.82, 95% CI 0.50–1.35) (Table
2). In contrast, the relative incidence of tendon ruptures was not significantly elevated with current co-amoxiclav exposure (Table
2).
Table 2
Incidence rate ratios for the association between tendon rupture and current systemic fluoroquinolone and co-amoxiclav exposure
Any tendon rupture | | | | | |
Fluoroquinolones | 111/4836 | 236/18,356 | 1.79 (1.41–2.27) | 1.61 (1.25–2.09) | < 0.001 |
Co-amoxiclav | 98/4836 | 314/18,356 | 1.15 (0.90–1.45) | 1.02 (0.79–1.31) | 0.900 |
Achilles tendon rupture | | | | | |
Fluoroquinolones | 67/1577 | 82/6007 | 3.50 (2.45–5.02) | 3.14 (2.11–4.65) | < 0.001 |
Co-amoxiclav | 38/1577 | 114/6007 | 1.19 (0.81–1.77) | 1.00 (0.64–1.57) | 0.989 |
Biceps tendon rupture | | | | | |
Fluoroquinolones | 20/1316 | 62/4946 | 1.19 (0.71–2.00) | 1.07 (0.61–1.89) | 0.804 |
Co-amoxiclav | 23/1316 | 74/4946 | 1.16 (0.72–1.88) | 1.01 (0.61–1.66) | 0.978 |
Other tendon rupture | | | | | |
Fluoroquinolones | 24/1943 | 92/7403 | 0.94 (0.59–1.50) | 0.82 (0.50–1.35) | 0.439 |
Co-amoxiclav | 37/1943 | 126/7403 | 1.09 (0.75–1.60) | 1.01 (0.68–1.50) | 0.946 |
Increasing cumulative days of systemic fluoroquinolone exposure was significantly associated with increased risk of Achilles tendon rupture (IRR 1.06, 95% CI 1.03–1.09). In contrast, no significant association was observed with cumulative co-amoxiclav exposure (Online Supplementary Table S2). The relative incidence of Achilles tendon rupture was significantly increased with systemic fluoroquinolone exposure within 1–30 days (aIRR 2.97, 95% CI 1.98–4.43) and 31–60 days (aIRR 2.11, 95% CI 1.30–3.41) of the index date but not with systemic fluoroquinolone exposure occurring further in the past (aIRR 0.69, 95% CI 0.41–1.16 for 61–90 days and aIRR 1.23, 95% CI 0.88–1.71 for 91–180 days prior to the index date).
3.2 Relationship with Other Risk Factors
The adjusted relative incidence of tendon rupture was significantly elevated in people with a history of prior tendon rupture, in those with oral corticosteroid therapy, and with increasing BMI (Table
3). The risk of tendon rupture was not significantly associated with statin therapy or co-morbidity score, whilst smoking was associated with a reduced relative incidence of tendon rupture. A large significant interaction was observed with concomitant systemic fluoroquinolone and oral corticosteroid exposure (aIRR 6.88, 95% CI 3.94–12.03 and aIRR 19.36, 95% CI 7.78–48.19, for any tendon rupture and Achilles tendon rupture, respectively, Table
4).
Table 3
Association with any tendon rupture and Achilles tendon rupture and other potentially confounding variables and co-morbidities
Prior tendon rupture | 4.60 (3.51–6.04) | < 0.001 | 7.48 (4.53–12.35) | < 0.001 |
Oral corticosteroid | 2.25 (1.99–2.54) | < 0.001 | 3.60 (2.89–4.48) | < 0.001 |
Injectable corticosteroid | 5.47 (3.36–8.91) | < 0.001 | 1.82 (0.40–8.29) | 0.435 |
Fluoroquinolone | 1.61 (1.25–2.09) | < 0.001 | 3.14 (2.11–4.65) | < 0.001 |
Co-amoxiclav | 1.02 (0.79–1.31) | 0.900 | 1.00 (0.64–1.57) | 0.989 |
Body mass index | 1.01 (1.01–1.02) | < 0.001 | 1.01 (1.00–1.03) | 0.008 |
Statin therapy | 1.06 (0.98–1.16) | 0.129 | 0.96 (0.81–1.14) | 0.650 |
Hypothyroidism | 1.03 (0.90–1.17) | 0.693 | 0.91 (0.70–1.18) | 0.469 |
Hyperthyroidism | 0.89 (0.51–1.55) | 0.676 | 1.08 (0.41–2.89) | 0.873 |
Charlson co-morbidity | 0.99 (0.97–1.01) | 0.279 | 1.00 (0.96–1.05) | 0.975 |
Connective tissue disease | 2.03 (1.66–2.49) | < 0.001 | 1.02 (0.63–1.65) | 0.942 |
COPD | 1.07 (0.99–1.17) | 0.096 | 1.24 (1.08–1.44) | 0.003 |
Cancer | 0.97 (0.88–1.06) | 0.473 | 0.98 (0.81–1.19) | 0.854 |
Chronic kidney disease | 0.96 (0.86–1.07) | 0.452 | 1.02 (0.82–1.28) | 0.865 |
Dementia | 0.47 (0.34–0.66) | < 0.001 | 0.34 (0.14–0.79) | < 0.001 |
Diabetes mellitus | 1.01 (0.91–1.11) | 0.854 | 1.03 (0.85–1.25) | 0.758 |
Heart failure | 0.85 (0.71–1.01) | 0.062 | 0.87 (0.64–1.25) | 0.459 |
Liver disease | 0.87 (0.56–1.34) | 0.521 | 1.04 (0.49–2.23) | 0.916 |
Myocardial infarction | 1.07 (0.92–1.23) | 0.404 | 0.96 (0.71–1.30) | 0.796 |
Peptic ulcer disease | 1.09 (0.94–1.27) | 0.263 | 1.01 (0.76–1.36) | 0.921 |
Peripheral vascular disease | 0.90 (0.65–1.25) | 0.543 | 0.85 (0.46–1.57) | 0.606 |
Stroke | 1.04 (0.90–1.21) | 0.579 | 1.03 (0.75–1.41) | 0.878 |
Smoking | | | | |
Ex-smoker | 1.04 (0.96–1.12) | 0.360 | 0.85 (0.74–0.98) | 0.029 |
Current smoker | 0.85 (0.78–0.94) | 0.001 | 0.72 (0.61–0.85) | < 0.001 |
Table 4
Incidence rate ratios for the interaction between tendon rupture and current systemic fluoroquinolone and oral corticosteroid exposure
Any tendon rupture | | | | |
Oral corticosteroid alone | 287/4836 | 443/18,356 | 2.58 (2.19–3.03) | < 0.001 |
Oral corticosteroid plus fluoroquinolone exposure | 36/4836 | 20/18,356 | 6.88 (3.93–12.03) | < 0.001 |
Achilles tendon rupture | | | | |
Oral corticosteroid alone | 148/1557 | 180/6007 | 4.59 (3.43–6.14) | < 0.001 |
Oral corticosteroid plus fluoroquinolone exposure | 37/1557 | 10/6007 | 19.36 (7.78–48.19) | < 0.001 |
3.3 Absolute Risk
Adjusted rate differences for any tendon rupture and Achilles tendon rupture are presented overall and for age and sex (Table
5). Fluoroquinolone exposure caused an estimated 2.9 tendon ruptures and 2.1 Achilles tendon ruptures per 10,000 patients per year and was greatest in patients aged 60 years and over. Concomitant oral corticosteroid exposure had a large impact on absolute risk, with the highest rates of tendon rupture associated with concomitant fluoroquinolone and corticosteroid exposure in males and in patients aged 60 years and over.
Table 5
Adjusted rate differences in tendon rupture with fluoroquinolone exposure and concomitant oral corticosteroid exposure (per 10,000 patients)
Fluoroquinolone exposure | | | | |
Overall | 2.9 | 2.2–3.7 | 2.1 | 1.6–2.7 |
Males | 2.3 | 1.8–3.0 | 1.6 | 1.3–2.1 |
Females | 3.1 | 2.4–4.0 | 2.1 | 1.6–2.7 |
Age < 60 years | 1.4 | 1.0–1.8 | 1.2 | 0.9–1.6 |
Age ≥ 60 years | 5.6 | 4.3–7.2 | 3.0 | 2.3–3.9 |
Fluoroquinolone plus oral corticosteroid exposure | | | | |
Overall | 10.9 | 8.3–14.0 | 4.9 | 3.7–6.2 |
Males | 14.6 | 11.2–18.8 | 5.5 | 4.2–7.1 |
Females | 7.9 | 6.0–10.1 | 3.9 | 3.0–5.0 |
Age < 60 years | 6.0 | 4.6–7.7 | 2.1 | 1.6–2.7 |
Age ≥ 60 years | 19.6 | 15.0–25.2 | 6.6 | 5.0–8.4 |
3.4 Sensitivity Analyses
The relative incidence was elevated using 60-day and 90-day risk windows but was smaller in size with increasing risk-window duration, whilst the results of all other sensitivity analyse were similar to those in the main analysis (Online Supplementary Table S3).
4 Discussion
Fluoroquinolone exposure significantly increased the risk of tendon rupture, which appeared to last up to 60 days following exposure for Achilles tendon rupture. Risk was also estimated to increase by ~ 6% with each additional day exposed to fluoroquinolones within the current risk window and was increased markedly with concomitant exposure to oral corticosteroids. In contrast, co-amoxiclav exposure, which was chosen as a negative control, was not associated with an increased relative risk of any tendon rupture. Absolute risk of tendon rupture from fluoroquinolone exposure was greater than currently highlighted by product information and varied markedly according to age and concomitant exposure to oral corticosteroids.
Observational studies have previously investigated the risk of tendon rupture with fluoroquinolones with results varying in the size and precision of estimates. One case–control study consisting of only 38 cases of Achilles tendon rupture reported a relative risk with current exposure to fluoroquinolone antibiotics of 1.9 (95% CI 1.3–2.6), whilst a larger case–control study from Italy reported an 30% increased risk of any tendon rupture and a larger but less precise risk of Achilles tendon rupture (OR 4.1, 95% CI 1.8–9.6 for Achilles tendon rupture) [
16,
18]. Meanwhile, a small cohort study from Denmark has reported an age-standardized incidence ratio of Achilles tendon rupture of 3.1 (95% CI 1.0–7.3) within 90 days of incident fluoroquinolone exposure whilst a further case–control study reported a larger risk of Achilles tendon rupture (odds ratio (OR) 5.3, 95% CI 1.8–15.2) [
17,
19]. However, these studies did not include an antibiotic-treated comparator in their design to help assess the presence of residual confounding.
One case-crossover study, whereby the patient acts as their own control, reported a smaller association with Achilles tendon rupture (OR 2.0, 95% CI 1.2–3.3) and used a composite of nitrofurantoin, amoxicillin and trimethoprim exposure as a negative control with no significant association being observed [
10]. This comparator group consisted of medications weighted towards the treatment of milder urinary tract infections. In contrast, a cohort study from Canada reporting an increased risk of tendon rupture with fluoroquinolones did use an active comparator of amoxicillin exposure that was also significantly associated with tendon rupture, suggesting the presence of residual confounding can affect the validity and size of the relative risk [
20]. We used co-amoxiclav as a negative control because in the UK co-amoxiclav is a similar broader-spectrum antibiotic reserved for more severe types of infection and may be less subject to unmeasured confounding compared to amoxicillin, nitrofurantoin and trimethoprim. Similar to fluoroquinolones, co-amoxiclav is also associated with an increased risk of
Clostridium difficile infection, which has resulted in similar changes to UK antibiotic prescribing guidelines during the study period.
Our study extends knowledge by demonstrating that risk appears to be present up to 60 days following treatment and increases by ~ 6% with each day of current exposure. People with prior tendon rupture, co-morbidity, those with increasing BMI and those prescribed oral corticosteroids were at increased risk of tendon rupture, with a significant interaction detected between concomitant fluoroquinolone and oral corticosteroid therapy. This interaction has previously been reported but with variable precision, with an OR ranging from 9.1 to 43.2 [
10,
16,
19]. Information on absolute risk is limited. Van der Linden et al. [
16] report an excess absolute risk of Achilles tendon rupture of 3.2 cases per 1000 patient years, although the method used to calculate this was not reported. In a related study, van der Linden et al. [
17] report the incidence of Achilles tendon rupture in people aged 60 years and over as a population-attributable risk, estimating that 2.2% of Achilles tendon rupture in patients aged 60–79 years and 6.3% in patients aged 80 years and over are attributable to fluoroquinolone exposure. This absolute risk estimate may be dependent on the prevalence of exposure in the population though. Although low, we found that absolute risk in this population may be greater than that listed in the product information for fluoroquinolones (which states less than 1 in 10,000 patients). Although we estimate a population-average adjusted rate difference (akin to excess risk) of ~ 2.9 tendon ruptures per 10,000 person years, absolute risk was greater in certain subgroups, significantly varying by age, concomitant corticosteroid exposure and, to a lesser extent, gender. Lastly, statin therapy has previously been linked to tendon disorders using spontaneous reports and pharmacovigilance databases [
30]. Our study found no significant increased risk with statin use, in keeping with three other recent observational studies [
31‐
33].
Our study has strengths and limitations. We matched on general practice so that controls were more likely to have similar socio-economic deprivation status and health-care physician prescribing behavior, helping to reduce confounding by indication. Only small numbers of cases were included unmatched on general practice, with sensitivity analysis demonstrating this had negligible influence on the observed results. Despite adjustment for multiple confounders, risk of residual unmeasured confounding remains possible, which may include channeling bias, although evaluating the risk of tendon rupture with co-amoxiclav exposure consistently showed no statistically significant association. Very few traumatic tendon ruptures were explicitly recorded and it is not possible to determine what proportion of other events may have been associated with trauma, if any. Antibiotic exposures were identified through prescriptions issued within general practice. Our study focuses on tendon rupture only and further investigation on the risk of tendinitis may be useful for clinical decision making. Similarly, we focus on fluoroquinolone as a class and risk associated with individual fluoroquinolone products requires further evaluation.
Antibiotic stewardship aimed at reducing fluoroquinolone exposure may prevent unnecessary harm but this may not be possible or appropriate for all patients. Despite the relatively large increase in risk associated with concomitant exposure to systemic fluoroquinolones and corticosteroids, relatively little attention is given to this interaction among clinical guideline recommendations. This may have implications for special patient groups such as in the management of asthma, chronic obstructive pulmonary disease or bronchiectasis exacerbations, which may require concomitant use of both antibiotics and oral corticosteroids regimens, for example, and commonly have other risk factors such as co-morbidity [
34‐
36].
This study was conducted to provide further information to quantify the risk of tendon ruptures associated with fluoroquinolone antibiotics to support a review of safety information at the EMA PRAC in order to aid regulatory decision making for the use of fluoroquinolones across Europe. In this regard, tendon rupture is only one potential adverse effect of fluoroquinolone exposure, with other potential adverse effects associated with peripheral neuropathy and aortic aneurysm having been reported [
20,
37‐
40].
In conclusion, the risk of tendon rupture associated with fluoroquinolone therapy appears to depend on timing, dose and concomitant exposure to corticosteroids, and affects elderly patients the greatest in absolute terms; patients and healthcare professionals should be informed of these risks.