Outpatient fluoroquinolone use in relation to European Medicines Agency's recommendation: An Estonian nationwide drug utilization study.

PURPOSE: To determine possible changes in prescribing of fluoroquinolones in relation to the European Medicines Agency's (EMA) recommendation in October 2018. METHODS: We conducted a nationwide time-series study on outpatient use of fluoroquinolones during January 2016-June 2021 in Estonia. Joinpoint regression was used to identify change points over time. Several subgroup analyses by prescriber specialty, indication group, risk factors for tendon injury, aortic aneurysm/dissection or heart valve regurgitation/incompetence and the prescribing of other antibiotics were performed. RESULTS: During the study period 236 989 prescriptions of fluoroquinolones were dispensed to 142 659 persons. The number of episodes per month declined from 3780 (2.9/1000 inhabitants) to 2570 (1.9/1000 inhabitants). We identified three change points with four different trend segments: from January 2016 to November 2018 monthly percent change (MPC) -0.4%, from November 2018 to June 2019 MPC -2.5%, from June 2019 to July 2020 MPC 1.7% and from July 2020 to June 2021 MPC -3.3%. Prescribing for indications which were removed or restricted by EMA's recommendation comprised a small proportion of all fluoroquinolone episodes -2.8% and 6.3%, respectively. The risk factors for tendon injury and for cardiac disorders (aortic aneurysm/dissection or heart valve regurgitation/incompetence) were present in 46.4% and 57.8% episodes of fluoroquinolone users, respectively. No changes in the trend of prescribing to users with risk factors was detected. CONCLUSIONS: The EMA's recommendation may have contributed to the greater decline in the use of fluoroquinolones. However, there is still a high proportion of users with predisposing factors for tendon injury and serious cardiac disorders.

Pectoralis major rupture in body builders: a case series including anabolic steroid use.

BACKGROUND: Rupture of the pectoralis major (PM) muscle is a rare injury, with increasing incidence over the last decades, mainly due to participation in weightlifting and contact sports. Surgical management of PM injuries has been related with superior functional outcome, faster return to activities, better cosmesis and higher level of patients' satisfaction. The aim of the study is to present our experience in the management of this rare clinical entity and to correlate the use of anabolic steroids in the occurrence of the injury and the impact of type of injury, method of reconstruction and anabolic steroids on the post-operative outcome. CASES: We present a series of six male bodybuilding athletes who sustained PM rupture during weightlifting. We recorded the location & type of injury, the history and type of anabolic steroids use, the method of repair and the post-operative outcome. TREATMENT AND OUTCOMES: The mean follow-up period was 16 (12-24) months. All patients treated surgically had excellent results according to Bak criteria and returned to full activity within 5.4 (5-7) months following surgical reconstruction. No post-operative complications were recorded, despite the continued use of anabolic steroids, however one patient died from myocardial infarction within a year of surgical treatment. CONCLUSIONS: PM rupture is an injury with increasing incidence within bodybuilding athletes probably not related to the dominance of the limb. Fixation of the tendon with suture anchors results in excellent clinical outcome and patient's satisfaction postoperatively regardless the chronicity of the repair. Our observations in these cases suggest that anabolic steroids use may contribute to the injury due to an excessive upward adjustment of the athlete's goals in lifting weights and moreover the continuation of administration even in the recovery period does not seem to have a negative effect either on the time or on the level of adequate functional recovery postoperatively.

Association Between Third-Generation Fluoroquinolones and Achilles Tendon Rupture: A Self-Controlled Case Series Analysis.

PURPOSE: We investigated whether use of third-generation fluoroquinolones is associated with occurrence of Achilles tendon rupture using a case series analysis in which patients served as their own control. METHODS: We used administrative claims data to identify residents in a single Japanese prefecture who were enrolled in National Health Insurance and Elderly Health Insurance from April 2012 to March 2017 and experienced Achilles tendon rupture after receiving an antibiotic prescription. Antibiotics were categorized into 3 groups: first- and second-generation fluoroquinolones, third-generation fluoroquinolones, and nonfluoroquinolones. We used a conditional Poisson regression model to estimate the incidence rate ratio (IRR) of Achilles tendon rupture during the antibiotic exposure period relative to the nonexposure period for each patient. An exposure period was defined as 30 days from start of the prescription. RESULTS: Analyses were based on 504 patients with Achilles tendon rupture who had received antibiotic prescriptions. Risk of rupture was not significantly elevated during exposure to third-generation fluoroquinolones (IRR = 1.05; 95% CI, 0.33-3.37) and nonfluoroquinolones (IRR = 1.08; 95% CI, 0.80-1.47). In contrast, risk was significantly elevated during exposure to first- and second-generation fluoroquinolones (IRR = 2.94; 95% CI, 1.90-4.54). Findings were similar across subgroups stratified by sex and by recent corticosteroid use. CONCLUSIONS: Our analysis showed that third-generation fluoroquinolone use was not associated with an increased risk of Achilles tendon rupture. These antibiotics may be a safer option for patients in whom this risk is elevated, such as athletes.

Clinical implications of the association between fluoroquinolones and tendon rupture: The magnitude of the effect with and without corticosteroids.

AIMS: To estimate the relative, absolute and attributable risk of non-traumatic tendon rupture, at various sites, associated with use of fluoroquinolones, with and without concomitant corticosteroids. METHODS: We conducted cohort and nested case-control studies among fluoroquinolone users in the United Kingdom Clinical Practice Research Datalink Gold. We estimated the excess risk (cohort analysis) and odds ratios (ORs) (case control) of tendon rupture by fluoroquinolone (current, recent and past use versus unexposed) and corticosteroid (current versus unexposed) use. RESULTS: Among 740 926 patients with a fluoroquinolone prescription, 3957 cases of tendon rupture were identified. The excess risk due to current fluoroquinolone use was low: any tendon rupture 3.73 (95% confidence interval, CI, 2.08-5.39) per 10 000 person-years (PY) and Achilles tendon rupture 2.91 (1.71-4.11) per 10 000 PY. The excess risk of any tendon rupture was much higher for current concomitant fluoroquinolone and corticosteroid use versus corticosteroids alone: 21.2 (11.3-31.2) per 10 000 PY. In the case-control, OR (95% CI) among current fluoroquinolone users versus unexposed patients was elevated: any tendon rupture 1.60 (1.22-2.09), Achilles tendon 2.71 (1.76-4.17) and bicep tendon 1.53 (0.85-2.73). The risk of any tendon rupture was higher among women (OR 2.27 [1.54-3.34]), patients aged 60+ (OR 2.42 [1.74-3.37]), and concomitant corticosteroid use (OR 6.64 [3.99-11.1]). CONCLUSIONS: Fluoroquinolones increase the risk of Achilles tendon rupture and, to a lesser extent, bicep tendon rupture, but the attributable risk is low. The risk is materially increased with concomitant use of corticosteroids.

Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis.

PURPOSE: Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of tendon injury associated with fluoroquinolones. METHODS: A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling odds ratios (ORs) with their 95% confidence intervals (CIs). RESULTS: Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased risk of ATR (OR 2.52 (95% CI 1.81-3.52), p < 0.001, I2 = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11-5.01), p < 0.001, I2 = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62-2.43), p < 0.001, I2 = 84.5%). The initial risk estimates remained statistically significant among patients aged ≥ 60 years old. Risk estimates did not significantly change after depending on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this outcome, but not ciprofloxacin and levofloxacin. CONCLUSIONS: The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.

Molecular changes to tendons after collagenase-induced acute tendon injury in a senescence-accelerated mouse model.

BACKGROUND: Aging impairs tendon healing and is a potential risk factor for chronic tendinitis. During normal aging, tendons undergo structural and biomechanical degenerative changes, accompanied by a reduction in the number of tenocytes and changes to their properties. However, molecular changes in aged tendons under inflammatory conditions are not well understood. The present study analyzed the molecular changes in collagenase induced acute tendon injury using a senescence-accelerated mouse (SAM) model. METHODS: SAMP6 mice were used as an aging animal model and SAMR1 mice were used as a control to represent a senescence-resistant inbred strain. All the mice used in the study were 40 weeks old. Collagenase I from Clostridium histolyticum (20 µL) was injected percutaneously to the tendon-bone junction of the Achilles tendon. Two weeks after treatment, the Achilles tendons were harvested and stained using Picrosirius Red to determine collagen expression. Real-time PCR was performed to analyze gene expression of IL-6, tenomodulin, type I and type II collagen, MMP-9, TIMP-1, and TIMP-2. RESULTS: Collagenase injection resulted in significantly higher gene expression of IL-6 but significantly lower tenomodulin expression compared with the control in SAMP6 and SAMR1 mice. In SAMP6 mice, gene expression of type III collagen and MMP-9 was significantly higher in the collagenase-injected group compared with the control group. SAMP6 mice also showed lower expression of type I collagen, TIMP-1, and TIMP-2 in the collagenase-injected group compared with the control group. Picrosirius Red staining showed the highest expression of type III collagen in the collagenase-injected SAMP6 group compared with the other groups. CONCLUSIONS: The collagenase-injected SAMP6 group showed higher expression of IL-6, MMP-9, and type III collagen and lower expression of type I collagen, TIMP-1, and TIMP-2, which are known to suppress metalloproteinases. The results indicate that aging may lead to dysfunction of the tendon healing process after acute tendon injury.

Association between oral fluoroquinolone use and lateral canthal tendon rupture: case report.

It is well established and documented that fluoroquinolone use is associated with the development of tendinopathy. However, little is known about the possible effects of this class of antibiotics on the orbit. We present a case of lateral canthal tendon rupture that presented with an acute right lower eyelid ectropion in a young, renal compromised patient in the setting of recent fluoroquinolone use for pneumonia. Eye care clinicians need to be aware of the possible effects of fluoroquinolones on the eyelids.

[Drug induced tendon injury]. / Poskození slach vyvolané léky.

Tendon injury belongs to the less known side effects of some drugs, reported until recently only for glucocorticoids and fluoroquinolones. To date, some other classes of drugs such as statins, aromatase inhibitors, anabolic steroids, potentially causing tendon injury, have been added to the list. The authors discuss the most common clinical presentations, diagnosis, and management as well as latest experimental data regarding this issue. The most often, the Achilles tendon is affected, however, nearly every tendon of the entire body may be affected. Tendon rupture or drug induced tendinopathy should be strongly considered in those who have a tendon injury and have recently taken these drugs.Key words: anabolic steroids - aromatase inhibitors - fluoroquinolones - glucocorticoids - statins - tendon injury.

Do different tendons exhibit the same response following chronic exposure to statins?

Over the past few years, a number of cases of tendon injuries associated with statin therapy have been reported. In this study, we assessed whether statins can affect the extracellular matrix (ECM) of the deep digital flexor tendon (DDFT) and patellar tendon (PT). Wistar rats were assigned to groups treated with atorvastatin (A20, A80), treated with simvastatin (S20, S80), and control. Zymography, Western blotting for collagen I, non-collagenous proteins (NCP), glycosaminoglycans (GAGs), and hydroxyproline quantifications were performed. DDFT findings: NCP were increased in A20 and A80; higher concentration of hydroxyproline was found in S80; levels of GAGs was increased in all statin-treated groups; collagen I was increased in S80 and pro-MMP-2 activity was reduced in A80, S20, and S80. PT findings: NCP were reduced in A20, A80, and S80; GAGs was reduced in A80 and S20; collagen I was increased in A20 and pro-MMP-2 activity was reduced in the S20. Both the statins provoked marked changes in both tendons. All these changes may make the tendons more prone to microdamage and ruptures. Therefore, a better understanding of the behavior of the tendon ECM components under statin therapy may provide important insights into the mechanisms behind statin-induced tendon injuries.

MRI in flexor tendon rupture after collagenase injection.

Flexor tendon rupture is an unusual complication following collagenase injection to relieve contractures. These patients require a close follow-up and in the event of tendon rupture, a decision has to be made whether to repair the tendon or manage the complication conservatively. The authors report the utility of MRI in the prognostication and management of a patient with Dupuytren's contracture, who underwent collagenase injection and subsequently developed flexor digitorum profundus tendon rupture.

Complete tendon Achilles rupture following injection of Aethoxysklerol (polidocanol) for the treatment of chronic Achilles tendinopathy.

Achilles tendinopathy can be a chronic disabling condition affecting both athletic and sedentary patients. Multiple new treatment approaches have developed, including shock wave therapy and various types of injection. One of the novel treatment methods used is the injection of Aethoxysklerol or polidocanol, a sclerosing substance injected under ultrasound guidance targeting areas of neovascularisation. We report the case of a 78-year-old lady who suffered a complete Achilles tendon rupture following injection of Aethoxysklerol. This is the first case of Achilles tendon rupture following Aethoxysklerol injection in isolation to our knowledge in the literature and the first published complication of this treatment.

Bisphosphonate therapy start may transiently increase the risk of tendon rupture in patients with glucocorticoid co-medication: a population-based observational study.

PURPOSE: The effect of bisphosphonates on extra-osseous tissue is rarely investigated. We performed an exploratory analysis on the association of new bisphosphonate use and incident tendon rupture in patients with or without oral glucocorticoid co-medication. METHODS: We conducted a matched case-control study using data from the UK-based Clinical Practice Research Datalink. Cases were patients aged 30-89 years with an incident diagnosis of Achilles or biceps tendon rupture between 1995 and 2013. We compared new oral bisphosphonate use between cases and controls with or without oral glucocorticoid co-medication, by timing (last prescription

Bilateral Achilles Tendon Ruptures Associated With Ciprofloxacin Use in the Setting of Minimal Change Disease: Case Report and Review of the Literature.

Fluoroquinolones are widely used antibiotics; however, numerous side effects have been reported in published studies, including a spectrum of tendinopathies, affecting numerous anatomic sites. Several risk factors have been identified, including advanced age (>60 years), corticosteroid use, renal failure or dialysis, female sex, and nonobesity. We present the case of an elderly male with minimal change disease treated with glucocorticoids and acute kidney injury, who sustained spontaneous nontraumatic bilateral Achilles tendon tears 4 days after initiating ciprofloxacin.

A Case-Based Approach to Evaluate the Potential Risks Associated with Fluoroquinolones and Steroids.

Fluoroquinolones (FQs) are a frequently prescribed class of antibacterial agents. FQs are widely used but may carry serious side effects particularly pronounced in older adults, and the Food and Drug Administration recently suggested FQs should not be routinely used in certain conditions if alternative options are available. Research has demonstrated that the risk of tendinitis and tendon rupture associated with FQs is one of the highest in older adults who are concurrently treated with steroids. Health care providers and pharmacists involved in the treatment of older adults should be aware of this potential drug interaction, which may lead to serious side effects and safety concerns.

Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat.

BACKGROUND: Mesenchymal stromal cells attract much interest in tissue regeneration because of their capacity to differentiate into mesodermal origin cells, their paracrine properties and their possible use in autologous transplantations. The aim of this study was to investigate the safety and reparative potential of implanted human mesenchymal stromal cells (hMSCs), prepared under Good Manufacturing Practice (GMP) conditions utilizing human mixed platelet lysate as a culture supplement, in a collagenase Achilles tendon injury model in rats. METHODS: Eighty-one rats with collagenase-induced injury were divided into two groups. The first group received human mesenchymal stromal cells injected into the site of injury 3 days after lesion induction, while the second group received saline. Biomechanical testing, morphometry and semiquantitative immunohistochemistry of collagens I, II and III, versican and aggrecan, neovascularization, and hMSC survival were performed 2, 4, and 6 weeks after injury. RESULTS: Human mesenchymal stromal cell-treated rats had a significantly better extracellular matrix structure and a larger amount of collagen I and collagen III. Neovascularization was also increased in hMSC-treated rats 2 and 4 weeks after tendon injury. MTCO2 (Cytochrome c oxidase subunit II) positivity confirmed the presence of hMSCs 2, 4 and 6 weeks after transplantation. Collagen II deposits and alizarin red staining for bone were found in 6 hMSC- and 2 saline-treated tendons 6 weeks after injury. The intensity of anti-versican and anti-aggrecan staining did not differ between the groups. CONCLUSIONS: hMSCs can support tendon healing through better vascularization as well as through larger deposits and better organization of the extracellular matrix. The treatment procedure was found to be safe; however, cartilage and bone formation at the implantation site should be taken into account when planning subsequent in vivo and clinical trials on tendinopathy as an expected adverse event.

Incidence of full-thickness rotator cuff tear after subacromial corticosteroid injection: a 12-week prospective study.

INTRODUCTION: Rotator cuff tears (RCT) are a common source of shoulder pain, with an incidence ranging between 5% and 40%. The influence of corticosteroid injections on the incidence of RCT remains unknown. The aim of this study was to estimate the incidence of full-thickness RCT 12 weeks after a subacromial corticosteroid injection in patients with shoulder pain. PATIENTS AND METHOD: We made a prospective, open-label study in patients with unilateral painful shoulder without previous local corticosteroid injection. Ultrasound assessments were made at the first (baseline) and last (Week 12) visits by an experienced radiologist. A rheumatologist did the clinical examination. Patients with full-thickness RCT at the first visit were excluded. All patients received a subacromial injection of triamcinolone acetate 40 mg. RESULTS: One hundred and two patients with shoulder pain were initially evaluated: 49 (48%) were excluded due to full-thickness RCT on ultrasound assessment. Therefore, 53 patients completed the study (34 female, mean age 60.8 years, mean time of evolution 9.6 months). In the first ultrasound evaluation, 24 patients (45.3%) had a partial-thickness tear. At 12 weeks after the corticosteroid injection, 9 (17%) patients developed full-thickness RCT, 66.6% of which occurred in patients with previous partial-thickness RCT. Corticosteroid injection significantly improved symptoms (p = 0.0001 for pain VAS score) and range of motion (p = 0.002 for forward elevation and external rotation). CONCLUSIONS: Seventeen percent of patients with shoulder pain suffered a full-thickness RCT 12 weeks after subacromial corticosteroid injection. Corticosteroid injection is highly effective in improving clinical symptoms of rotator cuff tendinopathy at 12 weeks.

Aromatase Inhibitor-Associated Distal Radioulnar Joint Instability and Tear of the Extensor Digiti Minimi: A Case Report.

ABSTRACT: The addition of aromatase inhibitors has improved cancer-related outcomes in postmenopausal patients with estrogen receptor-positive breast cancer. However, aromatase inhibitor can be associated with a constellation of adverse musculoskeletal effects that comprises bone loss, arthralgia, myalgia, and tendinopathy. This medication complication, known as aromatase inhibitor-associated musculoskeletal syndrome, can limit treatment tolerability in many patients because of the high prevalence of aromatase inhibitor-associated musculoskeletal syndrome among those on aromatase inhibitor. The hand and wrist are the most affected joints in aromatase inhibitor-associated musculoskeletal syndrome, with patients presenting with symmetric arthralgia, stiffness, and tendinopathy. Radioulnar joint subluxation with extensor tendon tear has not been previously reported in patients with aromatase inhibitor-associated musculoskeletal syndrome. This is a case report of a 72-yr-old breast cancer survivor on an aromatase inhibitor presenting with chronic dominant wrist pain, weakness, and 5th digit finger drop. An extensor digitorum minimi tendon tear and radioulnar instability were identified using diagnostic musculoskeletal ultrasonography. This case illustrates the utility of in-office ultrasonography combined with dynamic examination for the often underrecognized pathology associated with aromatase inhibitor-associated musculoskeletal syndrome in breast cancer survivors.

Testosterone replacement therapy is associated with increased odds of Achilles tendon injury and subsequent surgery: a matched retrospective analysis.

BACKGROUND: Prescription of testosterone replacement therapy (TRT) has increased in the United States in recent years, and though anabolic steroids have been associated with tendon rupture, there is a paucity of literature evaluating the risk of Achilles tendon injury with TRT. This study aims to evaluate the associative relationship between consistent TRT, Achilles tendon injury, and subsequent surgery. METHODS: This is a one-to-one matched retrospective cohort study utilizing the PearlDiver database. Records were queried for patients aged 35-75 who were prescribed at least 3 consecutive months of TRT between January 1, 2010 and December 31, 2019. Achilles tendon injuries and subsequent surgeries were identified using ICD-9, ICD-10, and CPT billing codes. Multivariable logistic regression was used to compare odds of Achilles tendon injury, Achilles tendon surgery, and revision surgery, with a p-value < 0.05 representing statistical significance. RESULTS: A sample of 423,278 patients who filled a TRT prescription for a minimum of 3 consecutive months was analyzed. The 2-year incidence of Achilles tendon injury was 377.8 (95% CI, 364.8-391.0) per 100,000 person-years in the TRT cohort, compared to 245.8 (95% CI, 235.4-256.6) in the control (p < 0.001). The adjusted analysis demonstrated TRT to be associated with a significantly increased likelihood of being diagnosed with Achilles tendon injury (aOR = 1.24, 95% CI, 1.15-1.33, p < 0.001). Of those diagnosed with Achilles tendon injury, 287/3,198 (9.0%) of the TRT cohort subsequently underwent surgery for their injury, compared to 134/2,081 (6.4%) in the control cohort (aOR = 1.54, 95% CI, 1.19-1.99, p < 0.001). CONCLUSIONS: There is a significant association between Achilles tendon injury and prescription TRT, with a concomitantly increased rate of undergoing surgical management. These results provide insight into the risk profile of TRT and further research into the science of tendon pathology in the setting of TRT is an area of continued interest.

Demonstrating collagen tendon fibril segments involvement in intrinsic tendon repair.

Severed tendons can undergo regenerative healing, intrinsic tendon repair. Fibrillogenesis of chick tendon involves "collagen fibril segments" (CFS), which are the building blocks of collagen fibers that make up tendon fascicles. The CFS are 10.5 micron in length, composed of tropocollagen monomers arranged in parallel arrays. Rather than incorporating single tropocollagen molecules into growing collagen fibers, incorporating large CFS units is the mechanism for generating collagen fibers. Is intrinsic tendon repair through the reestablishment of tendon embryogenesis? Gentamicin treated 10-day-old chick embryo tendons released CFS were fluorescently tagged with Rhodamine (Rh). Organ cultured severed 14-day-old embryo tendon explants received Rh tagged CFS. At day 4 auto fluorescent tagged CFS were identified at the severed tendon ends by fluorescent microscopy. Accumulation of fluorescent tagged CFS was exclusively localized to the severed ends of tendon explants. Parallels between collagen fiber growth during embryonic fibrillogenesis and tendon repair reveal CFS incorporation is responsible for collagen fibers growth. CFS incorporation into frayed collagen fibers from severed tendons is the proposed mechanism for intrinsic tendon repair, which is an example of regenerative repair.

Diagnostic failure of ciprofloxacin-induced spontaneous bilateral Achilles tendon rupture: case-report and medical-legal considerations.

Rare side-effects of fluoroquinolone therapy are tendinitis and tendon rupture. Many reports have demonstrated that the concomitant use of corticosteroids, in patients aged 60 years or older, increase the risk substantially. We present a case of spontaneous bilateral Achilles tendon rupture induced by ciprofloxacin and methylprednisolone. A 61-year-old woman was diagnosed with Bronchiolitis Obliterans with Organizing Pneumonia (BOOP) and was started on oral ciprofloxacin 500 mg twice daily for 3 weeks and on oral methylprednisolone 16 mg twice daily for 2 weeks. The diagnosis was made after doctors, rather than stop drug therapy and advise complete rest, had mistakenly prescribed for the woman to undergo physiotherapy and local NSAIDs, thus favoring the onset of tendon ruptures and resulting in surgical and legal implications. Inspired by this case, we also submit a brief review on professional liability in Orthopaedics.