Fluoroquinolone-Induced Tendinopathy: Etiology and Preventive Measures

Abstract

Tendinopathy is a serious health problem and its etiology is not fully elucidated. Among intrinsic and extrinsic predisposing factors of tendinopathy, the impact of therapeutic agents, especially fluoroquinolone (FQ) group antibiotics, is recently being recognized. FQs are potent bactericidal agents widely used in various infectious diseases, including community acquired pneumonia and bronchitis, chronic osteomyelitis, traveler's diarrhea, typhoid fever, shigellosis, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea and prophylaxis of anthrax. FQs have an acceptable tolerability range. However, many lines of evidence for developing tendinitis and tendon rupture during FQ use have resulted in the addition of a warning in patient information leaflets. FQ-induced tendinopathy presents a challenge for the clinician because healing response is poor due to low metabolic rate in mature tendon tissue and tendinopathy is more likely to develop in patients who are already at high risk, such as elderly, solid organ transplant recipients and concomitant corticosteroid users. FQs become photo-activated under exposure to ultraviolet light, and this process results in formation and accumulation of intracellular reactive oxygen species (ROS). The subsequent FQ-related oxidative stress disturbs mitochondrial functions, leading to apoptosis. ROS overproduction also has direct cytotoxic effects on extracellular matrix components. Understanding the mechanisms of the FQ-associated tendinopathy may enable designing safer therapeutic strategies, hence optimization of clinical response. In this review, we evaluate multi-factorial etiology of the FQ-induced tendinopathy and discuss proposed preventive measures such as antioxidant use and protection from natural sunlight and artificial ultraviolet exposure.

Fluoroquinolone-induced serious, persistent, multisymptom adverse effects

“…As we have outlined elsewhere, mitochondrial injury may engender further oxidative stress (mitochondria are the leading source as well as target of intracellular free radicals); oxidative stress (also linked to FQs)16 68 69 in turn may produce more mitochondrial damage. Once triggered, this can, in some instances, create a cycle of oxidative stress and mitochondrial injury that can be self-sustaining or progressive, leading to the emergence of new symptoms as clinical detection thresholds (mitochondrial ‘threshold effects’) are reached 70…”

“…Widespread occurrence of new tendinopathy, due to its characteristic and distinctive nature, has had readier ascription to the FQ class, even when onset has been delayed. The linking of other AEs following FQs to tendon pathology, the linking of tendon pathology (and FQ effects) to mitochondrial dysfunction in the literature,16 20 31 61–64 delayed mitochondrial dysfunction following FQ exposure (cell culture),31 delayed and widely variable latency to the onset of symptoms in mitochondrial dysfunction in humans (including those with heritable defects in the same kindred)65 and the known relation of mitochondrial dysfunction to the other FQ-affected domains, provide a strong case for causal occurrence. Moreover, principles have been outlined by which these processes may be expected to produce problems with a compatible profile, entailing variable latency of onset following exposure to a significant mitochondrial toxin, manifest in vulnerable individuals, affecting domains involving muscle–tendon, CNS, peripheral nervous system, gastrointestinal, autonomic, special sensory and other domains observed here 66 67…”

“…‘A typical feature of FQ-induced tendinopathy is a considerable latency period in some cases between the commencement of treatment with an FQ and the onset of symptoms’ 30. FQs have been found to induce delayed mitochondrial toxicity (eg, mitochondrial depletion and mutation) and cytotoxicity,31 providing a foundation for reported occurrence of delayed FQ AEs 16 20…”

Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration’s adverse event reporting system

“…This overproduction has direct toxic effects in the extracellular matrix. In addition, FQs cause mitochondrial toxicity and apoptosis [10].…”

Chronic Tibialis Anterior Tendon Tear Treated With an Achilles Tendon Allograft Technique

“…13,14 Quinolone treatment has recently been recognized as causing tendinitis and tendon rupture. 15 Diabetes melli-tus, 16,17 rheumatoid arthritis, 17 psoriasis, 18 and deposition of gout tophi 19,20 also have been reported to be associated with tendon ruptures. In older patients and in partial tears, nonoperative treatment has been described.…”