Dr Muhammad Yousuf Hayat1 (MBBS, MSc), Dr Ahmed Shah Nazari2 (MBBS, BSc), Dr Ahsan Rashid3 (MBBS, BSc)
1Foundation Year 1 Doctor, University Hospital Southampton, United Kingdom
2Foundation Year 1 Doctor, Northampton General Hospital NHS Trust, United Kingdom
3Foundation Year 1 Doctor, Barking, Havering, and Redbridge University Hospitals NHS Trust
Abstract
Fluoroquinolone antibiotics are amongst some of the most commonly prescribed antibiotics for respiratory and urinary tract infections. Despite their utility in clinical medicine, concern has grown regarding the side effect profile on multiple organ systems.
This report details the case of a 22-year-old Asian male who suffered musculoskeletal and ocular side effects of oral Ciprofloxacin therapy – namely flashes and floaters as well as dry eyes. No causes were identified on examination for this presentation and with time his symptoms gradually improved.
Due to the known effects of fluoroquinolones on connective tissues, effects on the autonomic nervous system and chelation of various minerals, namely Magnesium and Zinc, postulated mechanisms as to why this young man and many others experience such symptoms are put forward in this case report.
Trainees should be reminded to adopt a risk vs benefit approach when prescribing such antibiotics and to be mindful of their effects on multiple organ systems and classes.
Introduction
Fluoroquinolone antibiotics are best known for their penetrative ability through a variety of tissues and efficacious activity against gram negative enteric organisms (1).
Despite their utility in modern medicine, broad spectrum activity and good bioavailability there has been increasing attention drawn to their side effects in both the academic world and the media.
The most notable is that of its effects on tendons and connective tissue (2). Other documented side effects range from effects on the central and peripheral nervous system including lowered seizure threshold and peripheral neuropathy as well as psychiatric and cardiovascular effects (2,3). The Medicines and Healthcare products Regulatory Agency (MHRA) have stated regarding the use of systemically administered fluoroquinolones that there are emerging “long-lasting or irreversible side effects” affecting multiple organ classes and senses (2,4).
Fluoroquinolones have also been stipulated to increase the risk of Rhegmatogenous retinal detachment (RRD) due to their well-established effects on connective tissues (5). Other documented forms of ocular toxicity includes optic neuropathy, retinal haemorrhages and interference with homeostasis of the corneal extracellular matrix (6).
The aim of this case report is to add to what is already known about the ocular side effects of fluoroquinolone therapy as highlighted through the case presentation and discussion.
Case Presentation
This report describes the case of a fit and active 22-year-old male of Asian descent with a past medical history of childhood asthma which was well controlled, physiological anisocoria and a refractive error of -1.25D in the left eye and 0.25D in the right eye.
This patient presented to their GP with a 3-day history of dull left sided testicular pain. There were no other associated symptoms, and the patient was not sexually active.
Antimicrobial treatment was started with oral Ciprofloxacin 500mg BD for suspected Epididymo-orchitis, and a referral was made for an urgent ultrasound testes to rule out any underlying malignant process.
After taking 2 doses of Ciprofloxacin (1 gram total over 24 hours), they experienced increasing left sided ankle stiffness and upon seeking medical advice, this was changed to Co-Amoxiclav 500/125mg TDS. Approximately 24-48 hours after starting the new course of antibiotics, this ankle stiffness progressively worsened, with worsening tenderness noted in the left Achilles tendon.
The patient also complained of a new onset burning sensation in their left hand which was short lived.
Over the coming weeks, they experienced a constellation of symptoms which persisted and gradually worsened. Of note were new onset insertional Achilles tendonitis in the right ankle, widespread tendon pain, joint pain, and muscle fasciculations. Their level of daily activity was drastically reduced, and the patient was unable to walk more than 20 metres without stopping due to pain.
From an ophthalmological perspective, the patient experienced new onset flashes and floaters bilaterally, but felt it was particularly worse in their left eye. In addition, they complained of ophthalmalgia and dry eyes bilaterally.
After seeking medical attention for these visual symptoms, a referral was made for an urgent assessment by their optometrist. No changes were noted in the refractive error of the patient’s eyes nor the visual acuity. Some floaters were noted in both eyes upon slit lamp examination however no cause could be identified on examination nor were there any abnormalities of note on Ocular Coherence Tomography (OCT). Fluorescein tear film break up time was approximately 5 seconds bilaterally (less than 10 seconds being widely considered indicative of tear instability).
The patient was safety netted and sent home with lubricating eye drops.
Over the coming 2-3 months, their symptoms continued to persist. They gradually reduced in frequency thereafter, until he no longer experienced any flashes and the number of floaters he could see reduced dramatically – 1 year post starting the course of Ciprofloxacin.
With time, the aforementioned musculoskeletal symptoms had also markedly improved.
Currently, this patient is buying over the counter lubricating eye drops for symptomatic dry eye with varying day to day use. They also report occasional short-lived episodes of ophthalmalgia.
Discussion
The symptoms this young male experienced were worrying for retinal detachment hence the clinical urgency of his assessment. Fluoroquinolones confer a raised theoretical risk of retinal detachment due to their effects on collagen synthesis with the proposed mechanism being due to upregulation of matrix metalloproteinases (2).
The evidence of the risk of ocular complications of systemically administered fluoroquinolones is debated. A cohort study by Etminan et al. (6) showed a 4.5 fold adjusted relative risk of retinal detachment compared to controls (6). It is important to note the mean age of participants is 61.1 years old, were more likely to be myopic and have had cataract surgery (6). These factors alone can increase the risk of RRD (7).
On the contrary, two notable meta-analyses of observational studies has shown no concrete association with the use of orally administered fluoroquinolones and retinal detachment (8,9).
In this case, there was no evidence of retinal detachment or posterior vitreous detachment upon examination or OCT hence this begs the question: what was the cause of his sudden new onset flashes and floaters?
Whilst it is impossible to say with certainty, this discussion could postulate further dialogue surrounding potential mechanisms driving these symptoms.
The relationship between fluoroquinolones and mitochondrial dysfunction is well established in the literature through various mechanisms including inhibition of topoisomerases (10). Increasingly, the constellation of symptoms that some patients experience after systemic fluoroquinolone therapy is being thought of as a disorder of mitochondria and oxidative stress (11,12). Fluoroquinolone Associated Disability (FQAD) is a term that has been used to describe severe cases of patients with long lasting and life changing consequences secondary to fluoroquinolone use (12) most likely secondary to mitochondrial dysfunction.
The aetiology behind dry eye disease is multifactorial (13). The role of mitochondrial dysfunction has been linked to dry eye disease in the literature especially given the increased production of Reactive Oxygen Species (ROS) (14). Antioxidative defence mechanisms are known to be present on the ocular surface (13) and a disruption in the balance of ROS and protective mechanisms can lead to inflammation and worsening of dry eyes (13,14).
Fluoroquinolones have been associated with autonomic nervous system (ANS) dysfunction and neuropathy (15,16). From the available literature, postulated theories may be through axonal neuropathic processes (17,18). Autonomic nervous system dysregulation and fluctuations in autonomic control has also been shown to affect tear stability in patients with dry eyes (19).
In addition, Fluoroquinolones have been noted to selectively antagonise GABAA receptors in the CNS and have been linked to reduced seizure threshold and vagal nerve dysfunction through a variety of mechanisms (16) as well as visual phenomena including fluoroquinolone associated hallucinations (16,20). Interestingly, Fraser (21) has put forward the mechanism that phenomena such as unexplained photopsia in those suffering with visual snow syndrome could be secondary to foci of hyperexcitability in the visual cortex (21) and hence it is proposed in this discussion that fluoroquinolone induced photopsia may be secondary to the selective antagonism of GABAA receptors.
Fluoroquinolones have been shown to interact with various trace minerals, most notably, Magnesium and Zinc (16) with chelation of Magnesium being consistently linked in the literature to the commonly associated negative musculoskeletal side effects of this antibiotic class (22).
Magnesium concentration is also noted to be high in the anterior chamber, cornea and lens (23,24) and deficiency has been linked to dry eyes, primary open angle glaucoma and infection (23,24). Magnesium has also noted to have neurovascular protective effects through mechanisms which result in retinal vessel vasodilation and has anti-apoptotic effects on retinal ganglion cells (25).
Similarly, the retinal-choroid complex contains the highest concentration of zinc in the human eye (26). It has been demonstrated that eyes with signs of Age Related Macular Degeneration are deficient in zinc with the postulated mechanisms being secondary to increasing oxidative stress (27) and it has been shown that zinc may exert suppressive effects on retinal degenerative pathways (26). Despite this, further clinical trials with measurable endpoints such as retinal dark adaptation are required to determine the clinical efficacy of supplementation in those who are deficient (26).
The retina has evolved a multitude of antioxidant defence mechanisms to protect against ROS (28). Salimiaghdam et al. (29) demonstrated that clinically relevant concentrations of ciprofloxacin on cultured human retinal pigment epithelial cells had detrimental effects in vitro with upregulation of genes to do with inflammation, apoptosis and antioxidant mechanisms (29). Hence, the argument may be put forward that Fluoroquinolones, via a multitude of mechanisms may hence confer a theoretical risk of retinal disease secondary to mitochondrial dysfunction, production of ROS and chelation of minerals important in the homeostasis of retinal health.
Conclusion
This case reports highlights the rare but serious complications of systemic fluoroquinolone use on multiple organ systems.
Postulated mechanisms behind the symptoms that this young man experienced have been put forward however further research is required on patients suffering from ophthalmic effects of systemic fluoroquinolone administration and FQAD in order to determine whether fluoroquinolone use is linked with a tangible clinical effect on various parameters, whether it be dry eyes, or retinal disease.
The MHRA has advised that fluoroquinolones should not be used in non-severe or self-limiting infections and that under-reporting is likely due to potential delayed onset of symptoms (4).
In the EU, approximately 300 million doses of fluoroquinolones are administered every day (4). Trainees should be reminded to adopt a risk vs benefit approach to management with said antibiotics, that alternatives should be utilised at the first signs of a reaction and to be aware of their effects on a variety of organ systems and senses (4).
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