The British Journal of Medicine published two interesting articles this month. The first is an education review on the overdiagnosis and medicalization of athletes (and the public at large)(1). The authors cite several factors supporting this trend in sports medicine, including: The belief that more intervention improves outcomes. Making the definition of disease more inclusive.... MORE
Fluoroquinolones and injury
Previous research reported by SIB suggested that fluoroquinolone antibiotics could pose a potential threat to tendon health in sportsmen and women. Andrew Hamilton looks at more recent research on fluoroquinolones and explore the implications for clinicians.
A torn Achilles’ tendon brings down Atlanta Hawks’ guard Emanual Davis in 2002.
The development of antibiotics is without doubt one of mankind’s greatest scientific achievements, saving countless millions of lives since their introduction. However, notwithstanding the current concerns about ‘superbug’ resistance, not everything is rosy in the antibiotic garden. A few years ago, we reported on growing evidence that one particular group of antibiotics – fluoroquinolones – might be implicated in rapid-onset tendon degeneration, exposing sportsmen and women to an increased risk of tendonitis or even tendon rupture. In the intervening years, more research into this topic has been carried out, providing a useful insight for clinicians dealing with athletes who may have athletes in their care who are either taking or have taken fluoroquinolone antibiotics.
|Table 1: Structural and biochemical changes in tendon cells induced by fluoroquinolones|
|Ciprofloxacin, Enrofloxacin Fleroxacin, Garenoxacin Gemifloxacin, Ofloxacin Pefloxacin||-Swelling and dilatation of cell mitochondria and endoplasmic reticulum
-Multiple vacuoles and large vesicles
-Densified nuclei and clumped chromatin
-Decrease of fibril diameter
-Increase of distance between collagenous fibrils
-Cell detachment from extracellular matrix
-Hyalinization of collagen bundles
|Ciprofloxacin & Levofloxacin||-Reduction of cytoskeletal and signaling proteins|
|Ciprofloxacin & Pefloxacin||-Inhibition of collagen synthesis
-Decrease of elastin and fibronectin
-Inhibition of proteoglycan synthesis
Fluoroquinolones are effective, broadspectrum antibiotics first developed in the 1970s, which play an important role in the treatment of serious bacterial infections such as pneumonia, typhoid, diarrhoea, kidney/urinary tract infections and many other stubborn and virulent infections. Indeed, some of the more recent iterations of fluoroquinolones are particularly effective against bacteria such as Staphylococcus Aureus and Staphylococcus Pneumoniae, which have become resistant to many other antibiotics.
The fluoroquinolones (see Figure 1) are a subgroup of the larger quinolone family of antibiotics. All quinolones work by preventing bacterial DNA from unwinding and duplicating. Examples of commonly used fluoroquinolone antibiotics include ciprofloxacin, levofloxacin, norfloxacin and gemifloxacin. All the fluoroquinolones share the same essential chemical structure (see figure 1). The ‘F’ denotes the fluorine atom (giving rise to the ‘fluoro’ in fluoroquinolones), while the ‘R’ denotes the chemical side group – it’s the different R groups that produce the different types of fluoroquinolone antibiotics.
Figure 1: Fluoroquinolone structure
Hailed by some as ‘wonder antibiotics’, fluoroquinolone use by physicians increased dramatically towards the turn of the century. In the late 90s however, evidence began to emerge linking fluoroquinolone antibiotic use with structural changes at the cellular level to connective tissue in the body – particularly to collagen, a major and vital component of tendon tissue.
Many of the initial findings came about as a result of studies on rats (see Table 1)1 2 3 4 5 6. However, studies on human cell samples seemed to indicate that by causing a decrease in essential components of tendon tissue such as collagen type I, elastin, fibronectin and proteoglycan, fluoroquinolone-induced degenerative structural changes to tendon tissue were also possible in human tendon tissue7.
Around about the same time, a growing number of tendonitis and tendon rupture cases were being observed among patients taking fluoroquinolone antibiotics. A 2003 Canadian study of 98 case studies from the scientific literature found that pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury had been reported with most fluoroquinolones8. The median duration of fluoroquinolone treatment before the onset of tendon injury was eight days, although symptoms occurred as early as two hours after the first dose and as late as six months after treatment was stopped. Up to one-half of patients experienced tendon rupture, and of these, almost one third had also received long-term corticosteroid therapy before or during fluoroquinolone use.
As concern over the association between fluoroquinolone use and tendonitis/tendon rupture grew, the US FDA issued a ‘prescribing warning’ followed in 2008 by a more general alert on the risks of fluoroquinolone use stating9: “Tendinitis and tendon rupture most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff, the hand, the biceps, and the thumb have also been reported. Tendon rupture can occur during or after completion of fluoroquinolone use; cases occurring up to several months after completion of therapy have been reported. Fluoroquinolones should be discontinued if the patient experiences pain or inflammation in a tendon (symptoms that may precede rupture of the tendon), or tendon rupture. Patients are advised, at the first sign of tendon pain, swelling, or inflammation, to stop taking the fluoroquinolone, to avoid exercise and use of the affected area, and to promptly contact their healthcare provider about changing to a non-fluoroquinolone antimicrobial drug.”
|Box 1: Clinical manifestations of fluoroquinolone-induced tendinopathy/tendon rupture|
|Fluoroquinolone-induced tendinopathy/rupture tends to manifest itself somewhat differently from ordinary tendon pathology. Signs that clinicians should be aware of include:
-An abrupt onset and sharp pain that occur spontaneously upon walking or palpation;
-Tendon rupture is almost always preceded by spontaneous pain at the bony insertion 2 to 3 centimetres above the insertion point, believed to be correlated with diminished vascularisation at this anatomic site;
-Pain, swelling, or inflammation is commonly observed in the tendon area for up to two weeks before rupture occurs;
-Difficulty performing plantar flexion (Thompson's sign);
-Bilateral pathology is extremely common, occurring in up to 50 percent of cases;
-The weight-bearing Achilles tendon is most commonly affected, occurring in over 90% percent of cases (although other tendons such as biceps brachii, supraspinatus, and extensor pollicis longus, can also be affected).
What does the recent science say about fluoroquinolone use and tendinopathy/ rupture? In terms of aetiology, compelling evidence suggests that fluoroquinolones can rapidly affect the chemical composition of tendon structure by depleting levels of glycosaminoglycans (GAGs – compounds vital to the elasticity and integrity of structural tissue) in the tendon.
In a study published earlier this year, researchers used a technique known as sodium magnetic resonance imaging (sodium MR) to study pathological changes and changes in GAG levels in the Achilles tendons in the 14 ankles of 7 men who took 500ms of Ciprofloxacin twice a day for 10 days10. As figure 2 shows, after 10 days, there was a marked reduction in the GAG content of the Achilles tendon, which though reversible, still hadn’t fully recovered 5 months after ending the Ciprofloxacin course.
Figure 2: GAG levels in the Achilles tendon after 10 days of Ciprofloxacin
The prolonged period of disrupted tendonpathology following fluoroquinolone administration may be aggravated by impaired tendon healing capacity. A recent study on mice looked at tendon healing capacity in those treated with Fleroxacin before rotator cuff surgery11. Compared to control mice who received no Fleroxacin, the treated mice showed significantly less fibrocartilage and poorly organized collagen at the healing enthesis. Moreover, the treated mice had a significantly reduced tendon cross-sectional area and the researchers concluded that the fluoroquinolone treatment had negatively influenced tendon healing, which could have implications for patients undergoing tendon surgery/repair in the months following a course of fluoroquinolones.
Recent risk data
In terms of the risk of particular fluoroquinolone drugs, recent research has suggested that Ciprofloxacin, Fleroxacin, Pefloxacin and Ofloxacin present the greatest threat to tendon health12. While other fluoroquinolones such as Trovafloxacin and Levofloxacin may present less of a risk, they are not risk free. For example, Levofloxacin has been implicated in Achilles tendon rupture in some case studies13, while for other fluoroquinolones, there may simply not be enough data to determine safety one way or the other.
More worryingly is that the recent evidence suggests that when it comes to tendonitis or tendon rupture, athletes and fitness enthusiasts may be especially vulnerable to the effects of fluoroquinolones. There are a number of reasons why this is the case. Firstly, excessive loading of tendons during physical training is regarded as a major pathologic stimulus f o r tendon degeneration. This is because exercise increases the production of enzymes known as’matrix metalloproteinases’, some of which can adversely alter the structure of the extracellular matrix of tendons14.
We also know that low-dose corticosteroids in isolation can increase the risk of Achilles tendon rupture, and evidence suggests that combined use of corticosteroids with fluoroquinolones potentiates this adverse effect15 16. Indeed, studies suggest that over 50% of patients with fluoroquinolone-related tendon rupture had received systemic or inhaled corticosteroids17, and that patients prescribed both fluoroquinolones and corticosteroids have a 46-fold greater risk of Achilles tendon rupture than those taking neither medication18!
Given these facts, a recent review of fluoroquinolone use among athletes has recommended that athletes should not be prescribed fluoroquinolones and should be given alternative antibiotics whenever possible19. This is particularly true in the light of the added risk of corticosteroid treatment; asthma is common among sportsmen and women20, many of whom may be using corticosteroid medication. Fluoroquinolone use in such athletes could therefore be very hazardous.
When fluoroquinolone antibiotics are the only option for an athlete, there’s some evidence from cell culture studies that the co-ingestion of vitamin E could help to alleviate some of the harmful effects21 22. This might occur due to the ability of vitamin E to help prevent of free-radical damage in biological membranes. However, whether this protective effect is significant in humans undergoing fluoroquinolone treatment is unknown and the best option by far is for athletes to avoid fluoroquinolones altogether if possible.
Rehab and fluoroquinoloneinduced tendinopathy
Graduated eccentric training regimes, in which muscle tendons are subjected to increasing loads during muscle elongation, have proved both popular and effective for treatment and rehab of tendinopathy – and this approach is supported by the literature23. For sportsmen and women, eccentric training programmes have been shown to be particularly effective, resulting in a success rate of around 90% in those with tendinopathy24 – a significantly better outcome than for the (more sedentary) population as a whole25.
However, while loading tendon with eccentric exercise may be appropriate for treating tendinopathy most athletes, this approach should not be used for treating fluoroquinolone-induced tendon conditions, at least in the early stages of symptoms. In study on this topic, Greene illustrated that patients with fluoroquinolone-related tendinopathy should be rehabilitated using a 2-phase approach (see box 2)26:
- A second phase, consisting of progressive loading
- An initial phase of bracing and support to allow the tendon to recover from the chemical injury caused by the fluoroquinolone
|Box 2: A two-phase approach for rehab of fluoroquinolone-induced tendinopathy|
|The approach advocated by Green consists of an overlapping 2-phased intervention. The first phase consisted of techniques to protect the tendon from overload stresses, and the second phase consisted of graduated loading of the tendon and muscle.
In the early stages of treatment, the tendon is likely to overload easily, causing inflammation. To protect the tendon from overloading forces, techniques should used initially to unload the tendon during weight-bearing activities – eg use of crutches and heel lifts for the purpose of decreasing tendon loading. During the third week of therapy, a counterforce Achilles tendon brace (a non-elastic constraint with a tension strap that crosses the Achilles tendon) can be used during functional weight-bearing activities, excluding specific exercises. The theory behind the tendon brace is pressure from the tension strap either broadens the musculotendinous attachment or limits muscle expansion at the time of contraction resulting in decreased stress within the tendon.
After three weeks, a progressive exercise program consisting of graduated loading of the tendon begins. The patient’s feedback in these early stages is important and the progression in loading needs to be very gradual and patients should be encouraged to keep a daily log of exercise performed and their responses to it. Ancillary exercise such as deep water walking, gentle stretching and stationary cycling (with the arch of his foot contacting the pedal to decrease the force on the Achilles tendon) can also be useful. This phase may take 3 months or more before full functionality is restored.
|-Athletes should avoid all use of fluoroquinolone antibiotics unless no alternative is available. This is especially true if corticosteroid medication is also used.
-If a fluoroquinolone antibiotic has been prescribed and no alternative is available, athletes should immediately reduce highintensity and ballistic activities and total training volume. These reductions should remain throughout the duration of the antibiotic course and athletes made aware of the increased risk for the development of musculoskeletal complications for up to 6 months following antibiotic treatment. Co-administration of vitamin E supplements might provide some protective effect.
-Oral or injectable corticosteroids should never be administered while an athlete is taking fluoroquinolones.
-If the athlete has no symptoms after completing the full course of the antibiotic, then a graduated return to full activity under direct medical supervision should be initiated, with close monitoring for the development of musculoskeletal symptoms.
-If any pre-rupture symptoms (see Box 1) are noted, all athletic activity should cease immediately and fluoroquinolone should be discontinued if possible.
-Clinicians treating fluoroquinoloneinduced tendinopathy should be aware that tendons may not respond well to the usual rehab protocols (eg eccentric training), and that an extended period of force unloading may be required before a very gradual programme if eccentric training begins
Summary and recommendations
Evidence continues to mount suggesting that fluoroquinolone antibiotics are harmful for sportsmen and women, who seem particularly vulnerable to their effects. Not only do they adversely affect the chemical composition and structural integrity of tendons, their use seems to inhibit the normal repair mechanisms that bring about recovery from tendon injury. Worse, the risk of fluoroquinoloneinduced tendinopathy is further increased when corticosteroid medication is being used, which is the case in many athletes with asthmatic conditions. In the light of the above, clinicians should follow the recommendations below when dealing with athletes who are or who have in the past 6 months been on fluoroquinolone antibiotics.
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