Fluoroquinolones and risk of tendon damage

As ciprofloxacin and other fluoroquino­lones are prescribed more frequently, tendon-related adverse effects are also becoming more common. Experts often do not recommend these drugs, particularly for athletes or elderly patients, and emphasize that all patients should know the risks.

By Barbara Boughton

Since the 1980s, scientific evidence has mounted about the tendon damage—including tendinitis and even tendon rupture—that can occur with use of the popular antibiotics called fluoroquinolones. This past summer, the US Food and Drug Administration (FDA) strengthened its black box warning for fluoroquinolones (such as levo­floxacin and ciprofloxacin), warning of possible damage to tendons as well as other health risks, and lower extremity clinicians have become increasingly concerned about the side effects of these drugs.

Tendinopathy with fluoroquinolone use is rare, but since the drugs are used so often, clinicians who specialize in orthopedics and musculoskeletal injuries are likely to see patients with fluoroquinolone-associated tendinitis and tendon rupture, according to experts interviewed by LER. In the medical literature, tendinitis has been reported to affect 2.4 of every 10,000 patient prescriptions for fluoroquinolones, and tendon rupture 1.2 of every 10,000 prescriptions.¹

“These are small numbers, but since these drugs are widely prescribed, it’s important that musculoskeletal clinicians and those who treat athletes be aware of the clinical presentation of tendinopathy that can occur with fluoroquinolones,” said Trevor Lewis, MSc, GDPhys, MCSP, a senior physiotherapist at Aintree University Hospital in Liverpool, UK, and author of a 2014 review on fluoroquinolones and tendinopathy.¹

Black box updates

In 2008, the FDA required a black box warning for fluoroquinolones that advised health professionals of the risks for tendon rupture and tendinitis. Now the FDA has strengthened its black box warning for these antibiotics, which are taken by 26 million Americans each year.^2,3 In July 2016, the FDA approved safety labeling changes for fluoroquinolones that warn of disabling side effects that can occur together and can be irreversible—including damage to muscles, tendons, joints, nerves, and the central nervous system; associated conditions include tendinopathy, peripheral neuropathy, and worsening symptoms for those with myasthenia gravis.

“Fluoroquinolones have risks and benefits that should be considered very carefully,” said Edward Cox, MD, director of the Office of the Antimicrobial Products in the FDA’s Center for Evaluation and Research, in a news release about the black box changes. “It’s important that both healthcare providers and patients are aware of both the risks and benefits of fluoroquinolones, and make an informed decision about their use.”

The FDA also notes in its warning that fluoroquinolones should be reserved only for patients for whom there is no alternative treatments, including those with serious bacterial infections such as anthrax and bacterial pneumonia.

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Almost all (95%) fluoroquinolone-associated tendinopathy occurs in the Achilles tendon, since its weightbearing role makes it more likely than other tendons to be injured.^1,4,5 Yet researchers have also reported tendinopathy associated with fluoroquinolone use in other tendons, including the peroneus brevis, patellar tendon, adductor longus, rectus femoris, triceps brachii, subscapularis, and tendons of the hip, among others.^6-10 Symptoms can occur within two hours of taking fluoroquinolones and as long as six months after the patient has stopped taking the antibiotic.¹¹ Up to 50% of patients experience tendon symptoms after the fluoroquinolone has been discontinued.

Patients who use corticosteroids and those older than 60 years are most likely to be affected by fluoroquinolone-associated ten­dino­pathy, according to recent research.^1,4,12,13 One reason is that inhaled and systemic corticosteroid use has been independently associated with tendon damage and rupture.^1,4,14

“Older patients are also more likely to experience tendinitis from fluoroquinolones, because they have tendons that have reduced strength and elasticity.¹¹ So using fluoroquinolones in an elderly patient, particularly patients with comorbidities and who are sedentary, simply adds insult to injury,” said Adam Budny, DPM, a researcher and practitioner at University Orthopedics Center in Altoona, PA.

Other risk factors that increase the chance of tendinopathy with fluoroquinolone use include renal insufficiency (fluoroquinolones are cleared through the kidney);¹⁵ having undergone a kidney, heart, or lung transplant; rheumatoid arthritis; and diabetes; among others. Participation in strenuous sports activities and athletics is also a risk factor.^1,4,10,16-19

Tendinopathy has long been considered a side effect of most fluoroquinolones, but recent studies in the pharmacology literature have highlighted the particular dangers associated with levofloxacin and its parent compound, ofloxacin. A 2016 review published in Pharmacotherapy, in fact, found that data from in vitro studies, animal studies, patient-level analyses, and large national and international surveillance reports showed levofloxacin and ofloxacin are more likely to cause tendon damage than other fluoroquinolones.²⁰ The risk associated with these two drugs appears to be dependent on exposure—with higher doses and longer duration associated with the greatest risk for tendinopathy.

Weighing the options

Given the side effects and complications associated with their use, and the sequelae associated with serious tendon injuries—including chronic pain and mobility restrictions—most clinicians interviewed by LER do not recommend prescribing these drugs, particularly to athletes or elderly patients. If they must be prescribed—when there are no other options—it’s vitally important that physicians inform their patients of the potential risk for tendinopathy as well as other possible side effects.

“Informing your patients about the risks is the right thing to do from a patient care perspective,” said Kris DiNucci, DPM, FACFAS, a practitioner at the Foot and Ankle Center of Arizona in Flagstaff and a former board member of the American College of Foot and Ankle Surgeons. “Clinicians also need to be aware of the possible physician liability if patients are not informed about the side effects of fluoroquinolones. As physicians, we need to document that patients have been informed of the possible side effects of fluoroquinolones, since many patients with tendon injuries have suc­cess­fully sued pharmaceutical companies.”

If a patient presents with tendinopathy while taking a fluoroquinolone, it’s best to switch them to an alternative antibiotic, according to research reports and clinicians.^1,21

“If it’s early enough in the process, stopping the antibiotic has the potential to prevent an inflammatory condition such as tendinitis from worsening and causing longer-term tendon damage,” said Kyle Goerl, MD, assistant professor in the Department of Family and Community Medicine at the Kansas University School of Medicine in Wichita, and head team physician for Wichita State University athletics.

Athletes who have no other option but fluoroquinolones for treatment of an infection should also be monitored closely for symptoms of tendinitis and tendinopathy, Lewis said.

“I would question the athlete on a daily basis about their tendon status while on fluoroquinolone treatment, and for at least six months following cessation of the drug,” he said.

Treating the tendinopathy

Yet most patients who present with tendinopathy after fluoroquinolone use do so weeks or months after the initial infection has resolved, and after they’ve finished the full course of antibiotics. In these cases, the only option is to treat the tendinopathy or tendon rupture in the most judicious way possible.

The treatment of tendinopathy, however, is not always easy. Goerl noted that athletes with tendon damage such as tendinitis or tendinosis, who are typically managed nonoperatively, can miss six to eight weeks of practice and competition. Tendon ruptures—whether treated surgically or conservatively—can have an athlete out of commission for up to a year.

“Recovery is a fairly lengthy process for tendon injuries, and many athletes struggle with getting back to their sport after tendon damage,” Goerl said. “Getting an athlete back from a tendon problem is one of the most challenging things we do in sports medicine.”

Goerl said that, in his experience, patients who sustain tendin­opathy from fluoroquinolone use take longer than the average patient with tendon damage to return to activity. Researchers^1,16 have also found fluoroquinolone-induced tendinopathy can take longer to heal than other tendinopathies, and a gradual approach to physical therapy is most likely to be successful, Lewis said.

Although the use of eccentric exercises in the rehabilitation of otherwise-healthy athletes with tendinopathy is gaining popularity, Lewis and colleagues suggested¹ using eccentric exercise in patients with fluoroquinolone-related tendinopathy with caution—based in part on the fact that in the medical literature the technique has been less successful in nonathletes than in athletes.^22,23

Lewis advocates a two-phase approach to rehabilitation similar to that described by physical therapist Brenda Greene, PT, PhD, in a 2002 case report.¹⁶ Particularly in the early stages of symptoms, the first phase consists of rest, and possibly bracing, to allow the tendon to recover from the chemical injury induced by fluoroquinolones, according to Lewis. Then a second phase of progressive loading can begin.

Greene, an assistant professor in the Department of Physical Therapy at Emory University in Atlanta, GA, used techniques aimed at protecting the tendon from load stresses in the first phase of recovery. The patient in the case report—a man aged 41 years who typically walked or bicycled three to five miles per week—was advised to use axillary crutches and heel lifts during the initial two weeks. In the third week, the physical therapist recommended the use of a counterforce Achilles tendon brace. By the sixth week, the patient was standing and walking for five minutes without crutches, but still used the counterforce brace. By the eleventh week of rehabilitation, the crutches were discontinued.¹⁶

For three months, the patient’s physical therapy program also emphasized progressive loading of the Achilles tendon. This progressive loading was accomplished by gradually increasing resistance during exercises that included stretching with a towel, walking on a rocker board, and walking in a pool of waist- to chest-deep water. The patient then progressed to riding his 24-speed bicycle in the lowest gear outdoors. After 11 weeks of physical therapy and home exercise, the patient’s pain had decreased from 3 to 1 on a 10-point visual analog scale, and his Lower Extremity Functional Scale score increased from 28 to 71 out of 80, according to the study. After three additional weeks of home exercise, the patient graduated to plyometric exercise, which Greene noted had the potential to improve muscular performance.¹⁶

In the early stages, tendinopathy from fluoroquinolone use is often treated with icing, rest, and nonsteroidal medications—in the hope these measures will prevent the tendon injury from getting worse, clinicians interviewed by LER said.

“We encourage athletes to rest and avoid aggressive exercise, because we’re afraid that the tendon injury could get worse—and the athlete could potentially rupture the tendon,” said Kristine Karlson, MD, associate professor of family medicine and orthopaedics at the Geisel School of Medicine at Dartmouth College in Hanover, NH.

The eventual use of eccentric exercise, since it loads and strengthens the tendon, is also important for recovery.

“Eccentric exercise is the gold standard for rehabilitation from tendon injury,” Karlson said.

Unlike Greene, however, Karlson does not recommend bracing.

“It really doesn’t make much of a difference in tendinopathy—and it can also cause the tendon to become really stiff,” she said.

More extensive damage

Once the tendon damage results in tendinosis—or worse, a tendon rupture—more dramatic treatments are inevitable, according to Stephen Conti, MD, a clinical professor of orthopedic surgery at the University of Pittsburgh School of Medicine. Treatments for tendinosis can include nonoperative procedures such as the injection of platelet-rich plasma or percutaneous tenotomy and percutaneous fasciotomy surgeries, performed with tools using ultrasonic energy to cut and remove diseased tissue.

“Patients who have age-related tendinopathies have small, discrete areas of internal damage to the tendon, whereas patients who experience tendinopathy from fluoroquinolone use tend to have more extensive abnormalities of the tendon,” Conti said.

Thus, nonoperative treatments and recovery in these patients tend to take longer, he added.

“Yet surgical treatments for tendinopathies are generally the same, whether or not the tendon damage stems from use of a fluoro­quinolone,” Conti said.

Choosing the right surgical treatments rely instead on factors such as the extent of tendon abnormality and whether the tendon is salvageable, Conti noted.

In the case of a tendon rupture, nonoperative procedures and surgeries can be used as treatment. With nonoperative treatment (such as use of a boot and heel lift), the two sections of the torn tendon are brought into proximity so the tendon eventually regrows and heals, Goerl said.

“With nonoperative treatment, you have no problems with infection or wound healing, but you can end up with a long, weak tendon,” Conti said. “The benefit of surgery is that it can produce a better and fuller repair without resulting in a weak tendon,” he added.

With surgery for a torn tendon, on the other hand, the two ends of the damaged tendon can be sewn together. If there isn’t enough healthy tendon tissue to salvage, a tendon transfer or graft can repair the damage.

“Once the tendon crosses the line to where it is no longer salvageable, then it has to be removed, and a tendon transfer should be performed,” Conti said.

Barbara Boughton is a freelance writer based in the San Francisco Bay Area.

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