Review
Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data

https://doi.org/10.1016/j.ijantimicag.2008.08.004Get rights and content

Abstract

Quinolones possess favourable antibacterial and pharmacokinetic characteristics and are often used as anti-infective agents in adults. They are contraindicated in children and adolescents because they damage weight-bearing joints in juvenile animals. In addition, they possess a tendotoxic potential. Since ciprofloxacin has been used off-label for decades in children and adolescents, it is known today that no pronounced risks for arthropathies or tendinopathies exist in humans. Recently published clinical studies with gatifloxacin in children support this clinical experience. However, a low risk for joint disorders cannot be excluded and tendinopathies are a generally accepted rare adverse effect of quinolones at least in adults. Isolated case reports of arthralgia in children following quinolone therapy have been published and in studies with levofloxacin the incidence of musculoskeletal disorders was significantly greater in levofloxacin-treated patients than in control patients treated with comparator antibiotics. As a consequence, only life-threatening infections for which other antimicrobials cannot be used are possible indications for quinolones in children, for example the use of ciprofloxacin in cystic fibrosis patients with a bronchopulmonary exacerbation, chronic suppurative otitis media caused by Pseudomonas sp., complicated urinary tract infections and enteritis caused by invasive multidrug-resistant pathogens (e.g. Salmonella, Shigella).

Introduction

Quinolones are contraindicated during pregnancy and lactation as well as in children and adolescents. Only a few exceptions to this rule are accepted. This restrictive use of a valuable class of antimicrobial agents is mainly based on toxicological findings in animals during postnatal growth. The results derive from studies that were conducted in addition to the routinely performed toxicological tests. The strict attention to these toxicological findings was often criticised. Some authors regard the quinolone-induced arthropathies as irrelevant for humans and demand a broad use in paediatric indications. The discussion about using quinolones in paediatrics has been intensified by the development of quinolones that are effective against penicillin-resistant pneumococci, for example gatifloxacin, levofloxacin and moxifloxacin. During recent years the benefits and risks of new quinolones have been studied in several paediatric clinical trials. The relevant experimental and clinical data published so far will be reviewed here, with a focus on the recently published clinical studies.

Section snippets

Chondrotoxicity of quinolones in animal testing

Initial papers describing quinolone-induced chondrotoxicity in growing animals were published ca. 30 years ago. In juvenile dogs treated with pipemidic acid, toxic effects on the immature joint cartilage were described for the first time in 1977 [1]. The authors observed stiffness of gait in these animals and found that the younger the animal, the earlier the onset of signs of arthropathy. These findings were confirmed a few years later in other studies. Blister formation and lesions in the

Tendinopathies

Besides their effects on immature joint cartilage and growth plates, quinolones can also affect tendons [3], [9]. An inflammatory reaction with an oedematous swelling of the tendon is often described as an initial event. Symptoms can continue up to several weeks and may result in complete tendon rupture [10]. Even after an asymptomatic latency period of some weeks, a rupture of the tendon may occur. Often the Achilles tendon is affected. Tendinopathies have been described in association with

Possible mechanism responsible for chondrotoxic and tendotoxic effects

A possible mechanism for the quinolone-induced arthropathy and tendinopathy, postulated on the basis of published biochemical and ultrastructural findings, involves impaired function of β1 integrins as an initial event resulting in disturbed signal transduction between the extracellular matrix and chondrocytes (Fig. 1). Owing to their chelating properties, quinolones form complexes with magnesium ions and thus interrupt the normal function of the signal receptors of the β1 integrin family, the

Clinical experience with quinolones in children

Until now, chondrotoxic effects of quinolones on immature joint cartilage have been proven only in animal testing, and case reports are always associated with considerable uncertainty with respect to a causal relationship (e.g. [24]). Pefloxacin was used in France for children with cystic fibrosis (CF) and Pseudomonas infections before ciprofloxacin became available. It possibly caused some quinolone-associated arthropathies described by French authors as early as 1989 [25]. Most experience

Differences in velocity of growth in animals and man: an explanation for the low risk of quinolone-associated toxicity in children?

The chondrotoxic risk associated with the use of quinolones in children is obviously low. Some authors even assume that the findings of animal testing are completely irrelevant for humans. However, a conclusive explanation for the fundamental difference in the reaction of connective tissues in man and in animals, which could explain the observed species differences, is not known. No major principal differences between the morphology or biochemical composition of the cartilage in animals and man

Selected indications for quinolone therapy in children

Over the past 10 years the Committee on Infectious Diseases of the American Academy of Paediatrics published several reviews and listed indications for which quinolones might be considered after careful individual consideration of the benefits and risks. These recommendations were supported by and commented upon several times by leading paediatricians [45], [46], [47], [48], [49], [50], [51]. Based on these statements, treatment with quinolones in paediatrics may be considered for the following

Conclusions

In paediatrics, a very restrictive use of quinolones is still recommended, because: (i) a slight risk of quinolone-induced arthropathy cannot be excluded; and (ii) there are concerns about the rapid spread of resistant pneumococci. Treatment with a quinolone is only acceptable if, first, the patient suffers from a life-threatening or difficult-to-treat infection and, second, other antibiotics cannot be used because the patient is allergic or does not tolerate the drug for other reasons, or the

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