Quinolone-Induced Lesions of Connective Tissue Structures (Arthropathies, Tendopathies)

[Drug - and Reproductiontoxicology]

I. Arthropathies

Antibacterial quinolones induce joint cartilage lesions in juvenile animals at relatively low doses. They are therefore contraindicated in children and adolescents as well as in pregnant and lactating women.

Despite their chondrotoxic effects in juvenile animals restricted use in pediatrics has repeatedly been demanded and is considered to be justified in well-defined indications (e.g. ciprofloxacin treatment of infections due to P. aeruginosa in cystic fibrosis patients).

Observations made so far in man do not give a clear-cut answer to the question as to the degree of a quinolone therapy risk. The arthropathogenic risk of therapeutic doses certainly differs among the individual fluoroquinolones.

Quinolones differ especially in their antibacterial spectrum. The most important fluoroquinolnes now available include: Ciprofloxacin, Levofloxacin and Moxifloxacin.

In animal studies we were able to show that

1. feeding an Mg2+-deficient diet to juvenile rats causes joint cartilage lesions that cannot be distinguished from quinolone-induced lesions [Stahlmann et al., Antimicrob Agents Chemother 39: 2013-2018, 1995]
2. Mg2+ substitution prevents fluoroquinolone-induced lesions in the rat [Pfister et al. 2007]
3. treatment of an animal with subtoxic doses of a quinolone at slight Mg2+ deficiency induces lesions [Schwabe et al., Naunyn-Schmiedeberg's Arch Pharmacol 359/3: R163, 1999, Abstract 638]
4. after fluoroquinolone administration concentrations are reached in cartilage that are higher than the corresponding concentrations in plasma at the same stage [Schwabe et al., Drugs 58 (Suppl 2): 385-387, 1999]

II. Tendopathies

Currently we are investigating the mechanisms and risk factors of quinolone-induced tendopathies in animal studies as well as in in vitro experiments.

All known fluoroquinolones are likely to induce lesions of Achilles tendons, although this is a rare side effect. Nevertheless, several hundreds of cases have so far been described in the literature.

In view of the aspect of drug safety it is of special importance that after treatment with these quinolones several months may go by before - possibly also caused by additional factors - tendinitis or ruptures occur. Therefore, it is very difficult to clearly define the causal relationship between drug exposure and side effects so that a systematic investigation of this unusual effect in an animal model gains in importance.

In electron microscopic investigations we were able to show in cooperation with Prof. Dr. M. Shakibaei (Inst. f. Anatomie, Uni München) that

1. tendons of juvenile rats are more sensitive than those of adult animals
2. simultaneous Mg2+ deficiency increases the degree of lesions
3. electron microscopically demonstrable changes persist for several months

[Shakibaei et al., Antimicrob Agents Chemother 44/2: 261-266, 2000].

The main topics of our present investigations include:

1. an exact biochemical characterisation of the changes using the immunoblotting method and other techniques
2. comparisons of the tendotoxic potential of various quinolones
3. investigation of possible synergistic effects of quinolones in combination with other drugs (i.e. steroids). [Sendzik et al., 2010 Int J Antimicrob Agents]
4. recognition of risk factors, i.e. chronic diseases and development of possibilities to prevent effects in patients at special risks. [Sendzik et al., 2005 Toxicology]. 

Relevant Publications of our Research Team at Pubmed

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Letzte Änderung: 10. Februar 2012, 11:20:43.