Risk/benefit analysis of quinolone use in children: the effect on diarthrodial Joints

Quinolones constitute a large class of antimicrobial drugs with marked activity against Enterobacteriaceae, other Gram-negative bacteria and staphylococci, while streptococci and enterococci have intermediate sensitivity. The quinolones show a high bioavailability after oral administration and a large volume of distribution, while their protein binding is low or negligible. Despite these positive characteristics a specific contraindication, the fear of a possible effect on the joint cartilage of growing subjects, limits their use to adult patients. The first indication of a possible arthralgic effect of quinolones was reported with nalidixic acid in 1972 by Bailey, Natale & Linton. As a consequence many toxicological studies have been performed in animals of various species with a wide range of quinolone derivatives: nalidixic acid, pipemidic acid, oxolinic acid, cinoxacin, ciprofloxacin, ofloxacin and pefloxacin (Ingham et ^ 1977. Bouissou et al.. 1978; Tatsumi et al.. 1978; Gough et al., 1979; Mayer, 1987; Christ, Lehnert & Ulbrich, 1988). Virtually all quinolones may cause lesions of the major diarthrodial joints when administered to immature or juvenile animals, but the absolute potency of different compounds is quite variable (Schluter, 1987). The same variability has been observed as far as the sensitivity of different animal species is concerned. Dogs are by far the most sensitive animals; in this species damage to the weightbearing joints occurred in three to four month old puppies after 7-28 days of oral treatment with 20mg/kg/day of ofloxacin or 30mg/kg/day of ciprofloxacin (Mayer, 1987; Christ et al., 1988); in four to five week old rats, however, the doses of the same drugs required to obtain similar effects were 100-300 mg/kg/day and 500 mg/kg/day, respectively (Mayer, 1987; Schluter, 1987; Christ et al., 1988). In addition, the age of the animal is important in determining the arthropathic effect of quinolones. The younger the animal, the worse the lesion and the shorter the interval between drug administration and lesion development. Arthropathic effects have been observed in adult dogs only after chronic (one-year) treatment with an oral dose of 140 mg/kg/day of pefloxacin, and no articular damage has been noted in monkeys treated for the same period with an oral daily dose of 40 mg/kg of the same drug (Mayer, 1987). The pathogenesis and the biochemical mechanism involved at the molecular level in the development of the arthropathic lesion are still unknown. Morphological findings include erosions of the joint cartilage with blister-like degeneration, accompanied by a cell-free noninflammatory effusion in the joint cavity (HOODCT & Wolfson, 1985; Chevais et al., 1987). The decomposition of the cartilage matrix can cause an additional irritative reaction of the synovia (Chevais et al., 1987). The contraindication to using quinolones in children is essentially based on the results of these phase 1 studies. A direct extrapolation of these results to human beings is not easy to justify, especially considering the wide variability of animal experience and the fact that most animal species were sensitive to doses far above (10-35 times) the clinically recommended ones. Only in the dog, the most sensitive species, were articular lesions observed after treatment with oral doses closer to human ones on a body weight basis (1.5-2 times greater) administered for a period of time that could be compared with the duration of a ' common antimicrobial treatment in humans. On the other hand, the difference in doses necessary to induce similar effects in different species might be explicable by the specific pharmacokinetic characteristics in a given species; after administration of the same dose, dogs show the highest peak concentration, the longest half-life and the greatest AUC, in comparison with other species (Okazaki et al., 1984; Stahlmann & Lode, 1988).