Cytofluorometric analysis of chondrotoxicity of fluoroquinolone antimicrobial agents

Hayem, Gilles; Petit, Patrice X.; Levacher, M.; Gaudin, C; Kahn, M F; Pocidalo, J J

doi:10.1128/aac.38.2.243

Cited by 69 publications

(34 citation statements)

References 39 publications

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“…Certain antimicrobials may have direct toxic effects on beta cells. Because of the structural and functional similarities between bacteria and human mitochondria, exposure to macrolides and quinolones may inhibit the mitochondrial synthesis of DNA and enzymes in beta cells, resulting in beta cell death [5]. Antimicrobials have been shown to induce apoptosis by different mechanisms in many types of cells [6].…”

Section: Discussionmentioning

confidence: 99%

Use of antimicrobials and risk of type 1 diabetes in a population-based mother–child cohort

Kilkkinen¹,

Virtanen

Klaukka

et al. 2005

Diabetologia

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Aims/hypothesis: The aim of this study was to investigate whether the use of antimicrobials is associated with the risk of childhood type 1 diabetes. Materials and methods: The study population included all children born in Finland between 1996 and 2000 who were diagnosed with type 1 diabetes by the end of 2002. For each case (n=437), four matched controls were selected. Data on diabetes and the maternal use of antimicrobials was derived from nationwide registries. Results: Maternal use of phenoxymethyl penicillins (odds ratio [OR]=1.70, 95% CI 1.08-2.68, p=0.022) or quinolone antimicrobials (OR=2.43, 95% CI 1.16-5.10, p=0.019) before pregnancy was associated with an increased risk of type 1 diabetes in the child, whereas the use of other specific antimicrobials was not related to the risk. The risk was also higher among mother-child pairs where macrolides were used both by the mother before pregnancy and by the child, compared with pairs where neither used macrolides (OR=1.76, 95% CI 1.05-2.94, p=0.032). Maternal use of antimicrobials during pregnancy was not associated with an increased risk. The high use of antimicrobials by the child (more than seven vs seven or less purchases) was related to greater risk (OR=1.66, 95% CI 1.24-2.24, p=0.001). Conclusions/ interpretation: Overall, the use of antimicrobials before pregnancy, during pregnancy or during childhood was not related to the risk of childhood type 1 diabetes. However, the use of some specific antimicrobials by the mother before pregnancy and by the child may be associated with an increased risk. Further studies are needed to confirm these associations and to elucidate the underlying mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Use of antimicrobials and risk of type 1 diabetes in a population-based mother–child cohort

Kilkkinen¹,

Virtanen

Klaukka

et al. 2005

Diabetologia

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“…Previous reports suggested compromised mitochondrial activity, and a precocious stimulation of the oxidative metabolism within immature articular chondrocytes was also described (11,33), with both of these resulting in the generation of reactive oxygen species. Therefore, we looked for an eventual pefloxacin-induced oxidative stress on the collagen isolated from the Achilles tendon.…”

Section: Discussionmentioning

confidence: 99%

“…As an oxidative event was observed in cartilage (11,33), we considered the attractive hypothesis that the pathophysiological effects due to pefloxacin administration result from the same effects on both articular cartilage and tendon. On the one hand, the Achilles tendon and articular cartilage are characterized by a low level of or no blood perfusion, respectively, resulting in a low O 2 pressure (18).…”

mentioning

confidence: 99%

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Simonin

Gégout-Pottie

Minn

et al. 2000

Antimicrob Agents Chemother

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Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.Fluoroquinolones are widely used in clinical practice because of their excellent antibacterial activity, wide spectrum of activity, and high degree of bioavailability. These antibiotics are generally considered well tolerated, although quinoloneinduced chondropathy has been observed in young animals of several species (3,4,9,31).Since 1992, tendinopathy has been described as another side effect in patients treated with fluoroquinolones, with the tendinopathy sometimes resulting in the rupture of the tendon. The cause of this rare (Յ1%) (7) but severe complication remains unexplained (13,14,28). Probably both because of the large number of prescriptions for pefloxacin and because of the high level of diffusion of pefloxacin into tissue, pefloxacin has been the subject of several reports on such secondary effects, and the Achilles tendon seems to be especially vulnerable to fluoroquinolone-promoted tendinopathy (14). The low incidence of this tendon-damaging effect suggests that it may result from some intrinsic effects of fluoroquinolones that could be realized as a result of certain factors, such as age, sex (the male-to-female ratio of those affected is 3:1), concomitant corticosteroid therapy, especially in renal graft patients (27), duration of treatment (26...

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“…Concerning the effect of quinolones on mitochondrial functions of chondrocytes, Hildebrand et al (14) used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay to show that quinolones inhibit mitochondrial dehydrogenase activity in cultured chondrocytes of dog articular cartilage. Hayem et al (13) reported that oral administration of OFLX and pefloxacin increased the respiratory burst of chondrocytes in juvenile rabbits, suggesting the generation of reactive oxygen species. On the basis of our finding of decreased uptake of rhodamine 123 and 3 H-thymidine by chondrocytes in 24-and 48-h cultures, respectively, we speculate that mitochondrial dysfunction precedes DNA synthesis inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of their findings, Stahlmann et al suggested that a possible mechanism of this quinolone chondrotoxicity may be impairment of mitochondrial DNA metabolism. Against this, recent in vitro and ex vivo studies have shown that the synthesis of proteoglycans and collagen and the mitochondrial function of chondrocytes are susceptible to inhibition in the presence of quinolones (7,13,14,26). Meanwhile, Stahlmann et al (28) subsequently reported another hypothesis, namely, that by forming stable chelate complexes with magnesium, quinolones may affect the electrolyte balance, impair the function of integrins, and cause degeneration of the matrix, thereby leading to severe damage of articular cartilage.…”

mentioning

confidence: 99%

Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo

Kato

Takada

Ogawara

et al. 1995

Antimicrob Agents Chemother

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We investigated the toxic effect of levofloxacin (LVFX), a quinolone antibacterial agent, on cartilage by examining aspects of its in vivo toxicokinetics and effect on the function of cultured chondrocytes of the femoral articular cartilage from juvenile New Zealand White rabbits. Repeated administration of LVFX (100 mg/kg) orally for 7 days induced focal necrosis and superficial erosion in the articular cartilage of the femoral condyle, but 30 mg/kg did not. Concentrations of LVFX in the cartilage were highest at the first sampling point (30 min) after a single administration, being 4.93 and 12.2 g/g in the 30-and 100-mg/kg groups, respectively. The arthropathic concentration of LVFX in the cartilage was then shown to be 12.2 g/g or more. For an in vitro study, chondrocytes were separated from the articular cartilage of the rabbit femoral condyle and cultured for 7 days until confluence. 35SO 4 uptake by cultured chondrocyte sheets was most susceptible to LVFX, decreasing at drug concentrations of 5 g/ml or more in 24-and 48-h cultures but not in a 72-h culture. Furthermore, 3 H-thymidine uptake was decreased at concentrations of 10 g/ml or more in a 48-h culture but not in 24-and 72-h cultures. Rhodamine 123 accumulation was susceptible to inhibition in cultured chondrocytes at an LVFX concentration of 10 g/ml or more. These results suggest that LVFX inhibits glycosaminoglycan synthesis initially and DNA synthesis and mitochondrial function secondarily at actual arthropathic concentrations in cultured rabbit chondrocytes but that these changes are reversible and not enough to kill the cells.Adverse effects of quinolone antibacterial drugs, including arthralgia, joint swelling, arthropathy, and arthritis, have been reported at incidences of less than 0.5% in healthy volunteers and juvenile and adult patients (17). Quinolones are well known to induce cavitation in the articular cartilage of juvenile rats, rabbits, guinea pigs, dogs, marmosets, and crab-eating monkeys but not in that of adults; of these species, dogs are thought to be most susceptible to this chondrotoxicity (4,5,11,12,15,16,24,25,27,29,31). However, the relationship between the adverse clinical effects of these drugs and their toxic lesions in laboratory animals has not been clarified.The initial changes in quinolone-induced toxicity in the articular cartilage of juvenile animals are thought to occur in chondrocytes (6,8,19) or in the matrix (4). In our previous ex vivo study, ofloxacin (OFLX) inhibited the uptake of 3 H-thymidine and 35 SO 4 by the articular cartilage of juvenile rats 12 h after oral administration of a single large dose (20). Considering the inhibitory effect of the drug on topoisomerase II of mammalian cells, we then speculated that the initial target of OFLX in its induction of cartilage damage was the DNA synthesis of chondrocytes. Histopathological examinations by Stahlmann et al. (29) and Burkhardt et al. (6,8) after administration of OFLX and difloxacin revealed mitochondrial swelling and distention of the rough endopla...

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Cytofluorometric analysis of chondrotoxicity of fluoroquinolone antimicrobial agents

Cited by 69 publications

References 39 publications

Use of antimicrobials and risk of type 1 diabetes in a population-based mother–child cohort

Use of antimicrobials and risk of type 1 diabetes in a population-based mother–child cohort

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo

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