Ciprofloxacin Inhibition of Experimental Fracture-Healing*

Background: Fluoroquinolones, such as ciprofloxacin, have an adverse effect on growing cartilage and endochondral ossification in children. This study was carried out to determine whether ciprofloxacin also has an adverse effect on the healing of experimental fractures. Methods: Sixty male 300-gram Wistar rats were divided equally into three groups, which received ciprofloxacin, cefazolin, or no treatment for three weeks, beginning seven days after production of a closed, nondisplaced, bilateral femoral fracture. The serum concentrations of the ciprofloxacin and the cefazolin were 2.4 and 146 micrograms per milliliter, respectively. Radiographic, histological, and biomechanical studies were used to evaluate fracture-healing. Results: Radiographs revealed significantly more advanced healing of the control fractures compared with the fractures in the ciprofloxacin-treated group (average stage, 2.1 compared with 1.5, p = 0.01). The cefazolin-treated group was not different from the controls with respect to radiographic healing (average stage, 1.8 compared with 2.1, p = 0.18). Torsional strength-testing of fracture callus exposed to ciprofloxacin revealed a 16 percent decrease in strength compared with the controls (284 compared with 338 newton-millimeters, p = 0.04) and a 49 percent decrease in stiffness (twenty compared with thirty-nine newton-millimeters per degree, p = 0.001). The biomechanical strength in the cefazolin-treated group was not different from that of the controls. Fracture calluses in the animals treated with ciprofloxacin showed abnormalities in cartilage morphology and endochondral bone formation and a significant decrease in the number of chondrocytes compared with the controls (0.77 x 104 compared with 1.3 x 104 cells per square millimeter, p = 0.004). Conclusions: These data suggest that experimental fractures exposed to therapeutic concentrations of ciprofloxacin in serum demonstrate diminished healing during the early stages of fracture repair. The administration of ciprofloxacin during early fracture repair may compromise the clinical course of fracture-healing.

[1]  C. Steiner,et al.  Effects of ciprofloxacin and ofloxacin on adult human cartilage in vitro , 1997, Antimicrobial agents and chemotherapy.

[2]  G. Schlüter,et al.  Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver. , 1999, Mutation research.

[3]  R. Janknegt Fluoroquinolones. Adverse reactions during clinical trials and postmarketing surveillance. , 1989, Pharmaceutisch weekblad. Scientific edition.

[4]  S. Takada,et al.  Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo , 1995, Antimicrobial agents and chemotherapy.

[5]  V. Weissig,et al.  Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells. , 1996, Molecular pharmacology.

[6]  Michiyuki Kato,et al.  Morphological investigation of cavity formation in articular cartilage induced by ofloxacin in rats. , 1988, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[7]  J. Washington Initial Processing for Cultures of Specimens , 1981 .

[8]  R. Pelker,et al.  The influence of ibuprofen on fracture repair: Biomechanical, biochemical, histologic, and histomorphometric parameters in rats , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[9]  K. Heiple,et al.  Bone grafting: Role of histocompatibility in transplantation , 1985, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[10]  C. K. Pearson,et al.  Effect of drugs on deoxyribonucleic acid synthesis in isolated mammalian cell nuclei. Comparison with partially purified deoxyribonucleic acid polymerases. , 1979, Biochemical Journal.

[11]  D. Hungerford,et al.  The effects of ciprofloxacin on human chondrocytes in cell culture , 1996, Infection.

[12]  W. Carlton,et al.  Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin , 1992, Toxicologic pathology.

[13]  M M Panjabi,et al.  The four biomechanical stages of fracture repair. , 1977, The Journal of bone and joint surgery. American volume.

[14]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  E. McGuire,et al.  Juvenile canine drug-induced arthropathy: clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids. , 1979, Toxicology and applied pharmacology.

[16]  A. Spurr A low-viscosity epoxy resin embedding medium for electron microscopy. , 1969, Journal of ultrastructure research.

[17]  F. Castora,et al.  The effect of bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria. , 1983, Biochimica et biophysica acta.

[18]  D. Branstetter,et al.  Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin. , 1995, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[19]  S. Takada,et al.  Comparison of lesions induced by intra-articular injections of quinolones and compounds damaging cartilage components in rat femoral condyles. , 1994, Journal of toxicology and environmental health.

[20]  M. Salam,et al.  Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission , 1995, The Pediatric infectious disease journal.

[21]  K Banovac,et al.  Effect of Nonsteroidal Antiinflammatory Drugs on Fracture Healing: A Laboratory Study in Rats , 1995, Journal of orthopaedic trauma.

[22]  T. Gootz,et al.  Use of in vitro topoisomerase II assays for studying quinolone antibacterial agents , 1989, Antimicrobial Agents and Chemotherapy.

[23]  A. Harvey,et al.  Passive Role of Articular Chondrocytes in Quinolone-Induced Arthropathy in Guinea Pigs , 1990, Toxicologic pathology.

[24]  T. Einhorn,et al.  Production of a standard closed fracture in laboratory animal bone , 1984, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  Roger L. Black,et al.  Goodman and Gilman's The Pharmacological Basis of Therapeutics , 1991 .

[26]  J. Turek,et al.  Ultrastructural Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin, a Fluoroquinolone , 1992, Veterinary pathology.