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Antimicrobial Agents and Chemotherapy, January 2007, p. 54-63, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00729-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines{triangledown}

N. Duewelhenke,1* O. Krut,2 and P. Eysel1

Department of Orthopedic Surgery, Cologne University Hospitals, Cologne, Germany,1 Institute for Medical Microbiology, Immunology, and Hygiene, Cologne University Hospitals, Cologne, Germany2

Received 8 June 2005/ Returned for modification 25 October 2005/ Accepted 22 October 2006

Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 µg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 µg/ml for macrolides, clindamycin, and rifampin, 60 to 80 µg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 µg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.

* Corresponding author. Mailing address: Klinik und Poliklinik für Orthopädie, Universitätsklinikum Köln, Joseph-Stelzmann-Str. 24, 50931 Köln, Germany. Phone: (49) 0221-478-86535. Fax: (49) 0221-478-86536. E-mail: Nicole.Duewelhenke{at}uk-koeln.de.

{triangledown} Published ahead of print on 6 November 2006.

Antimicrobial Agents and Chemotherapy, January 2007, p. 54-63, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00729-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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