JAC Advance Access originally published online on June 12, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 24-28
© 2003 The British Society for Antimicrobial Chemotherapy
Accumulation and activity of cethromycin (ABT-773) within human polymorphonuclear leucocytes
1 Department of Microbiology, School of Medicine, Seville; 2 University Hospital V. Macarena, Seville, Spain
Received 19 December 2002; returned 19 February 2003; revised 25 March 2003; accepted 15 April 2003
Objectives: To evaluate the penetration of ketolide cethromycin (ABT-773) into human polymorphonuclear leucocytes (PMNs) and its intracellular activity.
Methods: The uptake of radiolabelled cethromycin by PMNs was determined by a velocity gradient centrifugation technique. The activity of cethromycin against intracellular Staphylococcus aureus ATCC 25923 in PMNs was also evaluated.
Results: The cellular to extracellular concentration (C/E) ratio for cethromycin was >200 at an extracellular concentration of 2 mg/L. The uptake of cethromycin into PMNs was rapid and saturable. Cethromycin was slowly released from the loaded PMNs (cell associated drug>50% after 2 h of incubation). Intracellular penetration was significantly affected by the environmental temperature (C/E ratio at 4°C and 37°C: 13 ± 6 and 226 ± 31, respectively; P < 0.05), by cell viability (C/E ratio for dead and viable cells: 100 ± 38 and 226 ± 31, respectively; P < 0.05), by pH (C/E ratio was significantly increased at basic pH) and by the metabolic inhibitors 2,4-dinitrophenol and carbonyl cyanide m-chlorophenylhydrazone. The intracellular accumulation of cethromycin also decreased significantly when cells were activated with phorbol myristate acetate or opsonized zymosan. These data indicate that a potentially active mechanism could be involved in the uptake of cethromycin by PMNs. At high extracellular concentrations of 5 and 10 mg/L, cethromycin showed significant intracellular activity against S. aureus.
Conclusions: Cethromycin achieves high intracellular concentrations within human PMNs, remaining active intracellularly.
Keywords: phagocytes, intracellular concentration, intracellular activity, ketolides
* Correspondence address. Department of Microbiology, School of Medicine, Avda. Sánchez Pizjuán s/n, Apdo 914, 41080-Seville, Spain. Tel: +34-5-4552862; Fax: +34-5-4377413; E-mail: igarcial{at}us.es
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