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  • Title: Accumulation and activity of cethromycin (ABT-773) within human polymorphonuclear leucocytes.
    Author: García I, Pascual A, Ballesta S, del Castillo C, Perea EJ.
    Journal: J Antimicrob Chemother; 2003 Jul; 52(1):24-8. PubMed ID: 12805263.
    Abstract:
    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 degrees C and 37 degrees 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.
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