JAC Advance Access published online on June 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg290
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Microbiology,
School of Medicine, Seville
* Corresponding author. E-mail: igarcial{at}us.es.
Received 19 December 2002
; 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
Accumulation and activity of cethromycin (ABT-773)
within human polymorphonuclear leucocytes
2 Department of Microbiology,
School of Medicine, Seville; University
Hospital V. Macarena, Seville, Spain
3 University
Hospital V. Macarena, Seville, Spain
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