JAC Advance Access published online on September 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg431
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Unité de Pharmacologie
Cellulaire et Moléculaire, UCL 73-70, avenue E.
Mounier 73, B-1200 Brussels
* Corresponding author. E-mail: hugues.chanteux{at}facm.ucl.ac.be.
Received 1 May 2003
; revised 23 July 2003
; accepted 28 July 2003
Aims: To determine the intracellular
accumulation in a macrophage cell line of ampicillin and ampicillin esters,
and to measure their activity against intracellular Listeria
monocytogenes. Methods: Quantitative evaluation of the activity
of ampicillin, phthalimidomethylampicillin (PIMA) or pivaloyloxymethylampicillin
(PIVA) against intracellular L. monocytogenes,
and direct measurement of cellular ampicillin concentration in J774
macrophages. Results: Ampicillin, PIMA and PIVA caused a
0.5 log decrease in cell-associated cfu within 5 h when used at an
extracellular concentration of 3.6 µM [10 x MIC of ampicillin (1.25 mg/L); 1.83
mg/L for PIMA and 1.67 mg/L for PIVA]. Addition of Conclusions: This is the first demonstration
that PIVA (a prodrug of ampicillin) can be used to promote ampicillin
cellular accumulation and, thereby to increase ampicillin intracellular
activity. PIVA could be useful for control of the intracellular
multiplication of L. monocytogenes.
Keywords: prodrugs, Intracellular accumulation and activity of ampicillin
used as free
drug and as its phthalimidomethyl or pivaloyloxymethyl ester (pivampicillin)
against Listeria monocytogenes in J774 macrophages
2 Unité de Chimie
Pharmaceutique et de Radiopharmacie, Université Catholique
de Louvain, B-1200 Brussels, Belgium
-lactamase in the extracellular milieu
abolished the activity of ampicillin and of PIMA but not that of
PIVA. At low extracellular concentrations [0.5 x MIC
ampicillin (62.5 µg/L); equimolar concentrations
for PIMA (91.5 µg/L) and PIVA (83.5 µg/L)], ampicillin and PIMA
lost all activity (compared with controls), but PIVA remained as
active as at the higher concentration. Incubation of cells with
PIVA at the low concentration (83.5 µg/L)
for 20 h caused a 2 log reduction of cfu if the medium was changed
every 5 h (to compensate for the degradation of extracellular PIVA).
Incubation of cells with PIVA allowed for a marked (four- to 25-fold)
cell accumulation of ampicillin, whereas no ampicillin accumulation
was seen for cells incubated with ampicillin or with PIMA.-lactams, -lactamases, infections
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