1: J Antimicrob Chemother. 2003 Oct;52(4):610-5. Epub 2003 Sep 12. 

Intracellular accumulation and activity of ampicillin used as free drug and as
its phthalimidomethyl or pivaloyloxymethyl ester (pivampicillin) against
Listeria monocytogenes in J774 macrophages.

Chanteux H, Mingeot-Leclercq MP, Sonveaux E, Van Bambeke F, Tulkens PM.

Unite de Pharmacologie Cellulaire et Moleculaire, UCL 73-70, avenue E Mounier
73, B-1200 Brussels, Belgium. hugues.chanteux@facm.ucl.ac.be

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 microM [10 x
MIC of ampicillin (1.25 mg/L); 1.83 mg/L for PIMA and 1.67 mg/L for PIVA].
Addition of beta-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 microg/L); equimolar concentrations for PIMA (91.5
microg/L) and PIVA (83.5 microg/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
microg/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. 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.

PMID: 12972457 [PubMed - in process]