1: J Antimicrob Chemother. 2007 Feb;59(2):246-53. Epub 2007 Jan 12.

Combined effect of pH and concentration on the activities of gentamicin and
oxacillin against Staphylococcus aureus in pharmacodynamic models of
extracellular and intracellular infections.

Baudoux P, Bles N, Lemaire S, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F.

Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de
Louvain, Brussels, Belgium.

BACKGROUND: Staphylococcus aureus survives in acid media, including
phagolysosomes. Conflicting in vitro/in vivo data exist on its susceptibility to
antibiotics in such environments. METHODS: Oxacillin and gentamicin activities
against methicillin-susceptible S. aureus ATCC 25923 were compared
extracellularly (broth; different pH) and assessed intracellularly (THP-1
macrophages), using a pharmacological approach (antibiotic concentrations:
0.01-1000 x MIC). Antibiotic cellular contents were determined by
microbiological assay. RESULTS: MICs and MBCs increased 72-fold for gentamicin,
and decreased 8-fold for oxacillin between pH 7.4 and 5.0. Plots of log(10)
colony-forming unit changes at 24 h versus log(10) of antibiotic concentration
followed sigmoidal shapes, allowing calculation of EC(50) (relative potency) and
apparent E(max) (relative efficacy) in all conditions. In broth, the EC(50) of
gentamicin rose 316-fold and that of oxacillin decreased 15-fold with unchanged
apparent E(max) [-5 log (limit of detection)] between pH 7.4 and 5.
Intracellularly, EC(50)s were similar to those observed extracellularly at pH
7.4, but E(max) values were much lower (-1 log) for both antibiotics.
Calculations based on the assumed pH in phagolysosomes (5.4) and on local
accumulation of antibiotics (gentamicin, 23-fold; oxacillin, 0.05-fold) suggest
that the contrasting effects of acid pH on relative potencies of gentamicin and
oxacillin could be almost exactly compensated for by differences in
accumulation. CONCLUSIONS: The weak activity of gentamicin and oxacillin towards
intraphagocytic S. aureus compared with extracellular forms is not related to an
overall decrease of their relative potencies but to impaired efficacy,
suggesting the need for new approaches to improve the eradication of
intracellular S. aureus.

PMID: 17220162 [PubMed - indexed for MEDLINE]

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