JAC Advance Access originally published online on January 12, 2007
Journal of Antimicrobial Chemotherapy 2007 59(2):246-253; doi:10.1093/jac/dkl489
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Combined effect of pH and concentration on the activities of gentamicin and oxacillin against Staphylococcus aureus in pharmacodynamic models of extracellular and intracellular infections
Unité de Pharmacologie cellulaire et moléculaire, Université catholique de Louvain, Brussels, Belgium
Received 8 July 2006; returned 1 September 2006; revised 19 September 2006; accepted 8 November 2006
* Corresponding author. Tel: +32-2-764-73-78; Fax: +32-2-764-73-73; E-mail: vanbambeke{at}facm.ucl.ac.be
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 log10 colony-forming unit changes at 24 h versus log10 of antibiotic concentration followed sigmoidal shapes, allowing calculation of EC50 (relative potency) and apparent Emax (relative efficacy) in all conditions. In broth, the EC50 of gentamicin rose 316-fold and that of oxacillin decreased 15-fold with unchanged apparent Emax [–5 log (limit of detection)] between pH 7.4 and 5. Intracellularly, EC50s were similar to those observed extracellularly at pH 7.4, but Emax 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.
Keywords: acid pH , ß-lactams , aminoglycosides , pharmacodynamics , antibiotic accumulation
Present address: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université libre de Bruxelles, Belgium.
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