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] Related Links Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. [Antimicrob Agents Chemother. 2006] PMID:16495241 Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages. [Antimicrob Agents Chemother. 2003] PMID:12821480 Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. [J Antimicrob Chemother. 2006] PMID:17062609 Activities of LY333328 and vancomycin administered alone or in combination with gentamicin against three strains of vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacodynamic infection model. [Antimicrob Agents Chemother. 2000] PMID:11036011 Consistent rates of kill of Staphylococcus aureus by gentamicin over a 6-fold clinical concentration range in an in vitro pharmacodynamic model (IVPDM). [J Antimicrob Chemother. 2006] PMID:16735429