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Acta Physiologica 2008; Volume 194, Supplement 668
Belgian Society for Fundamental and Clinical Physiology and Pharmacology, Autumn Meeting 2008
11/1/2008-11/30/2008
Université Catholique de Louvain, Louvain-en-Woluwé, Belgium
IN VITRO PHARMACODYNAMIC EVALUATION OF INTRACELLULAR ACTIVITY OF ANTIBIOTICS (ABS) ALONE OR IN COMBINATION AGAINST A SMALL COLONY VARIANT (SCV) OF STAPHYLOCOCCUS AUREUS
Abstract number: P-01
Nguyen1 H.A., Denis2 O., Vergison2 A., Tulkens1 P.M., Struelens M.J., Van Bambeke1 F.
1Universit Catholique de Louvain and
2Universit Libre de Bruxelles, Brussels, Belgium
Background:
SCVs show reduced AB susceptibility and persist intracellularly, which may cause therapeutic failures. The intracellular activities of OXA (oxacillin), FA (fusidic acid), CLI (clindamycin), GEN (gentamicin), RIF (rifampin), VAN (vancomycin), LNZ (linezolid), Q-D (quinupristin-dalfopristin), DAP (daptomycin), TGC (tigecycline), MXF (moxifloxacin), TLV (telavancin), and ORI (oritavancin), alone or in combination, were examined in THP-1 macrophages infected by a stable thymidine-dependent SCV in comparison with normal phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient.
Methods:
Intracellular activities were determined in THP-1 macrophages after 24 h or 72 h of exposure to ABs. Combinations were tested at fixed concentrations and then using the Fractional Maximal Effect method (FME).
Results:
At Cmax, ORI caused a 2 log CFU reduction at 24 h, RIF, MXF, and Q-D, a similar reduction at 72 h. All other ABs showed a static effect at 24 h and 1 log CFU reduction at 72 h. Dose-effect studies showed a bimodal curve with 2 successive plateaus at -0.4 and -3.1 log CFU for ORI; maximal effects of -1.1 to -1.7 log CFU for TGC, MXF, and RIF, and of <= - 0.6 log CFU for the other ABs. Addition of thymidine restored the SCV intracellular growth, but did not modify the AB activity except for Q-D. All drugs showed higher intracellular activity against normal or revertant phenotypes than against SCVs, except TGC and ORI. At Cstatic, all combinations with RIF or ORI proved more active (in particular OXA, GEN and MXF). At Cmax, all combinations with RIF were less active than RIF alone, while combinations of ORI with GEN, Q-D, or RIF were more active than ORI alone. Using the FME method, RIF and ORI were synergistic at all concentration ratios investigated, ORI and MXF were also synergistic but at large ORI concentrations only. RIF and MXF were additive.
Conclusion:
Intracellular SCV are poorly susceptible to most ABs, which may contribute to the difficulty of eradicating such infections. Our studies may help in selecting most active drugs or appropriate combinations to rationalize AB treatment of persistent infections involving SCVs.
To cite this abstract, please use the following information:
Acta Physiologica 2008; Volume 194, Supplement 668 :P-01