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Staphylococcus aureus small colony variants (SCVs) are slow-growing morphological variants associated with persistent infections. While vancomycin activity has been shown to be attenuated against SCVs of S. aureus, few data exist regarding daptomycin. The objective was to evaluate the pharmacodynamics of daptomycin against defined S. aureus mutants displaying the SCV phenotype.Two S. aureus hemB mutants (Ia48 and III33) displaying the SCV phenotype and their parental strains (COL and Newman) were evaluated. Time-kill experiments were performed using a starting inoculum of 10(6) cfu/mL at 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32 and 64 times the MIC. Samples were obtained at 0, 1, 2, 4, 6, 8 and 24 h, plated and incubated to determine colony counts. A Hill-type pharmacodynamic mathematical model was fitted to the data to characterize the effect.Bactericidal activity for daptomycin was achieved and occurred in a concentration-dependent manner against both hemB mutants and their parental strains. Against strains with normal phenotype, bactericidal activity was achieved rapidly, within 2 h at concentrationsor =16 times the MIC, while against SCVs, bactericidal activity was achieved within 6 h at concentrationsor =16 times the MIC. Against both hemB mutants, daptomycin maintained bactericidal activity at 24 h, with similar profiles of killing activity when compared with their parental strains.Daptomycin achieved bactericidal activity against S. aureus hemB mutants and parenteral isolates. Daptomycin represents a potential therapeutic option for infections caused by S. aureus strains displaying the SCV phenotype and additional studies are warranted.