title: Pharmacodynamic evaluation of the activity of antibiotics against hemin- and menadione-dependent small-colony variants of Staphylococcus aureus in models of extracellular (broth) and intracellular (THP-1 monocytes) infections.
abstract: Staphylococcus aureus small-colony variants (SCVs) persist intracellularly, which may contribute to persistence/recurrence of infections and antibiotic failure. We have studied the intracellular fate of menD and hemB mutants (corresponding to menadione- and hemin-dependent SCVs, respectively) of the COL methicillin-resistant S. aureus (MRSA) strain and the antibiotic pharmacodynamic profile against extracellular (broth) and intracellular (human THP-1 monocytes) bacteria. Compared to the parental strain, SCVs showed slower extracellular growth (restored upon medium supplementation with menadione or hemin), reduced phagocytosis, and, for the menD SCV, lower intracellular counts at 24 h postinfection. Against extracellular bacteria, daptomycin, gentamicin, rifampin, moxifloxacin, and oritavancin showed similar profiles of activity against all strains, with a static effect obtained at concentrations close to their MICs and complete eradication as maximal effect. In contrast, vancomycin was not bactericidal against SCVs. Against intracellular bacteria, concentration-effect curves fitted sigmoidal regressions for vancomycin, daptomycin, gentamicin, and rifampin (with maximal effects lower than a 2-log decrease in CFU) but biphasic regressions (with a maximal effect greater than a 3-log decrease in CFU) for moxifloxacin and oritavancin, suggesting a dual mode of action against intracellular bacteria. For all antibiotics, these curves were indistinguishable between the strains investigated, except for the menD mutant, which systematically showed a lower amplitude of the concentration-effect response, with markedly reduced minimal efficacy (due to slower growth) but no change in maximal efficacy. The data therefore show that the maximal efficacies of antibiotics are similar against normal-phenotype and menadione- and hemin-dependent strains despite their different intracellular fates, with oritavancin, and to some extent moxifloxacin, being the most effective.
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: L G
authors.initials: LG
authors.lastname: Garcia
authors.forename: S
authors.initials: S
authors.lastname: Lemaire
authors.forename: B C
authors.initials: BC
authors.lastname: Kahl
authors.forename: K
authors.initials: K
authors.lastname: Becker
authors.forename: R A
authors.initials: RA
authors.lastname: Proctor
authors.forename: O
authors.initials: O
authors.lastname: Denis
authors.forename: P M
authors.initials: PM
authors.lastname: Tulkens
authors.forename: F
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology; D005839:Gentamicins / Q000493:pharmacokinetics / Q000494:pharmacology; D006020:Glycopeptides / Q000493:pharmacokinetics / Q000494:pharmacology; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000382:microbiology*; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000031:analogs & derivatives; D024483:Vitamin K 3 / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D014640:Vancomycin; D024483:Vitamin K 3; D006427:Hemin; D017576:Daptomycin; C100708:oritavancin; D012293:Rifampin