1. Antimicrob Agents Chemother. 2012 Jul;56(7):3700-11. Epub 2012 May 7.

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.

Garcia LG, Lemaire S, Kahl BC, Becker K, Proctor RA, Denis O, Tulkens PM, Van
Bambeke F.

Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.

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.

PMID: 22564838  [PubMed - in process]