1: Clin Microbiol Infect. 2008 Aug;14(8):766-77.

Activities of antistaphylococcal antibiotics towards the extracellular and
intraphagocytic forms of Staphylococcus aureus isolates from a patient with
persistent bacteraemia and endocarditis.

Lemaire S, Kosowska-Shick K, Julian K, Tulkens PM, Van Bambeke F, Appelbaum PC.

Unité de Pharmacologie cellulaire et moléculaire, Université catholique de
Louvain, Bruxelles, Belgium.

Decreased susceptibility of Staphylococcus aureus to antistaphylococcal agents
may be associated with inability to eradicate intracellular forms, which could
explain therapeutic failures. This hypothesis was tested using clinical isolates 
obtained from a patient with persistent staphylococcal bacteraemia under therapy.
Four isogenic isolates (three from tissue, one from blood) with increased MICs
for vancomycin (1-4 mg/L) and for daptomycin (1-4 mg/L) were collected after an
initial 16-day treatment with vancomycin-rifampicin-gentamicin, followed by 13-20
days of treatment with daptomycin-rifampicin-gentamicin. Isolates were tested for
MICs and for: (i) vancomycin (BODIPY-FL-vancomycin) and daptomycin binding; (ii) 
cell wall turnover (loss of N-acetyl-d-[1-(14)C]glucosamine in 30 min after 1 h
of labelling); and (iii) Triton X-100-induced autolysis. Extracellular (broth)
and intracellular (THP-1 macrophages) activities of rifampicin, linezolid and
fusidic acid at C(max), and of vancomycin, daptomycin, quinupristin-dalfopristin 
and oritavancin over a wide range of extracellular concentrations (with
pharmacological modelling to determine E(max)), were measured at 24 h. Increases 
in vancomycin MICs correlated with increased drug binding, and decreased cell
wall turnover and detergent-induced autolysis. Increases in daptomycin MICs
correlated with decreased daptomycin binding. Intracellular activity was weak
(E(max) <1 log(10) CFU decrease) for vancomycin against all isolates, and for
daptomycin against isolates with MICs >1 mg/L. Among all antibiotics tested, only
quinupristin-dalfopristin and oritavancin provided close to bactericidal
intracellular activities (1.6-2.5 log(10) CFU decreases at C(max)). Determination
of the intracellular susceptibility of S. aureus, combined with improved methods 
of diagnosis, could be useful when dealing with persistent staphylococcal
infections and could improve therapy.

PMID: 18727801 [PubMed - in process]

Related Links

    In vitro activities of Daptomycin, Linezolid, and Quinupristin-Dalfopristin
against a challenge panel of Staphylococci and Enterococci, including
vancomycin-intermediate staphylococcus aureus and vancomycin-resistant
Enterococcus faecium. [Microb Drug Resist. 2003] PMID:15000746

    In vitro bactericidal activity of daptomycin against staphylococci. [J Antimicrob
Chemother. 2002] PMID:11864946

    Pharmacodynamic evaluation of the intracellular activities of antibiotics against
Staphylococcus aureus in a model of THP-1 macrophages. [Antimicrob Agents
Chemother. 2006] PMID:16495241

    Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA),
vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood
isolates from 2001-05. [J Antimicrob Chemother. 2007] PMID:17623693

    Comparative bactericidal activities of daptomycin, glycopeptides, linezolid and
tigecycline against blood isolates of Gram-positive bacteria in Taiwan. [Clin
Microbiol Infect. 2008] PMID:18076671