1. Antimicrob Agents Chemother. 2010 Jun;54(6):2391-400. Epub 2010 Mar 22.

Intra- and extracellular activities of dicloxacillin against Staphylococcus
aureus In Vivo and In Vitro.

Sandberg A, Jensen KS, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Møller N.

National Center for Antimicrobials & Infection Control, Statens Serum Institut,
Copenhagen S DK-2300, Denmark. asa@ssi.dk

Antibiotic treatment of Staphylococcus aureus infections is often problematic due
to the slow response and recurrences. The intracellular persistence of the
staphylococci offers a plausible explanation for the treatment difficulties
because of the impaired intracellular efficacies of the antibiotics. The intra-
and extracellular time- and concentration-kill relationships were examined in
vitro with THP-1 cells and in vivo by use of a mouse peritonitis model. The in
vivo model was further used to estimate the most predictive
pharmacokinetic/pharmacodynamic (PK/PD) indices (the ratio of the maximum
concentration of drug in plasma/MIC, the ratio of the area under the
concentration-time curve/MIC, or the cumulative percentage of a 24-h period that 
the free [f] drug concentration exceeded the MIC under steady-state
pharmacokinetic conditions [fT(MIC)]) for dicloxacillin (DCX) intra- and
extracellularly. In general, DCX was found to have similar intracellular
activities, regardless of the model used. Both models showed (i) the relative
maximal efficacy (1-log-unit reduction in the numbers of CFU) of DCX
intracellularly and (ii) the equal relative potency of DCX intra- and
extracellularly, with the MIC being a good indicator of the overall response in
both situations. Discordant results, based on data obtained different times after
dosing, were obtained from the two models when the extracellular activity of DCX 
was measured, in which the in vitro model showed a considerable reduction in the 
number of CFU from that in the original inoculum (3-log-unit decrease in the
number of CFU after 24 h), whereas the extracellular CFU reduction achieved in
vivo after 4 h did not exceed 1 log unit. Multiple dosing of DCX in vivo revealed
increased extra- and intracellular efficacies (2.5 log and 2 log units of
reduction in the numbers of CFU after 24 h, respectively), confirming that DCX is
a highly active antistaphylococcal antibiotic. PK/PD analysis revealed that
fT(MIC) is the index that is the most predictive of the outcome of infection both
intra- and extracellularly.

PMID: 20308386 [PubMed - in process]