Intra- and extracellular activity of dicloxacillin against Staphylococcus aureus in vivo and in vitro.
(2010) Antimicrobial Agents and Chemotherapy — Vol. 54, n° 6, p. 2391-2400 (2010)
Files
pdfdocument.pdf
Restricted Access - Adobe PDF
- 1.87 MB
Details
- Authors
- Abstract
- Antibiotic treatment of Staphylococcus aureus infections is often problematic due to slow response and recurrence. Intracellular persistence of the staphylococci offers a plausible explanation for the treatment difficulties because of impaired intracellular efficacy of the antibiotics. The intra- and extracellular time- and concentration-kill relationships in vitro was examined using THP-1 cells, and, in vivo, using a mouse peritonitis model. The in vivo model was further used to estimate the most predictive pharmacokinetic/pharmacodynamic (PK/PD) indicies (Cmax/MIC, AUC/MIC, or fT>MIC) for DCX intra- and extracellularly. Similar intracellular activity of DCX was in general reached regardless of the model used. Both showed (i) a relative maximal efficacy (Emax; 1 log CFU reduction) intracellular (ii) equal relative potency of DCX intra- and extracellularly, with MIC being a good indicator of the overall response in both situations. Discordant results, based on different timing, were obtained from the two models when measuring the extracellular activity of DCX, for which the in vitro model showed a considerable reduction of the inoculum (3 log CFU decrease after 24 h) whereas the extracellular CFU reduction achieved in vivo after 4 h did not exceed 1 log. Multiple dosing of DCX in vivo revealed increased extra- and intracellular efficacy (2.5 log and 2 log CFU reduction after 24 h, respectively) confirming, that DCX is a highly active anti-staphylococcal antibiotic. PK/PD analysis revealed that the fraction time during which the non protein-bound DCX concentration exceeds the MIC (fT>MIC) is the most predictive index for the infection outcome both intra- and extracellularly.
- Affiliations
Citations
Sandberg, A., Jensen, K. S., Tulkens, P. M., Baudoux, P., Van Bambeke, F., & Frimodt-Møller, N. (2010). Intra- and extracellular activity of dicloxacillin against Staphylococcus aureus in vivo and in vitro. Antimicrobial Agents and Chemotherapy, 54(6), 2391-2400. https://doi.org/10.1128/AAC.01400-09 (Original work published 2010)