In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure.
Antimicrob Agents Chemother. 2015 Nov 30;
Authors: Hamada Y, Kuti JL, Nicolau DP
Vancomycin is considered a first line antibiotic for complicated skin and skin structure infections (cSSSI) due to the risk of methicillin-resistant Staphylococcus aureus (MRSA). Tissue exposure of vancomycin can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitro pharmacodynamic model was used to simulate three tissue exposures of vancomycin 1g q12h, based on the median (50(th)), 25(th) and 10(th) percentile tissue AUC observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates [2 MRSA (vancomycin MIC: 1 and 2μg/ml, 2 MSSA (MIC: 1 and 2μg/ml)] were evaluated. Experiments were performed over 72h in duplicate. Time-kill curves were constructed and the area under the bacterial killing and regrowth curve (AUBC) from the final 24h dosing interval (48-72h) was calculated. Reductions in 72h CFU/ml and AUBC48-72 were compared between exposures. Target vancomycin tissue exposures for the 50(th) (AUC0-12: 102.0±9.1μg*h/ml), 25(th) (AUC0-12: 44.3±1.8μg*h/ml), and 10(th) (AUC0-12: 25.3 ± 3.1μg*h/ml) percentile were obtained in all studies. No differences in 72h CFU or AUBC were observed between exposures when all isolates were analyzed together. However, for the two MRSA isolates, the 10(th) % exposure achieved reduced 72h CFU/ml (-1.4 ± 0.4 log10CFU/ml, p=0.007) and greater AUBC48-72 (97.1 ± 20.0 log10CFU*h/ml, p=0.011) compared with higher exposures. The majority of tissue exposures achieved by a vancomycin 1g q12h dosing regimen achieved substantial killing against MSSA and MRSA; however, the lowest exposures observed in a minority of the population may explain poor vancomycin response.
PMID: 26621619 [PubMed - as supplied by publisher]