In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure.

Abstract

Vancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus (MRSA). The vancomycin exposure of tissue 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 exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 μg/ml] and two of methicillin-susceptible S. aureus [MSSA] [MIC, 1 and 2 μg/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC48-72) was calculated. Reductions in the 72-h number of CFU/ml and AUBC48-72 at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC0-12, 102.0 ± 9.1 μg · h/ml), 25th (AUC0-12, 44.3 ± 1.8 μg · h/ml), and 10th (AUC0-12, 25.3 ± 3.1 μg · h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72-h number of CFU/ml (-1.4 ± 0.4 log10 CFU/ml, P = 0.007) and a greater AUBC48-72 (97.1 ± 20.0 log10 CFU · h/ml, P = 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response.