Humanized tissue pharmacodynamics of cefazolin against commonly isolated pathogens in skin and skin structure infections

The objective of this study was to assess the efficacy of humanized cefazolin tissue concentrations against methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae in an in vitro pharmacodynamic model. Nine clinical isolates [five MSSA (cefazolin MIC range 0.5-2.0 mg/L), two Escherichia coli (cefazolin MICs 1.0 and 2.0 mg/L) and two Klebsiella pneumoniae (cefazolin MICs of 1.0 and 2.0 mg/L)] were evaluated with a starting inoculum (0 h) of 10(6) cfu/mL. Time-kill curves were built and the area under the bacterial killing and regrowth curve (AUBC) was calculated. The starting inoculum had a mean ± SD of 6.3 ± 0.28 log10 cfu/mL. Cefazolin human simulated targets for peak, trough and half-life were 13.0 mg/L, 2.6 mg/L and 2.6 h, respectively. Control isolates grew to 8.5 ± 0.2 log10 cfu/mL. Against MSSA, cefazolin achieved a reduction from 0 h of -1.18 ± 0.67 and -3.58 ± 1.24 log10 cfu/mL, at 4 and 24 h, respectively. Cefazolin achieved a reduction in bacterial density of -3.45 ± 0.35 and -2.68 ± 0.99 log10 cfu/mL at 4 and 24 h, respectively, when tested against Enterobacteriaceae. No significant difference was observed when comparing AUBC based on MIC values. The rate of initial bacterial reduction of Enterobacteriaceae was rapid, with a decrease of >3 log10 cfu/mL by 4 h, while MSSA exhibited a gradual reduction in bacterial density over one dosing interval. The observed antibacterial effects of cefazolin support its continued utility against susceptible S. aureus, E. coli and K. pneumoniae in skin and skin structure infections.