Effects of human albumin and serum on the in vitro bactericidal activity of cefditoren against penicillin-resistant Streptococcus pneumoniae

Objectives Attempts to interpret antibiotic pharmacodynamics using reported protein binding may underestimate true activity. To elucidate this issue we examined bacterial killing kinetics at cefditoren concentrations equal to Cmax in the presence of 90% human serum or albumin at physiological concentrations. Methods Killing curves (final inocula of approximately 107 cfu/mL, cefditoren concentration of 4.2 mg/L) were performed against Streptococcus pneumoniae strains exhibiting cefditoren MICs (mg/L) of 0.12 (strain 1), 0.25 (strain 2) and 0.5 (strain 3) in different media: (i) Cmax-MH, Mueller-Hinton broth plus 5% lysed horse blood (MH), (ii) Cmax-HS, MH broth with a final human serum concentration of 90%; and (iii) Cmax-HAlb, MH broth with 4 g/dL human albumin. Killing curves were also performed with a final cefditoren concentration of 0.5 mg/L (similar to free-drug Cmax considering 88% protein binding) in MH broth (12% Cmax). Results No significant differences were found between the different media or concentrations with strain 1 (log10 reductions ≥4 at 24 h). Against strains 2 and 3, we observed significantly higher initial inocula decreases at 24 h for Cmax-HS as compared with Cmax-HAlb or 12% Cmax. Bactericidal activity (≥3 log10 reduction) was obtained at 24 h against the three strains only with Cmax-HS and Cmax-MH. Conclusions The presence of physiological concentrations of human albumin, but not 90% human serum, limited bactericidal activity as did the use of concentrations similar to free-drug Cmax, suggesting that extrapolation of active drug from total drug by using the protein binding rate is not an accurate method to study antibacterial activity.