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Background  Although protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics.    Methodology/Principal Findings  Activity of cefditoren, a highly protein bound 3 rd  generation cephalosporin, over 24h after an oral 400 mg cefditoren-pivoxil bid regimen was studied against six  S. pneumoniae  strains (penicillin/cefditoren MICs; µg/ml): S1 (0.12/0.25), S2 (0.25/0.25), S3 and S4 (0.5/0.5), S5 (1/0.5) and S6 (4/0.5). A computerized pharmacodynamic simulation with media consisting in 75% human serum and 25% broth (mean albumin concentrations = 4.85±0.12 g/dL) was performed. Protein binding was measured. The cumulative percentage of a 24h-period that drug concentrations exceeded the MIC for total (T>MIC) and unbound concentrations ( f T>MIC), expressed as percentage of the dosing interval, were determined. Protein binding was 87.1%. Bactericidal activity (≥99.9% initial inocula reduction) was obtained against strains S1 and S2 at 24h (T>MIC = 77.6%,  f T>MIC = 23.7%). With T>MIC of 61.6% ( f T>MIC = 1.7%), reductions against S3 and S4 ranged from 90% to 97% at 12h and 24h; against S5, reduction was 45.1% at 12h and up to 85.0% at 24h; and against S6, reduction was 91.8% at 12h, but due to regrowth of 52.9% at 24h. Cefditoren physiological concentrations exerted antibacterial activity against strains exhibiting MICs of 0.25 and 0.5 µg/ml under protein binding conditions similar to those in humans.    Conclusions/Significance  The results of this study suggest that, from the pharmacodynamic perspective, the presence of physiological albumin concentrations may not preclude antipneumococcal activity of highly bound cephalosporins as cefditoren.

High Protein Binding and Cidal Activity against Penicillin-Resistant S. pneumoniae: A Cefditoren In Vitro Pharmacodynamic Simulation