Sevillano Fernández, DavidAguilar, LorenzoAlou Cervera, LuisGiménez, María JoséGonzález, NataliaTorrico, MarthaCafini, FabioFenoll, AsunciónCoronel, PilarPrieto, JoséEleftherios Mylonakis2024-07-292024-07-292008-07-23Sevillano D, Aguilar L, Alou L, Giménez MJ, González N, Torrico M, Cafini F, Fenoll A, Coronel P, Prieto J. High protein binding and cidal activity against penicillin-resistant S. pneumoniae: a cefditoren in vitro pharmacodynamic simulation. PLoS One. 2008 Jul 23;3(7):e27171932-620310.1371/journal.pone.0002717https://hdl.handle.net/20.500.14352/107146Background: 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; microg/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 (fT > MIC), expressed as percentage of the dosing interval, were determined. Protein binding was 87.1%. Bactericidal activity (> or = 99.9% initial inocula reduction) was obtained against strains S1 and S2 at 24h (T > MIC = 77.6%, fT > MIC = 23.7%). With T > MIC of 61.6% (fT > 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 microg/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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.1371/journal.pone.0002717https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002717open access611.02Microbiología médica2414 Microbiología