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

David Sevillano,Fabio Cafini,María-José Giménez,Luis Alou,Pilar Coronel,Lorenzo Aguilar,Martha Torrico,José Prieto,Natalia González,Asunción Fenoll,Eleftherios Mylonakis

doi:10.1371/journal.pone.0002717

Abstract

BackgroundAlthough protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics.Methodology/Principal FindingsActivity of cefditoren, a highly protein bound 3rd 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 (fT>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%, 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 µg/ml under protein binding conditions similar to those in humans.Conclusions/SignificanceThe 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.

Highlights

Antibiotics kill or inhibit the growth of bacteria by well known mechanisms of action
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
The dominant pharmacodynamic index determining effects of b-lactams against S. pneumoniae is the time that drug concentrations remains over the MIC, and determining the size of this pharmacodynamic index for predicting optimal antibacterial activity is critical and helps to determine dosing regimens, breakpoints, and relevant clinical resistance [16]

Summary

Introduction

Antibiotics kill or inhibit the growth of bacteria by well known mechanisms of action. While in vitro antibiotics interact directly with bacteria without interference, in vivo (whether in natural or experimental infection) antibiotic and bacteria interactions are more complex due to the presence of serum proteins acting as an interface. As gammaglobulins and complement enhance the antipneumococcal activity of b-lactams as 3rd generation cephalosporins [1,2], others as albumin produce limitations in antibacterial activity in highly protein bound agents. It is generally accepted that only the unbound fraction of the antibiotic is active in vitro (and presumably in vivo), the quick reversibility of the protein drug binding indicates that the presumed limitations of antimicrobial activity can be far from absolute, for highly protein bound antibiotics [3]. Protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics

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