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Antimicrobial Agents and Chemotherapy, November 2008, p. 3994-4000, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00427-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effect of Protein Binding on the Pharmacological Activity of Highly Bound Antibiotics{triangledown}

Stephan Schmidt,1 Katharina Röck,1 Martina Sahre,1 Olaf Burkhardt,1,2 Martin Brunner,3 Maximilian T. Lobmeyer,4 and Hartmut Derendorf1*

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida,1 Department of Pulmonary Medicine, Medical School Hannover, Hannover, Germany,2 Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria,3 Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, Florida4

Received 31 March 2008/ Returned for modification 8 July 2008/ Accepted 30 August 2008

During antibiotic drug development, media are frequently spiked with either serum/plasma or protein supplements to evaluate the effect of protein binding. Usually, previously reported serum or plasma protein binding values are applied in the analysis. The aim of this study was to evaluate this approach by experimentally measuring free, unbound concentrations for antibiotics with reportedly high protein binding and their corresponding antimicrobial activities in media containing commonly used protein supplements. Free, unbound ceftriaxone and ertapenem concentrations were determined in bacterial growth medium with and without bovine/human serum albumin, as well as adult bovine serum and human plasma using in vitro microdialysis. The corresponding antimicrobial activity was determined in MIC and time-kill curve experiments using Escherichia coli ATCC 25922 and Streptococcus pneumoniae ATCC 6303 as test strains. A semimechanistic maximum effect model was simultaneously fitted to the data and respective EC50 (concentration at half-maximum effect) values compared. Protein binding differed significantly for ceftriaxone (P < 0.05) between human plasma (76.8 ± 11.0%) and commercially available bovine (20.2 ± 8.3%) or human serum albumin (56.9 ± 16.6%). Similar results were obtained for ertapenem (human plasma, 73.8 ± 11.6%; bovine serum albumin, 12.4 ± 4.8%; human serum albumin, 17.8 ± 11.5%). The MICs and EC50s of both strains were significantly increased (P < 0.05) for ceftriaxone when comparing human and bovine serum albumin, whereas the EC50s were not significantly different for ertapenem. Free, unbound antibiotic concentrations differed substantially between plasma and protein supplements and correlated well with antimicrobial efficacy. Therefore, free, active concentrations should be measured in the test system instead of correcting for literature protein binding values.

* Corresponding author. Mailing address: University of Florida, College of Pharmacy, Department of Pharmaceutics, P.O. Box 100494, Gainesville, FL 32610-0494. Phone: (352) 273-7856. Fax: (352) 392-3249. E-mail: hartmut{at}ufl.edu

{triangledown} Published ahead of print on 8 September 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3994-4000, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00427-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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