Defining the Active Fraction of Daptomycin against Methicillin-Resistant Staphylococcus aureus (MRSA) Using a Pharmacokinetic and Pharmacodynamic Approach.
Our objective was to study the pharmacodynamics of daptomycin in the presence of varying concentrations of human serum (HS) in vitro to quantify the fraction of daptomycin that is 'active'. Time kill experiments were performed with daptomycin (0 to 256 mg/L) against two MRSA strains at log-phase growth, in the presence of HS (0%, 10%, 30%, 50%, 70%) combined with Mueller-Hinton broth. Daptomycin ≥ 2 mg/L achieved 99.9% kill within 8 h at all HS concentrations; early killing activity was slightly attenuated at higher HS concentrations. After 1 h, bacterial reduction of USA300 upon exposure to daptomycin 4 mg/L ranged from -3.1 to -0.5 log10CFU/mL in the presence of 0% to 70% HS, respectively. Bactericidal activity was achieved against both strains at daptomycin ≥ 4 mg/L for all fractions of HS exposure. A mechanism-based mathematical model (MBM) was developed to estimate the active daptomycin fraction at each %HS, comprising 3 bacterial subpopulations differing in daptomycin susceptibility. Time-kill data were fit with this MBM with excellent precision (r2 >0.95). The active fraction of daptomycin was estimated to range from 34.6% to 25.2% at HS fractions of 10% to 70%, respectively. Despite the reported low unbound fraction of daptomycin, the impact of protein binding on the activity of daptomycin was modest. The active fraction approach can be utilized to design in vitro experiments and to optimize therapeutic regimens of daptomycin in humans.
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.
Samira M
SM
Garonzik
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.|New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, NY, United States of America.
Justin R
JR
Lenhard
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.|Department of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States of America.
Alan
A
Forrest
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.|New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, NY, United States of America.
Patricia N
PN
Holden
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.|Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United States of America.
Jϋrgen B
JB
Bulitta
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, Buffalo, NY, United States of America.|New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, NY, United States of America.
Brian T
BT
Tsuji
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D017576:Daptomycin / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D044967:Serum / Q000187:drug effects / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D012709:Serum Albumin; D017576:Daptomycin