Abstract
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.
Highlights
Significant controversy revolves around the impact of protein binding on antimicrobial activity, for drugs which display a similar affinity to their bacterial target and serum proteins [1, 2]
Based on the discrepancies between daptomycin’s activity and the free fraction of drug, we propose that an ‘active fraction’ of daptomycin may exist that differs from the ‘free-drug fraction’ calculated from reported protein binding values
Questions are often raised regarding the pharmacodynamics of daptomycin in the presence of protein, owing to the agent’s high protein binding value (90 to 93%, www.cubicin.com)
Summary
Significant controversy revolves around the impact of protein binding on antimicrobial activity, for drugs which display a similar affinity to their bacterial target and serum proteins [1, 2]. There have been reports of discrepancies between the observed increases in MIC in the presence of proteins (such as albumin), and the difference between total and unbound antibiotic concentrations determined by ultrafiltration [2, 3]. The novel mechanism of action utilized by daptomycin makes the agent an attractive option for the treatment of infections caused by Gram-positive species such as Staphylococcus aureus, strains with decreased susceptibility to vancomycin [4]. Qualitative in vitro reports have suggested that the presence of protein only impacts the rate of killing, and not the overall activity expressed by daptomycin [2, 6,7,8,9]
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