Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant staphylococcus aureus infection

Abstract

The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

Fig 1

Mean oritavancin concentration-time profiles for single-dose infusion over 3 h as obtained by population PK modeling (○; predicted free drug levels from a single 1,200-mg dose based on estimated 85% protein binding) and as measured in the in vitro PK/PD model (●; n = 8 independent experiments; actual measured drug level in model).

Fig 2

Pharmacodynamics of simulated dosing regimens of a single dose of 1,200 mg oritavancin (●), once-daily dosing with 6 mg/kg daptomycin (□), and q12h dosing with 1,000 mg vancomycin (△) against MRSA NRS123 (A), MRSA ATCC 33591 (B), and MRSA-hVISA 1561603 (C) over 72 h. The inset in panel B depicts the pharmacodynamic activity of daptomycin against MRSA ATCC 33591 in replicate experiments (three of eight replicates from four independent experiments) in which changes in susceptibility to daptomycin occurred. No-drug growth controls (○) for each MRSA isolate were performed using the flow rates for oritavancin PK simulations to supply fresh medium over 24 h. The limit of detection (dashed line) of viable bacteria is 66.7 CFU/ml.