In the Staphylococcus aureus neutropenic murine thigh-infection model, the ratio of the free area under the 24-hour concentration-time curve to the minimum inhibitory concentration (fAUC/MIC) was ...found to be the pharmacodynamic index most closely linked to bacterial effect, with a ratio of approximately 50 producing a static effect. Further work was undertaken in neutropenic versus non-neutropenic animals. The presence of granulocytes increased the activity of tedizolid considerably, 25-fold on average, and maximal effect was achieved at an exposure equivalent to approximately 200 mg tedizolid phosphate per day in humans (dosing regimen used in phase 2 and 3 clinical trials). The fAUC/MIC was also found to be the pharmacodynamically linked variable in the S. aureus neutropenic murine pneumonia model; the fAUC/MIC ratio required for a static effect was approximately 20. Pharmacokinetic (PK) data demonstrate that tedizolid penetrates well into the epithelial lining fluid (ELF) of the lung. Data from the pneumonia infection model and ELF penetration PK study support exploring its use in pneumonia.
Since the advent of the modern era of antimicrobial chemotherapy in the 1930s, animal infection models have allowed for the in vivo evaluation of antimicrobial agents for the treatment of ...experimentally induced infection. Today, animal pharmacokinetic-pharmacodynamic (PK-PD) infection models serve as a cornerstone of the preclinical assessment process for antibacterial agents and dose and dosing interval selection, as decision support for setting in vitro susceptibility breakpoints, and, finally, for the evaluation of the meaning of in vitro resistance. Over the past 15 years, considerable PK-PD data have been derived from infected patients for many classes of antimicrobial agents. These data provide the opportunity to confirm knowledge gained from animal PK-PD infection models.
Background. The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, “CPK ...elevation”) in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Methods. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Results. Significant relationships between the minimum concentration of drug (Cmin) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. Cmin (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a Cmin ⩾24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in Cmin, evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated Cmin to be a significant predictor of time to a CPK elevation (P ⩽ .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a Cmin ⩾24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. Conclusions. This analysis demonstrated that a daptomycin Cmin ⩾24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067.
Preclinical animal models of infection are employed to develop new agents but also to screen among molecules to rank them. There are often major differences between human pharmacokinetic (PK) ...profiles and those developed by animal models of infection, and these may lead to substantial differences in efficacy relative to that seen in humans. Linezolid is a repurposed agent employed to great effect for therapy of
In this study, we used the hollow-fiber infection model (HFIM) to evaluate the impact of different pharmacokinetic profiles of mice and nonhuman primates (NHP) versus humans on bacterial cell kill as well as resistance suppression. We examined both plasma and epithelial lining fluid (ELF) profiles. We examined simulated exposures equivalent to 600 mg and 900 mg daily of linezolid in humans. For both plasma and ELF exposures, the murine PK profile provided estimates of effect that were biased low relative to human and NHP PK profiles. Mathematical modeling identified a linkage between minimum concentrations (
) and bacterial kill and peak concentrations (
) and resistance suppression, with the latter being supported by a prospective validation study. Finding new agents with novel mechanisms of action against
is difficult. It would be a tragedy to discard a new agent because of a biased estimate of effect in a preclinical animal system. The HFIM provides a system to benchmark evaluation of new compounds in preclinical animal model systems against human PK effects (species scale-up estimates of PK), to safeguard against unwarranted rejection of promising new agents.
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