Abstract
Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.
Highlights
Omadacycline is a novel aminomethylcycline with activity against Grampositive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP)
As the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC/MIC ratio) is generally considered to be the PK-PD index most closely associated with efficacy for tetracyclines [22,23,24,25], the second objective was to determine the magnitude of the omadacycline AUC/MIC ratio associated with efficacy for a panel of H. influenzae isolates evaluated using a one-compartment in vitro infection model
The first was to evaluate the frequency of mutation of clinical H. influenzae isolates to omadacycline
Summary
Omadacycline is a novel aminomethylcycline with activity against Grampositive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. The median total-drug ELF AUC/ MIC ratios associated with net bacterial stasis and 1- and 2-log CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae. Given the importance of considering effect site drug exposures [26,27,28], which for patients with CABP is epithelial lining fluid (ELF), the studies described were carried out in the context of omadacycline total-drug ELF concentration-time profiles to characterize AUC/MIC ratio targets associated with efficacy
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