In Vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model

Abstract

Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R² = 0.74). The plasma 24-h static dose AUC/MIC values were 16 to 20 (24-h ELF AUC/MIC of 14 to 18). A 1-log₁₀ kill was achieved at 24-h plasma AUC/MIC values of 6.1 to 180 (24-h ELF AUC/MIC values 6.0 to 200). A 2-log₁₀ kill was achieved at 24-h plasma AUC/MIC values of 19 to 56 (24-h ELF AUC/MIC of 17 to 47). The targets identified in this study in combination with in vitro potency and favorable human pharmacokinetics make omadacycline an attractive candidate for further development and study in patients with CABP.

Keywords: omadacycline; pharmacodynamics; pneumonia.

FIG 1

Plasma concentrations of omadacycline in mice following single subcutaneous doses. Samples were obtained at seven time points over 24 h. Each symbol represents the mean and standard deviation from three mice. C_max, peak concentration; t_1/2, beta elimination half-life. The AUC is from 0 to infinity.

FIG 2

ELF concentrations of omadacycline in mice following single subcutaneous doses. Samples were obtained at seven time points over 24 h. ELF concentrations were determined using urea concentration correction methods. Each symbol represents the mean and standard deviation from three mice. C_max, peak concentration; t_1/2, beta elimination half-life. The AUC is from 0 to infinity.

FIG 3

In vivo dose-response curves for omadacycline against select S. pneumoniae strains using a neutropenic murine pneumonia model. Each symbol represents the mean and standard deviation from three mice. Five total drug dose levels were administered by the subcutaneous route every 12 h. The burden of organisms was measured at the start and end of therapy. The study period was 24 h. The horizontal dashed-line at 0 represents the burden of organisms in the lungs of mice at the start of therapy. Data points below the line represent cidal activity and points above the line represent net growth.

FIG 4

In vivo dose effect of omadacycline against select S. pneumoniae strains using a neutropenic murine pneumonia model. Each symbol represents the mean result from three mice. Five total drug dose levels were fractionated into an every-12-h regimen. The omadacycline exposure is expressed as the plasma 24 h AUC/MIC. The burden of organisms was measured at the start and end of therapy. The study period was 24 h. The horizontal dashed line at 0 represents the burden of organisms in the lungs of mice at the start of therapy. Data points below the line represent cidal activity and points above the line represent net growth. The R² represents the coefficient of determination. The line drawn through the data points is the best-fit line based upon the sigmoid E_max formula.

FIG 5

In vivo dose effect of omadacycline against select S. pneumoniae strains using a neutropenic murine pneumonia model. Each symbol represents the mean result from three mice. Five total drug dose levels were fractionated into an every-12-h regimen. The omadacycline exposure is expressed as the ELF 24-h AUC/MIC. The burden of organisms was measured at the start and end of therapy. The study period was 24 h. The horizontal dashed line at 0 represents the burden of organisms in the lungs of mice at the start of therapy. Data points below the line represent cidal activity, and points above the line represent net growth. The R² represents the coefficient of determination. The line drawn through the data points is the best-fit line based upon the sigmoid E_max formula.