Bactericidal activities of TMC207, PNU-1004800, rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA), against intracellular <i>M. tuberculosis</i> in sealed whole blood cultures differing according to duration, air space, and addition of dihydroxy-vitamin D.

<p>Negative values indicate killing.</p><p>*Results are carried over from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030479#pone-0030479-g002" target="_blank">figure 2</a>.</p

Predicted whole blood bactericidal activity of TMC207 (J, bedaquiline) 400 mg QD and 200 mg TIW, and PNU-100480 (U, sutezolid) 600 mg BID, singly and together.

<p>Predicted whole blood bactericidal activity of TMC207 (J, bedaquiline) 400 mg QD and 200 mg TIW, and PNU-100480 (U, sutezolid) 600 mg BID, singly and together.</p

Process for calculating cumulative whole blood bactericidal activity (WBA) of drug combinations.

<p>Process for calculating cumulative whole blood bactericidal activity (WBA) of drug combinations.</p

Predicted cumulative whole blood bactericidal activity of single drugs and multi-drug combinations against <i>M. tuberculosis</i>, based on published pharmacokinetic data, and the concentration-activity relationships and drug-drug pharmacodynamic interactions in figure 2.

<p>Drugs were tested by direct adding drugs directly to whole blood cultures of healthy volunteers except for: * drugs were administered orally; ⁺ subjects were TB patients. U = PNU-100480 600 mg BID; J = TMC207; Pa = PA-824; H = isoniazid; R = rifampin; E = ethambutol; Z = pyrazinamide; L = levofloxacin. The combination of PNU-100480, SQ109, and TMC207 400 mg QD was the most active of those tested.</p

Effects of substituting regression analysis for point-to-point interpolation in calculating Δ log CFU from time to positivity (TTP) in mycobacterial growth indicator tubes (MGIT).

<p>The left panel indicates the accuracy of curve fitting (the relationship between observed and predicted values). The right panel compares the results of the two methods (regression vs. interpolation).</p

Distributions of minimal inhibitory concentrations (MICs) to sutezolid (PNU-100480) pre and post treatment (rows and columns, respectively), according to dosing schedule.

<p>Values in each cell indicate numbers of patients. Cells shaded red are those in which MIC values increased, whereas they decreased in those shaded blue. No change was apparent in MIC values of the metabolite (PNU-101603, not shown).</p

Bactericidal activity in sputum according to treatment arm as assessed by colony counts (left) and time to positivity in automated liquid culture (MGIT TTP, right).

<p>Lines indicate prediction and shading 90% confidence interval (CI) as determined by mixed effects model repeated measures analysis, using day as a categorical variable. The vertical axis of the right hand figure is inverted to facilitate visual comparison with CFU findings. At 14 days, the 90% CI of all treatments excluded zero.</p

Geometric mean pharmacokinetic parameters in patients of sutezolid and its major metabolite following dosing for 14 Days.

<p>CV = coefficient of variation.</p

Treatment-emergent ALT increases in sutezolid-treated subjects.

<p>Treatment-emergent ALT increases in sutezolid-treated subjects.</p

Plasma concentrations of sutezolid (pink) and its major metabolite (yellow) at steady state (day 13–14) in patients treated with sutezolid 600 mg BID (left) or 1200 mg QD (right).

<p>Solid lines indicate medians; shading indicates 90% CI. Lower and upper dotted lines indicate median pre-treatment MIC values for parent and metabolite, respectively.</p