Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis

Rationale: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. METHODS: Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. RESULTS: All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. CONCLUSIONS: The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted. Trial Registration ClinicalTrials.gov NCT0122564

Rapid Evaluation in Whole Blood Culture of Regimens for XDR-TB Containing PNU-100480 (Sutezolid), TMC207, PA-824, SQ109, and Pyrazinamide

There presently is no rapid method to assess the bactericidal activity of new regimens for tuberculosis. This study examined PNU-100480, TMC207, PA-824, SQ109, and pyrazinamide, singly and in various combinations, against intracellular M. tuberculosis, using whole blood culture (WBA). The addition of 1,25-dihydroxy vitamin D facilitated detection of the activity of TMC207 in the 3-day cultures. Pyrazinamide failed to show significant activity against a PZA-resistant strain (M. bovis BCG), and was not further considered. Low, mid, and high therapeutic concentrations of each remaining drug were tested individually and in a paired checkerboard fashion. Observed bactericidal activity was compared to that predicted by the sum of the effects of individual drugs. Combinations of PNU-100480, TMC207, and SQ109 were fully additive, whereas those including PA-824 were less than additive or antagonistic. The cumulative activities of 2, 3, and 4 drug combinations were predicted based on the observed concentration-activity relationship, published pharmacokinetic data, and, for PNU-100480, published WBA data after oral dosing. The most active regimens, including PNU-100480, TMC207, and SQ109, were predicted to have cumulative activity comparable to standard TB therapy. Further testing of regimens including these compounds is warranted. Measurement of whole blood bactericidal activity can accelerate the development of novel TB regimens

NICU Language, Everyday Ethics, and Giving Better News: Optimizing Discussions about Disability with Families

The Neonatal Intensive Care Unit (NICU) has a language and culture that is its own. For professionals, it is a place of intense and constant attention to microdetails and cautious optimism. For parents, it is a foreign place with a new and unique language and culture. It is also the setting in which they are introduced to their child and parenthood for this child. This combination has been referred to as an emotional cauldron. The neonatal ethics literature mainly examines complex ethical dilemmas about withholding/drawing life sustaining interventions for fragile children. Rarely are everyday ethics or mundane ethics discussed. Microethics describe the mundane, discrete moments that occur between patients/families and clinicians. A key piece of these microethics is the language used to discuss patient care. Perception of prognoses, particularly around long-term neurodevelopmental outcome, is shaped with the language used. Despite this, clinicians in the NICU often have no specific training in the long-term neurodevelopment outcomes that they discuss. This paper focuses on the microethics of language used to discuss long-term neurodevelopmental outcomes, the developmental neuroscience behind language processing, and offers recommendations for more accurate and improved communication around long-term outcomes with families with critically ill neonates

Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis▿

Tuberculosis is a serious global health threat for which new treatments are urgently needed. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the oxazolidinone PNU-100480 in healthy volunteers, using biomarkers for safety and efficacy. Subjects were randomly assigned to PNU-100480 or placebo (4:1) at schedules of 100, 300, or 600 mg twice daily or 1,200 mg daily for 14 days or a schedule of 600 mg twice daily for 28 days to which pyrazinamide was added on days 27 and 28. A sixth cohort was given linezolid at 300 mg daily for 4 days. Signs, symptoms, and routine safety tests were monitored. Bactericidal activity against Mycobacterium tuberculosis was measured in ex vivo whole-blood culture. Plasma drug and metabolite concentrations were compared to the levels required for inhibition of M. tuberculosis growth and 50% inhibition of mitochondrial protein synthesis. All doses were safe and well tolerated. There were no hematologic or other safety signals during 28 days of dosing at 600 mg twice daily. Plasma concentrations of PNU-100480 and metabolites at this dose remained below those required for 50% inhibition of mitochondrial protein synthesis. Cumulative whole-blood bactericidal activity of PNU-100480 at this dose (−0.316 ± 0.04 log) was superior to the activities of all other doses tested (P < 0.001) and was significantly augmented by pyrazinamide (−0.420 ± 0.06 log) (P = 0.002). In conclusion, PNU-100480 was safe and well tolerated at all tested doses. Further studies in patients with tuberculosis are warranted. Biomarkers can accelerate early development of new tuberculosis treatments

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

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

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