Elaborations on Corallopyronin A as a Novel Treatment Strategy Against Genital Chlamydial Infections

Ascending Chlamydia trachomatis infection causes functional damage to the fallopian tubes, which may lead to ectopic pregnancy and infertility in women. Treatment failures using the standard regimens of doxycycline and azithromycin have been observed. We tested the polyketide-derived α-pyrone antibiotic Corallopyronin A (CorA) that inhibits the bacterial DNA dependent RNA polymerase and has strong activity against various extracellular and some intracellular bacteria. Extensive testing in cell culture infection models and in an ex vivo human fallopian tube model under different oxygen concentrations was performed to assess the anti-chlamydial efficacy of CorA at physiological conditions. CorA showed high efficacy against C. trachomatis (MICN/H: 0.5 μg/mL for serovar D and L2), C. muridarum (MICN/H: 0.5 μg/mL), and C. pneumoniae (MICN/H: 1 μg/mL) under normoxic (N) and hypoxic (H) conditions. Recoverable inclusion forming units were significantly lower already at 0.25 μg/mL for all tested chlamydiae. CorA at a concentration of 1 μg/mL was also effective against already established C. trachomatis and C. pneumoniae infections (up to 24 h.p.i.) in epithelial cells, while efficacy against C. muridarum was limited to earlier time points. A preliminary study using a C. muridarum genital infection model revealed corresponding limitations in the efficacy. Importantly, in an ex vivo human fallopian tube model, the growth of C. trachomatis was significantly inhibited by CorA at concentrations of 1–2 μg/mL under normoxic and hypoxic conditions. The overall high efficacies of CorA against C. trachomatis in cell culture and an ex vivo human fallopian tube model under physiological oxygen concentrations qualifies this drug as a candidate that should be further investigated

Flexible Designs für klinische Studien - eine grafische Repräsentation in Form eines Wahrscheinlichkeitsbaums

Background: Flexible design of clinical trials may allow tailoring ongoing investigations to better suit actual circumstances such as an unexpectedly low effect size without compromising error control properties. Available statistical methods are, however, complex.Method: A two-stage flexible design is represented in form of a simple chance tree. Critical limits accounting for one interim analysis are derived using only basic rules of probability calculus.Conclusion: By means of chance trees the principles of flexible trial design may be communicated more easily, thus hopefully adding to good design and conduct of clinical trials.Hintergrund: Flexible Designs für klinische Studien erlauben eine bessere Anpassung laufender Untersuchungen an aktuelle Umstände, wie z.B. eine unerwartet kleine Effektgröße, ohne die statistische Fehler-Kontrolle zu durchbrechen. Die vorhandenen statistischen Verfahren sind jedoch komplex.Methodik: Ein zweistufiges, flexibles Design wird in Form eines einfachen Wahrscheinlichkeitsbaums repräsentiert. Kritische Grenzen, die einer Zwischenauswertung Rechnung tragen, werden mittels fundamentaler Regeln der Wahrscheinlichkeitsrechnung abgeleitet.Schlussfolgerung: Mithilfe eines Wahrscheinlichkeitsbaums können die Prinzipien flexibler Studiendesigns einfach kommuniziert werden und somit hoffentlich zu guter Planung und Durchführung von klinischen Studien beitragen

Treatment outcomes in patients with proven/probable vs possible invasive mould disease in a phase III trial comparing isavuconazole vs voriconazole

Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P = 0.3, day 84: 26.2% vs 32.6%; P = 0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P = 0.01, 75.0% vs 63.1%; P = 0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment.status: publishe