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Zoliflodacin is a first‐in‐class oral spiropyrimidinetrione antibiotic being developed for patients with uncomplicated gonorrhea, including those infected with multidrug‐resistant strains. Because zoliflodacin is metabolized by cytochrome P450 3A4 (CYP3A4), concomitant administration with a CYP3A inhibitor has the potential to increase zoliflodacin plasma exposure. The aim of this phase 1 drug–drug interaction (DDI) study was to assess the effect of the strong CYP3A4 inhibitor itraconazole on the pharmacokinetics (PK) and safety of a 3 g single oral dose of zoliflodacin. This was an open label, 2‐period, 2‐treatment, fixed sequence crossover DDI study. Eighteen eligible adult participants were dosed and completed the study. When zoliflodacin was co‐administered with itraconazole at steady state, as determined by itraconazole trough plasma concentrations, zoliflodacin exposure increased as measured by peak concentration (Cmax) by 1.03‐fold and by area under the plasma‐concentration time curve (AUC) from time 0 to last measurable plasma concentration (AUC0‐last) and from time 0 extrapolated to infinity (AUC0‐∞) by 1.39‐ and 1.38‐fold, respectively. Eight participants (44.4%) had a total of 15 mild treatment‐emergent adverse events (TEAEs), with three considered related to treatment. There were no deaths or serious TEAEs and no participant withdrew. No clinically significant abnormal laboratory values, vital signs, or electrocardiogram findings were reported. In conclusion, the Cmax of zoliflodacin was essentially unchanged (1.03‐fold higher) when co‐administered with a strong CYP3A4 inhibitor, while AUC exposures increased by less than 1.5‐fold, which, combined with an acceptable safety profile, indicate a low DDI potential between zoliflodacin and CYP3A4 inhibitors. Study Highlights What is the current knowledge on the topic? ○Resistance of Neisseria gonorrhoeae to antibiotics is becoming a major barrier to access to effective treatment options for gonorrhea. Zoliflodacin is an oral, single‐dose, first‐in‐class spiropyrimidinetrione bacterial type II topoisomerase inhibitor with demonstrated activity against N. gonorrhoeae, including multidrug‐resistant strains. Efficacy and safety of zoliflodacin for the treatment of uncomplicated gonorrhea were studied in a global phase 3 trial that demonstrated it was generally well tolerated with no serious adverse events or deaths and showed non‐inferiority to ceftriaxone plus azithromycin combination therapy. Based on in vitro data which showed zoliflodacin is metabolized in part by cytochrome P450 3A4 (CYP3A4), and consistent with regulatory guidance, a clinical study to evaluate the impact of CYP3A4 inhibition was needed. What question did this study address? ○Concomitant administration of zoliflodacin with a cytochrome P450 inhibitor could lead to a potential drug–drug interaction (DDI) resulting in increased exposure. This study evaluated the effects of the co‐administration of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety of zoliflodacin in healthy adult participants. What does this study add to our knowledge? ○When zoliflodacin was co‐administered with itraconazole at steady state, the zoliflodacin peak (Cmax) exposure was unchanged and systemic (AUC0‐last and AUC0‐∞) exposure increased by less than 1.5‐fold, suggesting a low potential for DDI with CYP3A4 inhibitors. The safety profile was consistent with the observations made during the clinical development program. How might this change clinical pharmacology or translational science? ○Based on non‐clinical studies, the metabolism of zoliflodacin was predicted to be influenced by co‐administration of itraconazole. However, this clinical DDI study found that zoliflodacin plasma exposure in healthy participants after a 3 g single oral dose was increased by less than 1.5‐fold relative to zoliflodacin administered alone, which is unlikely to translate to a clinically meaningful safety risk at this dose. This trial underscores the importance of clinical DDI studies to validate nonclinical results.

Background Daptomycin has proven efficacy in patients with Gram-positive complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. Objective This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. Study Design This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients Patients Patients aged ≥65 years with a diagnosis of Gram-positive cSSTIs with or without bacteraemia were included. In addition, infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. Intervention Patients were randomized (2:1) to intravenous daptomycin or pooled intravenous standard therapies (semi-synthetic penicillin or vancomycin, referred to as the ‘comparator’). Duration of treatment was between 5 and 14 days for cSSTIs without bacteraemia and between 10 and 28 days for cSSTIs with bacteraemia. Main Outcome Measure The primary objective was descriptive comparison of clinical success in clinically evaluable patients at test of cure, 7–14 days post treatment. Secondary objectives were microbiological outcome, duration of treatment and safety. Results In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteraemia [five documented (daptomycin, n  = 3; comparator, n  = 2); and one suspected (daptomycin, n  = 1)]. Test-of-cure clinical success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49–5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) versus 69.2 % (9/13), respectively; percentage points difference, 20.5 (95 % confidence interval −12.2 to 50.9)]. Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi-synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concentrations (daptomycin). Conclusion In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility.

Therapeutic hypothermia (TH) for 72 h is the standard treatment to reduce neurological deficits in term newborns with hypoxic-ischemic encephalopathy. There is a large variability regarding nutritional supply during TH treatment in asphyxiated newborns. We performed a retrospective multicentre study in four level I (highest level of care in Germany) NICUs, including 135 asphyxiated term newborns undergoing TH. We analyzed enteral and parenteral nutritional supply during and after TH. We correlated nutritional supply with risk factors for encephalopathy, pH, Sarnat score, mechanical ventilation, seizures, and sedation. A total of 120 of 135 neonates received enteral nutritional supply within the first 24 h, and the majority of children were fully enterally fed within the first 10 days. The grade of encephalopathy and mechanical ventilation had a significant influence on the amount of enteral fluids (p = 0.01), whereas the pH and appearance of seizures did not affect the amount of nutritional supply significantly. Furthermore, we did not observe any correlation between enteral intake and abdominal complications such as necrotizing enterocolitis. We observed a large variability of feeding regimes in the four participating NICUs. Early enteral feeding among newborns undergoing TH was performed in each NICU and was well tolerated without increased rates of complications.