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Treatment of acute bacterial skin infection is becoming more complicated as antimicrobial resistance increases. In this trial of dalbavancin, a lipoglycopeptide with a long half-life, once-weekly dosing was shown to be noninferior to vancomycin–linezolid for treating infection. Acute bacterial skin and skin-structure infections are among the most common reasons for the hospitalization of adults in the United States today. 1 These infections are caused most often by Staphylococcus aureus and streptococci. 2 Methicillin-resistant S. aureus (MRSA) accounts for many of these infections and presents a particular treatment challenge because current therapies are limited by toxicity, resistance, or the lack of an oral formulation. 3 Associated medical costs are substantial. 4 Dalbavancin (Durata Therapeutics) is a lipoglycopeptide antibiotic agent with in vitro and in vivo activity against gram-positive pathogens, including a minimal inhibitory concentration (MIC) required to inhibit the growth of 90% . . .

Background. Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. Methods. This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare—associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. Results. Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). Conclusions. For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Major depressive disorder (MDD) in young people is a common psychiatric disorder, but treatment options are limited. Agomelatine has demonstrated short-term efficacy and safety in pediatric patients. We report here the results of a 92-week open-label extension (OLE). The international, multicenter, double-blind, study randomized 400 patients (80 children, 320 adolescents) with moderate-to-severe MDD to one of four treatment groups: agomelatine 10 mg (n = 102), agomelatine 25 mg (n = 95), placebo (n = 103), and fluoxetine 10–20 mg (n = 100). After 12 weeks, patients who could benefit from treatment continuation were offered entry into an optional OLE during which they received agomelatine 10 or 25 mg for a further 92 weeks. A total of 339 patients (271 adolescents) entered the OLE. Treatment groups considered for the OLE analysis reflected those received in the double-blind and OLE periods: agomelatine (10 or 25 mg) in both (ago/ago, n = 170); placebo then agomelatine 10–25 mg (pcb/ago, n = 85); or fluoxetine then agomelatine 10–25 mg (fluox/ago, n = 84). Mean age (± SD) at entry into the double-blind phase (Week 0) was 13.6 ± 2.7 years and 61.9% were female. Mean changes in Children’s Depression Rating Scale revised (CDRS-R) raw total score from Week 12 to last post-Week 12 value in the three groups were − 16.3 ± 12.2 (ago/ago), − 18.9 ± 16.1 (pcb/ago), and − 16.1 ± 15.5 (fluox/ago), reflecting the difference in efficacy between treatments during the double-blind period, and heterogeneity at W12 between the treatment groups. Adverse events considered related to treatment occurred in 14.5% of patients: 15.3% ago/ago, 16.5% pcb/ago, and 10.7% fluox/ago. Three patients (all adolescents) experienced treatment-related severe adverse events: two treated with ago/ago and one treated with pcb/ago. Among the adolescents, one treatment-related severe adverse event in a patient in the pcb/ago group led to study withdrawal. Agomelatine was associated with continuous improvement in depressive symptoms without unexpected safety signals. These findings support the safe use of agomelatine in a pediatric population with moderate-to-severe MDD for up to 104 weeks. Trial registration No : EUDRACT No. 2015-002181-23.

New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-positive pathogens. We aimed to assess the efficacy and safety of intravenous to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections. ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centres in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a minimum lesion area of 75 cm2 and were suspected or documented to be associated with a Gram-positive pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive intravenous once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geographic region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clinical response (≥20% reduction in lesion area at 48–72 h compared with baseline), with a non-inferiority margin of −10%. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01421511. 666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clinical response (difference 2·6%, 95% CI −3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group. Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings. Cubist Pharmaceuticals.

Background In general, traditional antidepressants often have limited efficacy in patients with major depressive disorder (MDD). Agomelatine, as an antidepressant with a different mechanism of action, might have adjunctive effects on traditional antidepressants. This study aimed to investigate the augmentation effect of agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). Methods This is an 8-week, multi-centred, double-blinded, randomized, and placebo-controlled trial. Participants diagnosed with MDD and demonstrated inadequate response to SSRI or SNRI lasting at least 2 weeks were randomly allocated to receive either agomelatine or placebo in conjunction with SSRIs or SNRIs. The 17 items of the Hamilton Depression Scale (HAMD-17) were employed to assess depression severity. The primary outcome is the total score of HAMD-17 at week 8. Secondary outcomes included HAMD-17 scores at weeks 2 and 4 and clinical remission and response over 8 weeks. Adverse events (AEs) reported in both groups were recorded. A linear mixed model was established for both primary and secondary outcomes. Results A total of 123 eligible participants were included, among which 60 were randomized into the agomelatine group, and 63 were randomized into the placebo group. The between-group difference in HAMD-17 score reduction from baseline to week 8 was not significant (difference = − 0.12, 95% CI = − 3.94 to 3.70,  P  = 0.90; Cohen’s d  = 0.022). In addition, we did not observe significant differences between the two treatment groups for secondary outcomes, including response remission, and AEs. Conclusions This study did not obtain significant findings in favour of the augmentation effect of agomelation for MDD patients. However, agomelatine was generally well tolerated and demonstrated a favourable safety profile when used in combination with SSRIs and SNRIs. Trial registration. This trial is registered at ClinicalTrials.gov ( https://clinicaltrials.gov ), the registration number is NCT 04589143.

This study aims to evaluate the acid inhibition and clinical improvement of the addition of bedtime lafutidine to esomeprazole in comparison with esomeprazole only in Gastroesophageal reflux disease (GERD) patients with nocturnal symptoms. We conducted a single-center, observer-blinded, randomized, clinical trial. Forty-eight consecutive GERD patients with nocturnal symptoms were randomized to take twice daily esomeprazole, 20 mg (ESO Group, n = 24) or twice daily esomeprazole, 20 mg, with bedtime lafutidine, 10 mg (LAF & ESO Group, n = 24) for one week. The 24-h impedance-pH monitoring, and high-resolution manometry were measured on the seventh day during the treatment. The symptoms and sleep quality were assessed both at baseline and following treatment. Intragastric pH > 4 holding time ratios were significantly higher in the LAF & ESO Group compared to the ESO Group, both overall (85.4% vs. 77.7%, P = 0.003) and specifically during nighttime (92.6% vs. 77.2%, P = 0.006). Furthermore, the incidence of nocturnal acid breakthrough (NAB) was markedly reduced in the LAF & ESO Group (29.2% vs. 75.0%, P = 0.001). Esophageal acid exposure times, however, were comparable between the two groups (P > 0.05). Although both groups experienced symptom improvement, patients in the LAF & ESO Group demonstrated superior enhancement in sleep quality, as measured by the Pittsburgh Sleep Quality Index. Notably, patients without NAB exhibited a more substantial improvement in sleep quality from baseline after treatment. Therefore, adding bedtime lafutidine to esomeprazole effectively inhibits nocturnal gastric acid secretion and reduces the incidence of NAB. GERD patients who received lafutidine in addition to esomeprazole achieved a more significant improvement in sleep quality correlated with NAB reduction.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) – a selective, potent, oral IDO1 inhibitor – combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320

Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

OBJECTIVE: To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy. RESEARCH DESIGN AND METHODS: Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks. RESULTS: For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar. CONCLUSIONS: Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.

Background. Dalbavancin, a novel lipoglycopeptide with a pharmacokinetic profile that allows weekly dosing, is active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The efficacy of dalbavancin for treatment of skin and skin structure infections (SSSIs) was demonstrated in a phase 2 study. Methods. In a phase 3 noninferiority study, patients with complicated SSSIs, including infections known or suspected to involve MRSA, were randomized (ratio, 2 : 1) in a double-blind manner to receive dalbavancin (1000 mg given intravenously on day 1 and 500 mg given intravenously on day 8) or linezolid (600 mg given intravenously or intravenously/orally every 12 h for 14 days). Efficacy was assessed by determining clinical and microbiological responses at the end of therapy and at the test-of-cure visit. Relapses were identified by additional follow-up ∼1 month later. Results. MRSA was identified in 51% of patients from whom a pathogen was isolated at baseline. Dalbavancin and linezolid demonstrated comparable clinical efficacy in the clinically evaluable population at the test-of-cure visit (88.9% and 91.2% success, respectively). The rate of clinical success at the end of therapy was >90% in both arms. Less than 1.0% of patients in either treatment arm experienced relapse after the test-of-cure visit. Both treatments yielded successful microbiological response in excess of 85% among microbiologically evaluable patients at end of therapy and at the test-of-cure visit for all pathogens combined, for all S. aureus strains, and for MRSA. Gastrointestinal symptoms were among the most common adverse events in both arms. A higher proportion of patients in the linezolid arm reported adverse events that were judged by the investigator to be probably/possibly related to treatment (dalbavancin arm, 25.4% of subjects; linezolid arm, 32.2% of subjects). Conclusions. Two doses of dalbavancin (1000 mg given on day 1 followed by 500 mg given on day 8) were as well tolerated and as effective as linezolid given twice daily for 14 days for the treatment of patients with complicated SSSI, including those infected with MRSA.