Skin and soft-tissue infections (SSTIs) account for 3% of all emergency department (ED) encounters and are frequently associated with inappropriate antibiotic prescribing. We characterized barriers and facilitators to optimal antibiotic use for SSTIs in the ED using a systems engineering framework and matched them with targeted stewardship interventions.

We conducted semistructured interviews with a purposefully selected sample of emergency physicians.

An interview guide was developed using the Systems Engineering Initiative for Patient Safety (SEIPS) framework. Interviews were recorded, transcribed, and analyzed iteratively until conceptual saturation was achieved. Themes were identified using deductive directed content analysis guided by the SEIPS model.

We conducted 20 interviews with physicians of varying experience and from different practice settings. Identified barriers to optimal antibiotic prescribing for SSTIs included poor access to follow-up (organization), need for definitive diagnostic tools (tools and technology) and fear over adverse outcomes related to missed infections (person). Identified potential interventions included programs to enhance follow-up care; diagnostic aides (eg, rapid MRSA assays for purulent infections and surface thermal imaging for cellulitis); and shared decision-making tools.

Using a systems engineering informed qualitative approach, we successfully characterized barriers and developed targeted antibiotic stewardship interventions for SSTIs managed in the ED work system. The interventions span multiple components of the ED work system and should inform future efforts to improve antibiotic stewardship for SSTIs in this challenging care setting.

Cariprazine is a potent D3/D2 partial agonist with preferential binding to D3 receptors.

To evaluate the efficacy and safety of cariprazine versus placebo in acute exacerbation of schizophrenia.

A multinational, multicenter, double-blind, randomized, placebo- and active-controlled, fixed-dose trial in patients aged 18–60 years with DSM-IV-TR-defined schizophrenia, current psychotic episode < 2 weeks, and PANSS total score between 80 and 120. After 1-week washout, patients received 6-weeks treatment (cariprazine 1.5, 3.0, or 4.5 mg/d, risperidone 4.0 mg/d, or placebo) and 2-week safety follow-up. Risperidone was used to assess assay sensitivity. Primary and secondary efficacy: baseline to Week 6 change (LOCF) in PANSS total and CGI-S scores, respectively. Safety: adverse events (AEs), vital signs, laboratory measures, extrapyramidal symptom (EPS) scales.

Of 732 randomized patients, 64% completed the study. Mean baseline PANSS (98) and CGI-S scores (4.8) were similar across groups. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d (placebo-adjusted improvements: −7.5, −8.9, −10.4, respectively; P < .001; LOCF) and risperidone (−15.0, P < .001, LOCF); significant improvement on CGI-S was demonstrated for all active treatments (P < .05). The most common cariprazine AEs were insomnia, EPS, akathisia, sedation, nausea, dizziness, and constipation. AE discontinuation rates were 15% for placebo, 10%, 5% and 8% for cariprazine 1.5, 3.0, and 4.5 mg/d, respectively, and 9% for risperidone 4.0 mg/d.

Cariprazine significantly improved PANSS and CGI-S scores versus placebo in acute exacerbation of schizophrenia and was generally well tolerated.

Clinically significant depressive symptoms are common in schizophrenia, and are associated with greater functional impairment and worse outcomes.

To evaluate the effect of lurasidone in patients with a DSM-IV-TR diagnosis of schizophrenia who presented with significant depressive symptoms.

Pooled data were analyzed from 4, six-week, double-blind, placebo-controlled schizophrenia trials, with available MADRS data. Patients with an acute exacerbation of schizophrenia were randomized to fixed, 40–160 mg (n=902) once-daily doses of lurasidone, or placebo (n=439). LOCF-endpoint data were analyzed using ANCOVA. MADRS remission was defined as an endpoint score <10.

At baseline, 45.0% and 24.5% of subjects had a MADRS score of ≥12, and ≥16 respectively. Treatment with lurasidone was associated with significantly greater improvement in the MADRS at LOCF-endpoint compared with placebo in the total sample (-2.8 vs. -1.4; p<0.001), and in each baseline depression severity subgroup: MADRS ≥12 (-6.7 vs. -4.8; p<0.005), and MADRS ≥16 (-9.3 vs. -6.3; p<0.005). Overall, the largest effect size was observed for the 160 mg dose of lurasidone (0.43). For the subgroup with MADRS≥16 at baseline, higher depression remission rates were observed for lurasidone 160 mg (47.8%) compared with lurasidone 80 mg (38.6%) and lurasidone 40 mg (28.6%).

In this pooled, post-hoc analysis, 40-160 mg once-daily doses of lurasidone significantly reduced the severity of depressive symptoms in patients with schizophrenia. Daily doses of 160 mg demonstrated the largest effect size. These results warrant further evaluation of lurasidone in patients with schizophrenia and co-morbid depression.

Effectiveness studies of therapeutic switching of antipsychotics provide valuable clinical information.

Assess effectiveness of switching patients to lurasidone.

To evaluate 3 dosing strategies when switching patients to lurasidone.

Patients were randomized to three open-label lurasidone dosing strategies: 40mg/day for 14 days (n=74); 40mg/day for 7 days then 80mg/day for 7 days (n=88); and 80mg/day for 14 days (n=82) and stratified by their previous treatment (sedating vs non-sedating). Prior antipsychotic was tapered (50% step-down, day 8, discontinued day 14), followed by 4 weeks of flexible dose treatment (40-120 mg/day). Primary outcome was time to treatment failure (TTF). Of the 198 subjects completing core 6-week study, 149 (75.3%) enrolled in a 6-month extension study.

Switching to lurasidone was well tolerated; 198 (81.1%) of subjects completed core study, 19 (7.9%) subjects experienced treatment failure of which 16 (6.7%) discontinued due to an AE. No clinically relevant differences were noted among the 3 dosing strategies. TTF was earlier in patients previously receiving sedating antipsychotics vs. non-sedating (log rank p=0.101). Core study yielded LS mean (SE) within-group improvement on PANSS total score -5.3 (±0.7), LOCF with further improvement of -1.5 (±0.9), LOCF, at Month 6 from extension baseline. Ninety-eight subjects (65.8%) completed extension phase. Premature discontinuation causes included consent withdrawal (12.1%) and AEs (11.4%). Weight and lipid changes at 6 months were minimal.

Switching to lurasidone was safe and well tolerated regardless of initial dosing strategy. Switched patients maintained or improved symptom control during core and extension treatment.

Long-term head-to-head studies comparing atypical antipsychotics are important for clinical decision making.

To evaluate long-term treatment of schizophrenia with lurasidone (LUR) vs. quetiapine XR (QXR; Study 234), or risperidone (RIS; Study 237).

To assess efficacy and safety of lurasidone relative to other antipsychotics.

In study 234(efficacy and safety), subjects received 12 months double-blind, flexible-dose lurasidone(40-160 mg/day) or QXR(200-800 mg/day) after completing a 6 week, randomized, double-blind, placebo-controlled trial with LUR or QXR. In Study 237 (safety) clinically stable adult outpatients received 12-months double-blind treatment with flexible-dose LUR 40-120 mg/day or RIS 2-6 mg/day.

Study 234: continued treatment of LUR responders (n=139) reduced relapse risk by 27.2% vs. continued QXR treatment of QXR responders (n=79). Hospitalization risk was 56.7% lower with LUR vs. QXR. More LUR subjects achieved sustained remission vs. QXR (61.9% vs. 46.3%; p=0.043; 12 months, LOCF), and lower all-cause discontinuation (48% vs 61%). Triglycerides were reduced with LUR; total and LDL cholesterol were unchanged or reduced. Median prolactin change was +0.6 for LUR vs. -0.7 ng/mL for QXR. Study 237: clinically significant weight gain was observed with LUR 13%) vs. RIS (19%) with median change in prolactin 0.4 vs. 14.8 ng/mL, respectively. Comparable efficacy was observed for LUR and RIS (change from baseline in PANSS total score:-4.7 vs. -6.5, and CGI-Severity score:-0.4 vs. -0.4, respectively).

The results of these two 12-month trials suggest that lurasidone is safe and well-tolerated with efficacy comparable to quetiapine XR and risperidone for long-term treatment of schizophrenia.

Lurasidone has demonstrated efficacy treating adults with schizophrenia, the majority of them with chronic, multi-episode schizophrenia.

To assess baseline characteristics and evaluate efficacy of lurasidone in patients with early-stage schizophrenia (ESS).

Evaluate efficacy of lurasidone in patients with ESS.

A pooled analysis of patients with ESS (defined as onset of illness within 3 years of study entry) from three, 6-week, randomized, placebo-controlled, phase 3 trials was performed. Additional analysis was conducted for patients with onset within 5 years. Efficacy was evaluated using a mixed-model repeated-measures analysis of change in PANSS total score and CGISeverity score. Treatment response was defined as ≥20% improvement in PANSS total score from baseline.

857 subjects were randomized to lurasidone and 366 to placebo of which 102(11.9%) lurasidone and 44(12.0%) placebo subjects had ESS (onset within 3 years). Among 146 ESS subjects, 70.5% were male, mean age was 28.6 years. Baseline PANSS total and CGI-S scores were 96.8 and 5.0 respectively. Lurasidone treatment of early-stage schizophrenia subjects showed significant improvement vs placebo in PANSS total score (-25.9 vs -17.3; p< 0.05, effect size=0.42), PANSS positive (-9.6 vs 6.0; p< 0.01) and negative (-5.6 vs -3.2; p=0.014) subscale scores, and improvement in CGI-S score (-1.7 vs -1.3; p=0.089, effect size=0.36). Responder rates were 69% for lurasidone vs 48% for placebo (NNT=5). Similar results were observed in subjects with within 5 years of onset of illness.

In this subgroup analysis, lurasidone was effective in the treatment of patients with early-stage schizophrenia.

Agitation is a common presentation among patients hospitalized for an acute exacerbation of schizophrenia. Rapid and effective control of agitation is an important early treatment goal.

The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in reducing agitation in patients with an acute exacerbation of schizophrenia.

The analysis was performed on pooled data from 5 six-week, placebo-controlled trials in the subgroup of patients with an acute exacerbation of schizophrenia who met (n=773), or did not meet (n=754), criteria) for agitation (PANSS-Excited Component [EC] score ≥14 at baseline, Citrome, J Clin Psych 2007;68:1876-1885). Patients were randomized to fixed once-daily doses of lurasidone (40-160 mg).

The mean baseline PANSS-EC scores were similar for lurasidone vs. placebo in the high (16.7 vs. 16.8) and low (10.9 vs. 10.7) agitation subgroups. In the high agitation subgroup, treatment with lurasidone (vs. placebo) was associated with significantly greater improvement in PANSS-EC scores at days 3/4 (-2.0 vs. -1.3; p<0.001) and day 7 (-2.6 vs. -1.8; p<0.001). At week 6 endpoint, improvement on lurasidone vs. placebo was greater in the high vs. low agitation groups on the PANSS-EC score (effect size, 0.43 vs. 0.31), and comparable on the PANSS total score (effect size, 0.57 vs. 0.58).

In this pooled post-hoc analysis, treatment with lurasidone significantly reduced agitation by day 3/4 in patients hospitalized with an acute exacerbation of schizophrenia. The magnitude of improvement at week 6 was similar in both the high and low agitation groups.

Atypical antipsychotics bind to multiple receptor types and subtypes. Improved outcomes in schizophrenia are linked to activity at D2 and serotonin receptors 5-HT7, 5-HT2A and 5-HT1A.

To characterize the receptor-binding profile of lurasidone and other antipsychotics.

To compare receptor-binding profiles of antipsychotics.

Replicated, side-by-side receptor-binding assays used human recombinant receptors (for 5-HT7, α2A, and α2C) or membrane-fractions of animal CNS tissue. Affinities were determined via Hill plot analysis for IC50values; Ki values were determined using Ki=IC50/(1+ S/Kd) (S=concentration of competing radioligand, Kd=dissociation constant).

Lurasidone displayed potent binding and full antagonism at dopamine D2(Ki, 1.68nM) and serotonin 5-HT2A(Ki, 2.03nM) receptors (the highest D2affinity of all tested agents). Lurasidone's dopamine binding was selective for D2receptors. Unlike other antipsychotics tested, lurasidone had very high affinity and full antagonism at serotonin 5-HT7(Ki, 0.49nM), and nanomolar affinity (Ki=6.75nM) with weak-moderate partial agonism at serotonin 5-HT1Areceptors., Lurasidone showed higher affinity for 5-HT7, 5-HT2A, and 5-HT1Areceptors relative to D2receptor-binding than other agents. Lurasidone displayed moderate affinity for α2C adrenoceptors (Ki, 10.8nM); moderate-weak affinity for α1adrenoceptors (Ki, 48nM); and minimal or unappreciable affinity for receptors associated with undesirable effects (5-HT2C [Ki, 415nM], histamine H1[IC50>1000nM] and muscarinic [cholinergic] M1[IC50>1000nM] receptors).

The unique pharmacological profile of lurasidone is consistent with observed antipsychotic efficacy, low-tomoderate likelihood of EPS, low weight-gain potential, and possible mood, anxiety, and cognitive benefits.

To assess the burden of bloodstream infections (BSIs) among pediatric hematology-oncology (PHO) inpatients, to propose a comprehensive, all-BSI tracking approach, and to discuss how such an approach helps better inform within-center and across-center differences in CLABSI rate

Prospective cohort study

US multicenter, quality-improvement, BSI prevention network

PHO centers across the United States who agreed to follow a standardized central-line–maintenance care bundle and track all BSI events and central-line days every month.

Infections were categorized as CLABSI (stratified by mucosal barrier injury–related, laboratory-confirmed BSI [MBI-LCBI] versus non–MBI-LCBI) and secondary BSI, using National Healthcare Safety Network (NHSN) definitions. Single positive blood cultures (SPBCs) with NHSN defined common commensals were also tracked.

Between 2013 and 2015, 34 PHO centers reported 1,110 BSIs. Among them, 708 (63.8%) were CLABSIs, 170 (15.3%) were secondary BSIs, and 232 (20.9%) were SPBCs. Most SPBCs (75%) occurred in patients with profound neutropenia; 22% of SPBCs were viridans group streptococci. Among the CLABSIs, 51% were MBI-LCBI. Excluding SPBCs, CLABSI rates were higher (88% vs 77%) and secondary BSI rates were lower (12% vs 23%) after the NHSN updated the definition of secondary BSI (P<.001). Preliminary analyses showed across-center differences in CLABSI versus secondary BSI and between SPBC and CLABSI versus non-CLABSI rates.

Tracking all BSIs, not just CLABSIs in PHO patients, is a patient-centered, clinically relevant approach that could help better assess across-center and within-center differences in infection rates, including CLABSI. This approach enables informed decision making by healthcare providers, payors, and the public.

Infect Control Hosp Epidemiol 2017;38:690–696