Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial.

Importance: Cefepime/enmetazobactam is a novel ß-lactam/ß-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. Objective: To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. Design, Setting, and Participants: A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Interventions: Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). Main Outcomes and Measures: The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Results: Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Conclusions and Relevance: Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. Trial Registration: ClinicalTrials.gov Identifier: NCT03687255.

Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia.

Cefepime-enmetazobactam is a novel ß-lactam-ß-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of ß-lactam-ß-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.

Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae.

The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.

[Maternal attachment patterns and personality in post partum depression]. / Modelli di attaccamento e personalità nella depressione post partum.

AIMS: This study investigates the prevalence of post partum depression (PPD) in a sample of Roman women, and the role of socio-demographic variables, personality structure and maternal attachment patterns, in order to identify primary and secondary prevention strategies. METHODS: Data were collected in two phases. During the third trimester of pregnancy, a sample of 453 women completed a socio-demographic data sheet and the Edinburgh Postnatal Depression Scale (EPDS). Among the patients scoring 12 or more at EPDS, 15 entered the second phase of the study and completed SCID-II and Adult Attachment Interview. PPD diagnosis was confirmed by the SCID-I. The study group was compared with a control group. RESULTS: Among the 453 women who were evaluated, 92 (20.3%) scored ≥12 at EPDS, 39 has been enrolled and 15 entered the study. Presence of depressive symptoms was associated with: complications in pregnancy, previous psychiatric disorders, family and marital conflicts. 66.6% of depressed mothers showed more than one diagnosis on Axis II (particularly avoidant/dependent + borderline or histrionic + dependent). The AAI showed a prevalence of insecure (33.3%) and unresolved/disorganized (46.6%) attachment pattern in the clinical group. DISCUSSION AND CONCLUSIONS: Our results suggest that psychological factors such as personality structure and attachment patterns are not only involved in post natal affective disorders, but have a key role in the onset and development of PPD.

Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4.

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S), GW679769] has previously been shown to be a potent and selective antagonist of the human neurokinin-1 receptor, the primary receptor of substance P, both in vitro and in vivo, with good brain penetration properties. On the basis of this mode of action it was evaluated for the prevention of chemotherapy-induced and postoperative nausea and vomiting, and for the chronic treatment of anxiety, depression, insomnia, and overactive bladder. Casopitant is shown to be a substrate, an inhibitor, and an inducer of CYP3A4, and, because of this complex behavior, it was difficult to identify the primary mechanism by which it may give rise to drug-drug interactions (DDIs) of clinical relevance. Moreover, the major circulating metabolite is itself an inhibitor of CYP3A4 in vitro. On the basis of the different clinical indications and the various potential comedications of casopitant, a relevant part of the clinical development plan was focused on the assessment of the importance of clinical DDIs. The present study provides an overview of the DDI potential profile of casopitant, based on in vitro data and clinical evidence of its interaction with CYP3A4 probe substrates midazolam and nifedipine, the strong inhibitor ketoconazole, and the inducer rifampin. Overall, the clinical data confirm the ability of casopitant to interact with CYP3A4 substrates, inhibitors, or inducers. The in vitro data are accurate and robust enough to build a reliable SimCyp population-based model to estimate the potential DDIs of casopitant and to minimize the clinical studies recommended.

[Clinician' emotional resonance as investigation tool: development and preliminary validation of a questionnaire]. / Il sentire del clinico come strumento di conoscenza: sviluppo e validazione preliminare di una scala di valutazione.

AIMS: A robust psychopathological and psychotherapeutic tradition underscores the importance of the clinician's feelings in the assessment and therapeutic process. Our aim is to develop an instrument to evaluate psychiatrist' experience induced by each patient. This paper describes the development and preliminary validation of this instrument. METHODS: Based on the relevant literature and our clinical experience, we developed a self-completed questionnaire consisting of 65 items covering various aspects of the clinician' emotional resonance. Ten psychiatrists completed our questionnaire immediately after first clinical interviews involving a total of 125 patients with various psychiatric diagnoses. Also, they completed the Profile of Mood State (POMS) immediately before and after these interviews. The factor structure and convergent validity of the questionnaire was examined. RESULTS: We identified a six-factor structure. The factors showed acceptable internal consistency and were interpretable as different aspects of the clinician-patient interaction as experienced by the clinician. There was a consistent pattern of correlations between factor scores and changes in POMS scale scores during the clinical interviews. DISCUSSION: The study results, though preliminary, suggest that clinicians' subjective reactions during their interactions with patients can be validly and reliably measured. Quantitative measurement of clinician's subjectivity is potentially useful in both clinical and research settings.

Bilastine: Quantitative Determination by LC with Fluorescence Detection and Structural Elucidation of the Degradation Products Using HRMS.

BACKGROUND: A liquid chromatography (LC) stability-indicating method was developed and validated for the quantitative determination of bilastine in coated tablets. OBJECTIVE: The procedure was validated for specificity, linearity, robustness, precision, and accuracy. Plackett-Burmann experimental design was used to determine the robustness of the method. METHOD: Chromatographic separation was performed on a Shim-pack® RP-18 column with fluorescence detection. The degradation products formed under oxidative conditions were isolated and identified using high-resolution mass spectrometry (HRMS). In silico prediction of degradation products and in silico toxicity studies were also performed. RESULTS: The LC method presented good recovery and precision (intraday and interday), the response was linear in a range of 0.20 to 0.70 µg mL-1, and the results demonstrated the robustness of the analytical method under the evaluated conditions. CONCLUSIONS: The degradation products were identified as benzimidazole (DP1) and amine N-oxide of bilastine (DP2). The results for the toxicity studies demonstrated the high mutagenic potential of DP1 and hepatotoxicity and hERG I inhibitor effects of DP2. HIGHLIGHTS: Bilastine degradation products were identified as benzimidazole and amine N-oxide using HRMS.

Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study.

BACKGROUND: Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). METHODS: We administered flexible asenapine doses ranging from 5-20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. RESULTS: Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. CONCLUSIONS: The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.

Protective role of Syzygium cumini leaf extracts against paraquat-induced oxidative stress in superoxide-dismutase-deficient Saccharomyces cerevisiae strains

The aim of this study was to evaluate the protective effect of three different extracts prepared from Syzygium cumini leaves against paraquat-induced toxicity in Saccharomyces cerevisiaestrains deficient in superoxide dismutase (SOD). Additionally, the extracts phenolic and flavonoid contents, in vitro antioxidant activity, and phytochemical composition (using high-pressure liquid chromatography) were determined. Bioactive compounds from S. cumini leaves were extracted with infusion (traditional method) or ultrasound (aqueous or hydroalcoholic). Compared to the infusion extract, the ultrasound extracts exhibited a greater protective capacity against paraquat toxicity in the yeast cells as well as higher antioxidant activity. These results may be directly related to the higher phenolic and flavonoid contents in these extracts, since they are recognized as having high antioxidant actions.

A contribuição do Projeto Apoiador Regional do COSEMS-MG no fortalecimento da gestão regional de saúde / The contribution of the Regional Project Supporter COSEMS-MG in strengthening the regional mnagement of health

O presente artigo relata a experiência do Colegiado dos Secretários Municipais de Saúde de Minas Gerais avaliando a estratégia de implementação do Projeto Apoiador na efetivação e no fortalecimento do espaço de gestão regional. A avaliação apresentada é fruto da aplicação de questionário para subsidiar a análise da contribuição do projeto nos eixos ‘informação’ e ‘participação’; avaliam-se, ainda, o perfil do entrevistado, seu conhecimento e sua percepção acerca da atuação do apoiador. Os principais resultados aferidos apontam que o projeto. Os resultados obtidos apontam que Projeto rebaixa os custos de transação, propiciando a cooperação na relação intergestores no espaço regional; promove a disseminação de informações; fortalece a atuação regional do colegiado bem como a capacidade político institucional dos municípios e da representação regional do mesmo nas relações intergovernamentais que precisam de cooperação e coordenação em nosso Estado Federativo; aglutina gestores no colegiado regional, e possibilita a contextualização da discussão estadual do colegiado mineiro com os demais entes..

This article reports the experience of the Colegiado dos Secretários Municipais de Saúde of Minas Gerais, evaluating the implementation strategy of the Project Supporter in the realization and strengthening of regional management space. The assessment presented is theresult of a questionnaire to help analyzing the contribution of the project in the axes ‘information’ and ‘participation’, and evaluates also the profile of the respondent and his knowledge and perception of the role of supporter. The main measured results show that design lowers transaction costs in providing cooperation against Inter in the regional space, promotes the dissemination of information, strengthen the role of the regional collegiate and political institutional capacityof municipalities and regional representation of that intergovernmental relations that requirecooperation and coordination in our federal state, binds managers in the regional college, and enables the contextualization of this collegiate’s state discussion with other entities..

Atuação conjunta SES/COSEMS no fortalecimento da regionalização em Minas Gerais: a ação do COSEMS/MG / Joint SES/COSEMS action in strengthening regionalization in Minas Gerais

Trata-se da experiência do Colegiado de Secretários Municipais de Saúde de Minas Gerais (COSEMS/MG) e de Gestão Regional no fortalecimento da gestão regional já instituída, destacando a implementação do Projeto Apoiador como instrumento na efetivação desta ação. Ressalta-se, ainda, a importância da parceria do COSEMS/MG com a Secretaria de Estado da Saúde de Minas Gerais para a implementação de ações pactuadas no âmbito estadual que trazem reflexos à gestão municipal de saúde.

This article recounts the experience of the Collegiate of Municipal Secretaries of Minas Gerais (COSEMS/MG) in strengthening the existing regional management, highlighting the implementation of the Supporter Project as an instrument in the realization of this action. Also underlined is the importanceof the partnership between the COSEMS/MG and the Secretariat of State for Health of Minas Gerais to implement actions agreed in the State sphere that bring repercussions for municipal health management.