Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Insights into the candidacidal mechanism of Ctn[15-34] - a carboxyl-terminal, crotalicidin-derived peptide related to cathelicidins.

PURPOSE: Ctn[15-34], a carboxyl-terminal fragment of crotalicidin (a cathelicidin from the venom gland of a South American rattlesnake), has shown antifungal activity against clinical and standard strains of Candida species. The aim of the present work was to investigate the underlying mechanisms of the candidicidal activity of Ctn[15-34]. METHODOLOGY: The time-kill profile and drug synergism were evaluated by means of a microdilution assay and multi-parametric flow cytometry. The presumptive interaction of Ctn[15-34] with lipid membranes was estimated in vitro with a lipid-mimic compound, the chromogenic substance 4-nitro-3-(octanoyloxy)benzoic acid (4N3OBA).Results/Key findings. The absorbance increment (at 425 nm) indicated a concentration- and time-dependent in-solution association between Ctn[15-34] and 4N3OBA. The interaction of Ctn[15-34] with Candida cells was confirmed by flow cytometric measurements with the 5(6)-carboxyfluorescein-labelled peptide (CF-Ctn[15-34]). Analysis of the killing time of Candida exposed to Ctn[15-34] and amphotericin B (AMB) showed that both the peptide and polyene drug reduce the number of c.f.u. but in mechanistically different ways. The Ctn[15-34] peptide alone caused yeast cell membrane disruption, which was confirmed by lactate dehydrogenase leakage and biomarkers of cell death mediated by necrosis. CONCLUSION: Overall, Ctn[15-34] displays a synergistic antifungal activity with AMB, an effect that can be further developed into a multi-target therapeutic option with other antimycotics currently in use.

Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues.

Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 microM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7+/-0.04 and 0.8+/-0.09 microM, respectively. Both compounds were not toxic towards the Vero cell line.

Synthesis and antiviral evaluation of isatin ribonucleosides.

A series of novel substituted isatin ribonucleosides 3b-3f were synthesized in good yields by a TMSOTf catalysed coupling reaction between the silylated nitrogenated base (1b-1f) and 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (2). Isatin nucleoside 3a previously reported was also prepared using this method giving high yield. From the compounds tested, ribonucleoside 3f proved to be the most active one when assayed for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibition of virus yield. All the isatin derivatives tested did not inhibit HIV-1 Reverse Transcriptase (RT) activity.

A Experiência da Comissão de Apoio Pedagógico na Faculdade de Medicina de Botucatu UNESP / The Experience of the Teaching Support Committee at Botucatu Medical School (UNESP)

Resumo: A Faculdade de Medicina de Botucatu, dentro de um processo de reforma curricular, organizou a partir de 1989 uma ampla avaliação através de seus docentes, alunos e ex-alunos. Como resultado, integrar disciplinas, introduzir metodologias inovadoras e estender o ensino para outros níveis de atenção médica do município foram as propostas mais contundentes. No início dos anos 90, a parceria da escola com o Programa UNI contribuiu para que a proposta se concretizasse. Em 1995, foi criada a Comissão de Apoio Pedagógica (CAP) para prestar apoio pedagógico aos órgãos colegiados na implementação do novo currículo, referente às inovações metodológicas em ensino, integração de disciplinas e produção de material didático. Para somar às avaliações Já desenvolvidas, a CAP coordenou o Projeto Cinaem. Como estratégia para integração das disciplinas, membros da CAP e docentes do ciclo básico organizaram dois módulos do atual primeiro ano de Medicina, introduzindo o método de ensino baseado em problemas (PBL). A filosofia do ensino ativo, centrado no aluno, norteou a proposta.

Abstract: Since 1989, as part of a process of curricular reform, Botucatu Medical School has been conducting extensive evaluation by way of faculty members, students and alumni: The most conspicuous outcomes are decisions to integrate subjects, introduce new and innovative methodologies and extend teaching to other levels of medical care in the municipality. This program was made possible partly by a partnership set up in the early nineties between the Medical School and the UNI Program. In 1995 the Teaching Support Committee (CAP) was set up to provide teaching support to the groups involved in implementing this new curriculum, as regards innovation in teaching methodology, integration among disciplines and production of teaching materials. To complement the existing evaluations, the CAP coordinated the Cinaem Project. As a strategy for integrating displines, members of the committee and professors of the foundation course, organized two modules of the present first year of Medicine, introducing Problem Basie Learning. The proposal was informed by the notion of active student-centered learning.

Gerenciamento dos recurso hídricos: a problemática do Nordeste / Water resources management: the scenario of Brazil's northeast

Analisa a situaçäo atual em nível institucional e legal do cenário brasileiro objetivando estabelecer um sistema de gerenciamento de recursos hídricos para a regiäo semi-árida do Nordeste. Sugere a necessidade de estabelecer, no futuro, uma base jurídica para a implantaçäo de um sistema regional (CAC)

Giant hydronephrosis.

A case of congenital, unilateral giant hydronephrosis containing 42 1/2 litres of urine in an adult male is reported. Diagnosis and management are discussed. Because of the possible effects of sudden abdominal decompression, a plea is made for a two-stage procedure. The hydronephrosis is first decompressed slowly by drainage and nephrectomy is then performed after the patient's cardiorespiratory and alimentary systems have been stabilised.