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ABSTRACTFluoroquinolones are some of the most prescribed antibiotics in the United States. Previously, we and others showed that the fluoroquinolones exhibit a class effect with regard to the CLSI-established breakpoints for resistance, such that decreased susceptibility (i.e., an increased MIC) to one fluoroquinolone means a simultaneously decreased susceptibility to all. For defined strains, however, clear differences exist in the pharmacodynamic properties of each fluoroquinolone and the extent to which resistance-associated genotypes affect the MICs of each fluoroquinolone. In a pilot study of 920 clinical Escherichia coliisolates, we uncovered tremendous variation in norfloxacin MICs. The MICs for all of the fluoroquinolone-resistant isolates exceeded the resistance breakpoint, reaching 1,000 μg/ml. Approximately 25% of the isolates (n= 214), representing the full range of resistant norfloxacin MICs, were selected for the simultaneous determinations of ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs. We found that (i) great MIC variation existed for all four fluoroquinolones, (ii) the ciprofloxacin and levofloxacin MICs of >90% of the fluoroquinolone-resistant isolates were higher than the resistance breakpoints, (iii) ciprofloxacin and levofloxacin MICs were distributed into two distinct groups, (iv) the MICs of two drug pairs (ciprofloxacin and norfloxacin by Kendall's Tau-b test and gatifloxacin and levofloxacin by paired ttest) were similar with statistical significance but were different from each other, and (v) ∼2% of isolates had unprecedented fluoroquinolone MIC relationships. Thus, although the fluoroquinolones can be considered equivalent with regard to clinical susceptibility or resistance, fluoroquinolone MICs differ dramatically for fluoroquinolone-resistant clinical isolates, likely because of differences in drug structure.

RESUMENEn este trabajo se desarrolla un modelo integrado de valoración de empresas de alto componente tecnológico combinando el descuento de flujos de caja disponibles y la valoración de opciones reales. Dadas las características que presentan este tipo de empresas resulta complicado realizar una predicción adecuada de los ingresos. En este sentido, se propone utilizar como inductores de valor, indicadores de tráfico web sobre los que se realizarán diferentes proyecciones mediante una simulación de Monte Carlo. Finalmente este valor será ajustado mediante la utilización de opciones reales, considerando el valor de las opciones de crecimiento y sus interrelaciones en el tiempo.

The paper considers the problem of estimating the dependence function of a bivariate extreme survival function with standard exponential marginals. Nonparametric estimators for the dependence function are proposed and their strong uniform convergence under suitable conditions is demonstrated. Comparisons of the proposed estimators with other estimators are made in terms of bias and mean squared error. Several real data sets from various applications are used to illustrate the procedures.