Showing papers by "Alicia Rodríguez-Gascón published in 2019"

MMP-9 Downregulation with Lipid Nanoparticles for Inhibiting Corneal Neovascularization by Gene Silencing.

Abstract: Gene silencing targeting proangiogenic factors have been shown to be a useful strategy in the treatment of corneal neovascularization (CNV). Among interference RNA (RNAi) molecules, short-hairpin RNA (shRNA) is a plasmid-coded RNA able to down-regulate the expression of the desired gene. It is continuously produced in the host cell, inducing a durable gene silencing effect. The aim of this work was to develop a solid lipid nanoparticle (SLN)-based shRNA delivery system to downregulate metalloproteinase 9 (MMP-9), a proangiogenic factor, in corneal cells for the treatment of CNV associated with inflammation. The nanovectors were prepared using a solvent emulsification-evaporation technique, and after physicochemical evaluation, they were evaluated in different culture cell models. Transfection efficacy, cell internalization, cell viability, the effect on MMP-9 expression, and cell migration were evaluated in human corneal epithelial cells (HCE-2). The inhibition of tube formation using human umbilical vein endothelial cells (HUVEC) was also assayed. The non-viral vectors based on SLN were able to downregulate the MMP-9 expression in HCE-2 cells via gene silencing, and, consequently, to inhibit cell migration and tube formation. These results demonstrate the potential of lipid nanoparticles as gene delivery systems for the treatment of CNV-associated inflammation by RNAi technology.

Pharmacokinetic/pharmacodynamic analysis as a tool for surveillance of the activity of antimicrobials against Pseudomonas aeruginosa strains isolated in critically ill patients

Abstract: Introduction To evaluate the changes in the susceptibility of Pseudomonas aeruginosa over time (2000–2017) against antimicrobials used in an intensive care unit of a Spanish tertiary hospital, and to compare them with the antimicrobial activity considering theoretical pharmacokinetic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolates to quantify susceptibility rates was also evaluated. Methods The susceptibility was studied considering the Clinical and Laboratory Standards Institute (CLSI) breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. Results A significant decrease in the susceptibility to gentamicin and imipenem was observed, and more recently the highest percentages of susceptible strains were found for amikacin, cephalosporins and piperacillin/tazobactam (>80%). The probability of success of an empiric treatment or CFR for most of the evaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem provided high probabilities (>90%) to achieve the PK/PD target. Cephalosporins provided moderate probabilities (>80%) although for ceftazidime, the highest dose (2 g/8 h) was required. Moreover, a significant decrease in the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed. Conclusions Both susceptibility rates and CFR values have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions. They are complementary tools and, they should be used jointly in surveillance programmes. In fact, susceptibility data are not always useful to detect changes in the CFR. No relevant differences were observed among the methods for handling repeated isolates.

Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study.

Abstract: Introduction We analysed the changes in the susceptibility of Pseudomonas aeruginosa to antimicrobials over an 18-year period (2000-2017) in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital (excluding the intensive care unit). In addition, the antimicrobial activity was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) criteria as a microbiological surveillance tool. Methods Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. Results In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones 90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses. Conclusions Analysis of susceptibility and PK/PD modelling, should be considered together to select the most appropriate antimicrobial drug and dosage regimen. Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered. In this study, the PK/PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates, such as carbapenems, and the selection of the most effective antimicrobials among those with high rates of susceptibility.

Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

Abstract: espanolObjetivo. Evaluar mediante analisis farmacocinetico/ farmadocinamico (PK/PD) si el cambio en la sensibilidad antimicrobiana tras la introduccion en Espana de la vacuna antineumococica heptavalente (VNC7) ha implicado cambios en la adecuacion del tratamiento antibiotico de la otitis media aguda (OMA) en ninos. Materiales y metodos. Los parametros PK y datos de sensibilidad de Streptococcus pneumoniae y Haemophilus influenzae fueron obtenidos de la bibliografia. Mediante simulacion de Montecarlo, calculamos la probabilidad de exito del tratamiento antibiotico, expresada como fraccion de respuesta acumulada (CFR). Para amoxicilina y amoxicilina/acido clavulanico, el objetivo farmacodinamico considerado fue el tiempo durante el cual las concentraciones libres en sangre permanecen por encima de la concentracion minima inhibitoria (CMI), expresado como porcentaje del intervalo de dosificacion (fT>CMI≥50%). Para cefuroxima axetilo y cefotaxima, el objetivo fue fT>CMI≥60%. Valores de CFR≥90% se consideraron indicativos de exito. Resultados. Si se tienen en cuenta todos los serotipos de S. pneumoniae, amoxicilina y cefotaxima proporcionaron una alta probabilidad de exito, sin apenas diferencia entre ambos periodos. En el caso de H. influenzae, los valores de CFR fueron mas altos con amoxicilina/acido clavulanico que con amoxicilina. Para ambos microorganismos, las probabilidades de exito de cefuroxima axetilo fueron bajas en ambos periodos de estudio. Conclusiones. La introduccion de la vacuna PCV7 no ha implicado cambios en la probabilidad de exito del tratamiento antibiotico empirico de la OMA. Hemos demostrado la utilidad del analisis PK/PD para detectar cambios en la adecuacion del tratamiento antibiotico tras la implantacion de una vacuna, proporcionando informacion complementaria al seguimiento de los valores de CMI. espanolObjectives. To evaluate, by applying pharmacokinetic/ pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). Material and methods. PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. Results. When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. Conclusions. We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implanta tion of a vaccination program, providing complementary information to the simple assessment of MIC values.

Antibiotic susceptibility trend before and after long-term use of selective digestive decontamination: a 16 year ecological study.

Abstract: OBJECTIVES The aim of this study was to compare antimicrobial susceptibility rates in a Spanish ICU before and after the introduction of selective digestive decontamination (SDD) and also to compare these with susceptibility data from other Spanish ICUs without SDD. METHODS We performed a retrospective study in the ICU of the University Hospital of Alava, where SDD was implemented in 2002. The SDD protocol consisted of a 2% mixture of gentamicin, colistin and amphotericin B applied on the buccal mucosa and a suspension of the same drugs in the gastrointestinal tract; additionally, for the first 3 days, systemic ceftriaxone was administered. From 1998 to 2013 we analysed the susceptibility rates for 48 antimicrobial/organism combinations. Interrupted time series using a linear dynamic model with SDD as an intervention was used. Data from other ICUs were obtained from the ENVIN-HELICS national registry. RESULTS Only amoxicillin/clavulanic acid against Escherichia coli and Proteus mirabilis, and a high concentration of gentamicin against Enterococcus faecalis, resulted in a significant decrease in the susceptibility rate after the implementation of SDD, with a drop of 20%, 27% and 32%, respectively. Compared with other Spanish ICUs without SDD, the susceptibility rate was higher in the ICU of our hospital in most cases. When it was lower, differences were <10%, except for a high concentration of streptomycin against Enterococcus faecium, for which the difference was 19%. CONCLUSIONS No relevant changes in the overall susceptibility rate after the implementation of SDD were detected. Susceptibility rates were not lower than those in the Spanish ICUs without SDD.