Development of a Mucoadhesive Vehicle Based on Lyophilized Liposomes for Drug Delivery through the Sublingual Mucosa.

A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive mixtures with mucoadhesive and taste-masking properties. Palatability was assayed on healthy volunteers. The lyophilization cycle was optimized, and the lyophilized product was compressed to obtain round and capsule-shaped tables that were evaluated in healthy volunteers. Tablets were also assayed regarding weight and thickness uniformities, swelling index and liposome release. The results proved that lyophilized liposomes in unidirectional round tablets have palatability, small size, comfortability and buccal retention adequate for sublingual administration. In contact with water fluids, the tablets swelled, and rehydrated liposomes were released at a slower rate than permeation efficiency determined using a biomimetic membrane. Permeability efficiency values of 0.72 ± 0.34 µg/cm2/min and 4.18 ± 0.95 µg/cm2/min were obtained for the liposomes with and without additives, respectively. Altogether, the results point to the vehicle proposed as a liposomal formulation suitable for systemic drug delivery through the sublingual mucosa.

Lyoprotective Effects of Mannitol and Lactose Compared to Sucrose and Trehalose: Sildenafil Citrate Liposomes as a Case Study.

The lyoprotective effects of mannitol and lactose have been evaluated in the production of sildenafil citrate liposomes. Liposomes were prepared by mixing the components under ultrasonic agitation, followed by a transmembrane pH gradient for remote drug loading. Mannitol and lactose, as compared to sucrose and trehalose, were used as the stabilizing agents, and different freeze-drying cycles were assayed. The remaining moisture and the thermal characteristics of the lyophilized samples were analyzed. Size, entrapment efficiency, biocompatibility, and cell internalization of original and rehydrated liposomes were compared. The type of additive did not affect the biocompatibility or cell internalization, but did influence other liposome attributes, including the thermal characteristics and the remaining moisture of the lyophilized samples. A cut-off of 5% (w/w) remaining moisture was an indicator of primary drying completion-information useful for scaling up and transfer from laboratory to large-scale production. Lactose increased the glass transition temperature to over 70 °C, producing lyoprotective effects similar to those obtained with sucrose. Based on these results, formulations containing liposomes lyophilized with lactose meet the FDA's requirements and can be used as a biocompatible and biodegradable vehicle for the pulmonary delivery of therapeutic doses of sildenafil citrate.

Xanthan Gum-Konjac Glucomannan Blend Hydrogel for Wound Healing.

Hydrogels are considered to be the most ideal materials for the production of wound dressings since they display a three-dimensional structure that mimics the native extracellular matrix of skin as well as a high-water content, which confers a moist environment at the wound site. Until now, different polymers have been used, alone or blended, for the production of hydrogels aimed for this biomedical application. From the best of our knowledge, the application of a xanthan gum-konjac glucomannan blend has not been used for the production of wound dressings. Herein, a thermo-reversible hydrogel composed of xanthan gum-konjac glucomannan (at different concentrations (1% and 2% w/v) and ratios (50/50 and 60/40)) was produced and characterized. The obtained data emphasize the excellent physicochemical and biological properties of the produced hydrogels, which are suitable for their future application as wound dressings.

Lyophilized tablets for focal delivery of fluconazole and itraconazole through vaginal mucosa, rational design and in vitro evaluation.

The present work deals with the rational design and in vitro evaluation of vaginal tablets for focal delivery of fluconazole (FLZ) and itraconazol (ITZ). Drug loaded liposomes with and without d-alpha-tocopheryl polyethylene glycol 1000 succinate (vit E TPGS) were prepared by direct sonication of the components and mixed with albumin to obtain albusomes. Tablets were obtained by direct compression of the lyophilized cake. The influence of vit E TPGS on size, zeta potential and entrapment efficiency (EE%) of liposomes and albusomes was evaluated. Tablet swelling and drug release were studied by in vitro assays. Vit E TPGS neither affected the zeta potential nor the EE% of liposomes and albusomes, but affected the liposomes size and the tablet disintegration time. A rapid erosion was observed for the tablets with the highest content of vitamin, while a slow swelling for those lacking the vitamin (swelling index = 57.76 ±â€¯13.51%). A faster drug release profile was obtained for the former compared to the latter. The in vitro assay showed that FLZ diffused and solved in the vaginal fluid simulant while ITZ remained into the albusomes, which slowly released ITZ-albumin complex and ITZ-loaded liposomes, both suitable carriers for drug transport to deeper vaginal endothelium.

Albumin micro/nanoparticles entrapping liposomes for itraconazole green formulation.

Itraconazole-loaded micro/nanoparticles containing albumin and liposomes were prepared by a technological process that avoids the use of organic solvents and crosslinker agents. The particles were characterized, lyophilized and formulated as tablets. Dynamic light scattering was used to determine the hydrodynamic diameter and zeta potential of the particles; optical and scanning-electron microscopy was used to evaluate their morphology. Spherical shaped particles of different sizes and zeta potential were obtained. An exponential relationship between the zeta potential and the albumin/cationic lipid molar ratio was established. Drug entrapment efficiency values were in the range of 51-68%, with no statistical differences among albumin feeding concentrations. Mannitol was used as lyophilization additive and the freeze-dried cake was directly compressed into tablets, suitable for vaginal administration. The results from the in vitro drug delivery assay show the influence of albumin on the itraconazole delivery profile; a rapid release was observed for particles with higher albumin amount compared to those with lower protein content. According to the results of this study, albumin particles entrapping liposomes prove to be a green pharmaceutical vehicle with a high potential for delivery of hydrophobic and highly albumin-bound drugs.

Development and In Vitro Evaluation of a Novel Drug Delivery System (Albumin Microspheres Containing Liposomes) Applied to Vancomycin.

A pharmaceutical vehicle based on the encapsulation of liposomes with unmodified albumin has been designed, formulated, and in vitro characterized. Microscopy was used to investigate particle morphology and dynamic light scattering to determine the size and zeta potential. Vancomycin was selected as a model drug for water-soluble and moderately albumin-bound products. The results indicated that regardless of the zeta potential of the liposomes these can be trapped within albumin microspheres. The zeta potential, drug entrapment efficacy, and drug delivery profile of the resulting microspheres were found to depend on the liposome composition and the conditions of flocculation. The protein concentration was observed to influence drug entrapment efficiency (from 13.17 ± 5.0% to 61.27 ± 4.54%), as did the zeta potential of the microspheres, which was also seen to depend on the initial charge of the liposomes. The relationship between the microsphere zeta potential or entrapment efficacy and the protein concentration used for flocculation was established. Regarding drug delivery, differences between microspheres prepared from cationic or anionic liposomes were observed. The combination of liposome versatility together with the drug-binding ability of albumin provides to a vehicle with multiple choices for theranostic delivery.

Vancomycin dosage optimization in patients with malignant haematological disease by pharmacokinetic/pharmacodynamic analysis.

BACKGROUND: The use of vancomycin against Staphylococcus aureus is currently debated because of the increasing resistance developed by this pathogen. Nevertheless, antibacterial effectiveness is a limited resource that must be protected and restored. Novel dosage strategies based on pharmacokinetic/pharmacodynamic analyses are needed to retain effectiveness that could improve drug exposure in patients infected with such pathogens. OBJECTIVE: The aim of this study was to assess whether standard or higher vancomycin dosages are required to increase the probability of attaining a target pharmacokinetic/pharmacodynamic index for several staphylococcal strains and thus to estimate the minimum vancomycin daily dose related to a high probability of effective treatment in patients with malignant haematological disease. METHODS: Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR) for different vancomycin daily dosages, using a population pharmacokinetic model previously defined in patients with malignant haematological disease and the minimum inhibitory concentration (MIC) distribution for vancomycin against several staphylococcal species (vancomycin-susceptible S. aureus and vancomycin-intermediate S. aureus [VISA], S. epidermidis, S. haemolyticus and coagulase-negative Staphylococcus [CNS] species) obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in order to predict the dose that would achieve the pharmacokinetic/pharmacodynamic index value associated with efficacy (the area under the concentration-time curve from 0 to 24 hours divided by the MIC [AUC(24)/MIC >/=400]). RESULTS: CFR values showed dependence on the renal function of the patient and the causative pathogen. Only in patients with a creatinine clearance (CL(CR)) <60 mL/min did the standard vancomycin dosage (2000 mg/day) induce CFRs >60% for all staphylococci, except the VISA strains. CFRs for S. aureus of 90.6%, 47.3% and 31.2% for CL(CR) values of <60, 60-120 and >120 mL/min, respectively, were obtained, whereas for the VISA strains, the corresponding values were only 14.0%, 0.3% and 0%. The impact of potential pathogens on CFRs is also significant. According to our pharmacokinetic/pharmacodynamic analysis, in patients with normal renal function (CL(CR) between 60 and 120 mL/min) vancomycin 2000 mg/day leads to a risk of not achieving the recommended AUC(24)/MIC breakpoint of 52.7%, 70.4%, 74.9% and 80.3% for S. aureus, S. haemolyticus, CNS and S. epidermidis, respectively. Application of our results to clinical practice graphically allows us to obtain the recommended dose for any a priori-selected probability of attaining the AUC(24)/MIC ratio of >/=400 and to evaluate the CFRs for any dosing regimen used in this population group, depending on the patients' renal function. CONCLUSIONS: Application of pharmacokinetic/pharmacodynamic analysis based on Monte Carlo simulation offers an excellent tool for selecting the therapeutic option with the highest probability of clinical success in patients with malignant haematological disease. Thus, for vancomycin-susceptible S. aureus, if a CFR >/=80 is assumed as clinically acceptable, vancomycin doses of 1500, 3000 and 4000 mg/day for a CL(CR) of <60, 60-120 and >120 mL/min, respectively, will be required.

Pulmonary versus systemic delivery of levofloxacin. The isolated lung of the rat as experimental approach for assessing pulmonary inhalation.

The present work was aimed to compare levofloxacin pulmonary disposition after systemic or inhalatory delivery and to evaluate the influence of respiratory pattern on lung distribution. An experimental model of the isolated lung of the rat was used. Twenty-four Wistar rats were distributed in four groups receiving levofloxacin under different experimental conditions including systemic or pulmonary delivery and higher or lower respiratory frequency with lower or higher tidal volume, respectively. Levofloxacin (500 microg) was administered as a bolus injection or by inhalation. Lung tissue samples as well as efferent and broncoalveolar fluid were collected. Quantification of levofloxacin levels in all samples was performed by a high-performance liquid chromatography (HPLC) technique. Pulmonary distribution coefficient of levofloxacin after systemic delivery showed mean values of 1.19+/-0.13 and 3.34+/-0.61 ml/g for each respiratory pattern assayed. The partition coefficients estimated from simultaneous drug level in lung tissue and efferent fluid (EF) are in agreement with the above values. Comparison of systemic and pulmonary administration reveals statistical significant differences between partition coefficients showing much higher values for the latter route (8.01+/-5.53 versus 2.86+/-1.35). In conclusion, inhalation compared to systemic administration improves levofloxacin access to the lung tissue; the experimental approach used here to assess the pulmonary drug disposition may be a useful model for biopharmaceutical studies of inhaled therapeutics.

Pharmacokinetic/pharmacodynamic analysis of vancomycin in ICU patients.

AIMS: To identify the variables affecting vancomycin pharmacokinetics in medical ICU patients and to evaluate the potential efficacy of dosage schedules by PK/PD analysis. DESIGN: A retrospective pharmacokinetic analysis of serum levels obtained in routine vancomycin monitoring was performed. SETTING: A 12-bed general ICU of a university teaching hospital. PATIENTS: Forty-six vancomycin-treated ICU patients fitting the following criteria: over 18 years old; more than three concentration data per patient; absence of renal replacement support, cardiac surgery and neoplastic disorders. INTERVENTIONS: Clinical information was collected from the patients' medical records. Details of vancomycin therapy, dosage and blood sampling times were obtained from pharmacokinetic reports. Population analysis were made by the standard two-stage approach. MEASUREMENTS AND MAIN RESULTS: Vancomycin clearance and distribution volume were estimated individually assuming a one-compartment pharmacokinetic model. PK/PD analysis was performed by Monte Carlo simulation. In the ICU patients, higher Vd (nearly twice the quoted value of 0.72 l/kg) and different vancomycin clearance-creatinine clearance relationship were found. Renal function, the APACHE score, age and serum albumin accounted for more than 65% of drug clearance variability. Vancomycin standard dosages led to a 33% risk of not achieving the recommended AUC(24h)/MIC breakpoint for Staphylococcus aureus. CONCLUSIONS: The population kinetics and PK/PD analyses based on Monte Carlo simulation procedures offer an excellent tool for selecting the therapeutic option with the highest probability of clinical success in ICU patients.

New formulations of amoxicillin/clavulanic acid: a pharmacokinetic and pharmacodynamic review.

The pharmacokinetic properties of amoxicillin and clavulanic acid when used alone or in combination are extensively reviewed and discussed in this article. The reported data support a nonlinear absorption process for amoxicillin. Saturable transport mechanisms, limited solubility and the existence of an absorption window are possibly involved in the gastrointestinal absorption of this antibacterial, all leading to a decrease in the peak plasma concentration (Cmax)/dose ratio, a prolongation of the time to reach Cmax, and broad variability for high doses of amoxicillin. Data available in the literature also suggest a possible interaction between amoxicillin and clavulanic acid that might decrease the absolute bioavailability of clavulanic acid. In the present review the intrinsic pharmacodynamics of each drug, together with the synergism produced by the amoxicillin/clavulanic acid association, are also reviewed and analysed. Not only beta-lactamase-producing strains, but also Streptococcus pneumoniae strains, seem to be more efficiently eradicated by the association of amoxicillin and clavulanic acid, and a relevant post-antibacterial effect and post-beta-lactamase inhibitor effect are likely to operate when amoxicillin is administered together with clavulanic acid. The principles of pharmacokinetic/pharmacodynamic analysis applied to amoxicillin are reviewed, with special emphasis being placed on the results obtained from in vitro studies and animal models regarding the new pharmacokinetically enhanced formulation. Theoretical considerations concerning the efficacy of this formulation provided by the application of pharmacokinetic/pharmacodynamic analysis to the scarce pharmacokinetic data available are also included. The broad pharmacokinetic variability of both amoxicillin and clavulanic acid, particularly when administered together and at high doses of amoxicillin, is highlighted and the interest in considering this aspect to improve predictions based on pharmacokinetic/pharmacodynamic analyses for the new formulations is indicated. Methodological recommendations such as the Monte Carlo simulation are proposed in order to obtain more realistic predictions in clinical practice.

Comparative study of the disposition of levofloxacin, netilmicin and cefepime in the isolated rat lung.

An experimental model of artificially perfused and mechanically ventilated lung has been applied to compare the kinetic behaviour of levofloxacin, cefepime and netilmicin in this body tissue. The study has been performed to explore the usefulness of the isolated lung technique in the pharmacokinetic field, particularly to study the disposition of antibiotics in pulmonary tissue. The lung was perfused with Krebs-Henseleit medium containing 3% bovine albumin at a flow rate of 5 mL min(-1). It was ventilated at 60 respirations/min with a 2-mL tidal volume of air previously humidified and warmed to 37 degrees C. The concentrations of the above antibiotics were determined by HPLC techniques and the outflow curves were analysed by stochastic, as well as by model-dependent, methods. The results show pharmacokinetic differences among these antibiotics, which are in accordance with previously reported data, levofloxacin being the drug with the highest distribution coefficient in this tissue (1.25 +/- 0.14 vs 0.39 +/- 0.07 and 0.41 +/- 0.06 mL g(-1) for netilmicin and cefepime, respectively). Accordingly, the isolated lung of the rat, under the experimental conditions used here, constitutes an alternative model to be incorporated to pharmacokinetic studies with a great potential use for those drugs that show a pharmacological or toxicological action depending on the kinetic profile in the lung tissue.

Pharmacokinetics and pharmacodynamics of levofloxacin in intensive care patients.

OBJECTIVE: A prospective pharmacokinetic study was performed in Caucasian patients from an intensive care unit with respiratory support to evaluate the influence of this circumstance on the pharmacokinetic behaviour of levofloxacin. PATIENTS AND METHODS: A standard dosage regimen of 500 mg/day was administered to nine Caucasian patients included in the study, irrespective of their demographic characteristics. The experimental data on plasma concentrations were analysed by independent-modelling techniques to estimate the following pharmacokinetic parameters: area under the plasma concentration-time curve (AUC), volume of distribution at steady state (V(ss)), plasma clearance (CL), maximum plasma concentration at steady state (C(max)(,)(ss)) and elimination half-life (t((1/2))(beta)). Multiple regression analysis was applied to establish the type of correlation between the pharmacokinetic parameters and patient characteristics; the Monte Carlo simulation technique was implemented for the pharmacokinetic/pharmacodynamic analysis based on the probability distribution of the values of AUC/minimum inhibitory concentration (MIC) and C(max)(,)(ss)/MIC observed in this group of patients. RESULTS AND CONCLUSION: The results show that for AUC the simplest linear model with creatinine clearance as the only independent variable fits the data at a 99% confidence level, explaining more than 85% of the observed variability in this parameter. The volume of distribution, however, showed a statistical correlation with the severity of the illness (Simplified Acute Physiology Score II), although total bodyweight also explains a high percentage of variability of these parameters. Since the group of patients included in the study was small and also included obese individuals, it is difficult to estimate with precision the contribution of each circumstance (overweight or illness severity) to the pharmacokinetic behaviour of levofloxacin.

Influence of flow rate on the disposition of levofloxacin and netilmicin in the isolated rat lung.

The objective of this study was to examine the influence of the rate at which the tissue is perfused on the disposition of levofloxacin and netilmicin in the pulmonary tissue, using an experimental model of the isolated rat lung. Analysis of the results was performed using two pharmacokinetic approaches. By stochastic analysis of outflow curves the corresponding statistical moments and derived distribution coefficient were calculated. Model-dependent analysis based on a three-compartment dispersion model was also applied to the outflow concentration data. A statistically significant decrease in the distribution coefficient was observed for both antibiotics when the flow rate was decreased. For levofloxacin this parameter takes values of 2.14 and 1.25 mL/g for 10 and 5 mL/min flow rates, respectively. In the case of netilmicin these values were 0.81 and 0.39 mL/g for the higher and lower flow rates, respectively. Model parameters related to the distribution process were also modified as a consequence of the flow rate decrease. Tissue flow rate seems to be a determinant factor on the distribution of levofloxacin and netilmicin in the isolated rat lung.

Pharmacokinetics of ciprofloxacin as a tool to optimise dosage schedules in community patients.

OBJECTIVE: To evaluate the dosage regimens of ciprofloxacin prescribed for outpatients by applying the principles of antibacterial therapy. DESIGN: Retrospective analysis of prescription and demographic data. SETTING: Community pharmacy in Valladolid, Spain. PATIENTS: Fifty male and female patients aged 18-93 years and with bodyweight 41-95kg. METHODS: Prescribed dosage regimen, age, weight, height, type of infection, comorbidity and coadministered drugs were recorded for each patient. Plasma concentration curves were simulated from literature values of the pharmacokinetic parameters of the drug and the age and weight of the patients. Urine concentrations were estimated from simulated plasma concentrations, literature values of renal clearance and an average urinary flow rate of 2 L/day. The potential efficacy of the prescribed treatment was evaluated from the ratio of the simulated peak plasma concentration (C(max)) to the literature value of the minimum inhibitory concentration (MIC) for the bacterium most probably responsible for the infection (C(max) /MIC). The ratio of area under the plasma concentration-time curve over 24 hours to MIC (AUC24 /MIC) was also estimated for non-urinary infections. RESULTS: Demographic variables such as age or bodyweight do not seem to be taken in consideration when ciprofloxacin is prescribed, at least in the patients considered here, leading to wide interindividual variability in plasma concentrations. This may not be relevant for urinary infections, since ciprofloxacin concentrates in the urine, leading to high Cmax /MIC ratios in all patients. Simulated plasma concentration-time curves revealed consistent underdosing for systemic infections in young patients over 60kg, for whom the plasma concentrations achieved led to Cmax /MIC and AUC24 /MIC ratios lower than those associated with clinical efficacy and minimal spread of bacterial resistance. CONCLUSIONS: The standard regimen of ciprofloxacin 250mg every 12 hours prescribed for urinary infections may not be the best choice, since a more convenient regimen of 500mg once daily leads to a higher Cmax /MIC ratio, which is associated with a more significant postantibiotic effect and higher efficacy of fluoroquinolones. For non-urinary infections, the age and weight of patients should be taken into account to achieve optimum plasma concentrations.

Pharmacokinetic/pharmacodynamic modelling of ciprofloxacin 250 mg/12 h versus 500 mg/24 h for urinary infections.

A simulation study was performed to evaluate and compare the standard dosage regimen of 250 mg/12 h versus 500 mg/24 h of ciprofloxacin for the treatment of urinary tract infections (UTIs). Pharmacokinetic parameters reported for healthy young and old individuals were used for the simulation of drug levels in urine, at different mean urine flow rates (1-2.5 L/day). Pharmacokinetic/pharmacodynamic analysis of the results revealed that 500 mg ciprofloxacin once a day produced a more favourable profile in urine than 250 mg/12 h, particularly in the elderly, due to the slower elimination of the drug in this group of patients. Circadian rhythms were also considered for the simulation of drug levels in urine. According to the results, 500 mg once a day administered in the morning would be a better choice than 250 mg/12 h at least for uncomplicated UTI; nevertheless, clinical assays are needed to prove this hypothesis.

Influence of the infusion rate on disposition of netilmicin in the isolated rat perfused kidney.

A study of the disposition of netilmicin in the isolated rat kidney was carried out in order to establish the influence of the infusion rate on the drug profile in this tissue. A dose of 800 microg administered as a bolus injection or at infusion times of 5, 7.5 and 10 min, respectively, was injected through the afferent cannula into the isolated kidney. Analysis of outflow curves was carried out using different kinetic approaches. Comparison of statistical moments and derived parameters pointed to changes in the distribution process with the infusion rate. In contrast, elimination remained constant, since the extraction coefficient and relative area under the curve values did not change with the infusion rate, although the MTT (mean transit time) and distribution volume decreased for the longest infusion times. The UDF (unit disposition function) profiles were not superimposed for the different infusion rates and combined with the results of the kinetic analysis revealed that the behaviour of netilmicin in the isolated kidney depends on infusion rate. The apparent partition coefficients in renal cortex and medulla showed higher values for the slower perfusion rates. Yet, a progressive decrease in the absolute amount of netilmicin was predicted in the tubular epithelium compartment whereas the residence time tended to increase. The latter phenomenon could account for the higher aminoglycoside nephrotoxicity reported when these drugs are administered over longer infusion times.

Influence of dose on the disposition kinetics of netilmicin in the isolated kidney of the rat.

The disposition of Netilmicin in the isolated rat kidney was studied in order to determine the influence of dose on the drug profile in this tissue. Doses of 50, 200, 800 or 10000 mg were injected through an afferent cannula into the isolated kidney as a bolus injection and outflow perfusate samples were collected. Statistical moments (AUC, MTT, VTT) were estimated from raw outflow curve data. Unit disposition function (UDF) was obtained by mass balance for each studied dose. The results of control assays addressing the viability of the isolated kidney preparations point to a high reproducibility for this preparation under the experimental conditions used, together with an acceptable viability. Comparison of statistical moments and derived parameters such as the extraction coefficient, distribution volume and drug renal clearance (E, Vd, ClE) suggest the existence of modifications in the distribution process with the dose, while elimination seems to remain unvariable; accordingly, the unit disposition function profiles were not superimposed for the different doses but differences during the early and final phases were observed.

Atención farmacéutica en antibioterapia: fluoroquinolonas / Antibiotherapy pharmaceutical care: fluoroquinolones

El incremento progresivo de microorganismos resistentes causantes de infecciones de difícil tratamiento ha llevado a la implantación de diversos programas destinados a evitar el abuso y mal uso de los antibióticos, al ser ésta una causa directamente relacionada con la aparición de resistencias. El objetivo de este estudio ha sido el de evaluar las pautas posológicas de las fluoroquinolonas prescritas en el ámbito comunitario en relación con su potencial eficacia, así como establecer un protocolo de actuación farmacéutica destinado a prevenir y evitar los PRMs más probables para este grupo de fármacos. Para ello se ha aplicado una metodología, previamente descrita, basada en la simulación de curvas de niveles de fármaco en sangre u orina considerando la variabilidad famacocinética asociada a las características demográficas de los pacientes. Los resultados obtenidos demuestran que las pautas de dosificación prescritas corresponden a unos estándares preestablecidos, independientemente de la edad o peso del paciente para el que se prescribe la quinolona. En consecuencia, las concentraciones de fármaco simuladas difieren significativamente de unos casos a otros, lo que puede no tener trascendencia clínica en infecciones urinarias debido a las altas concentraciones alcanzadas en orina, pero sí en infecciones de otro tipo, ya que los niveles en plasma simulados para ciprofloxacino son, en algunos casos, inferiores a los recomendados para optimizar la eficacia del tratamiento y minimizar la aparición de resistencias (AU)

Progressive resistance emergence responsible for infections with complicated treatments has lead to the establishment of different types of programs aimed at controlling the misuse of these drugs since the latter has been related to the emerging resistance. The aim of this study was to evaluate the dosage patterns of the fluoroquinolone prescriptions for the community patients in relation with its potential efficacy as well as to establish a protocol to be applied at the community pharmacy to avoid the most probable FRM for this group of drugs. The methodology used has been previously described and, briefly, it consists in the simulation of the urine and plasma drug levels taking into account the variability in pharmacokinetics, according to the demographics of the patient.The results show that a standard dosage pattern is prescribed with no consideration of the age and body weight, leading to a significant inter-variability in the simulated levels of the drug. This may not show clinical implications for urinary infections since these drugs concentrate in urine and reach sufficiently high values in this fluid. Nevertheless, despite urine levels simulated plasma concentrations of ciprafloxacin are in some cases lower than the recommended values for improving efficacy and reducing resistance emergence (AU)

Optimización de la posología antibacteriana (II): metodología para la individualización posológica dual en la práctica clínica / Antibiotic Therapy Optimization (II): methodology for dual posologic individualization in clinical practice

La individualización de la posología antimicrobiana debe realizarse en la práctica clínica en base a la optimización del índice de eficacia mejor correlacionado con la respuesta. De forma general se acepta que Cmaxss /CMI es el índice óptimo para aminoglucósidos, fluoroquinolonas y aquellos antimicrobianos que presentan un efecto postantibiótico (EPA) marcado, siendo el tsupraCMI el recomendado para los antibióticos sin EPA, como es el caso de los beta-lactámicos; sin embargo, existen otros índices dependientes del área bajo la curva cuya correlación con la respuesta a distintos tratamientos antibacterianos también ha sido probada. En base a esto resulta aconsejable establecer, en cada ámbito sanitario, el grado de correlación entre distintos índices de eficacia y la respuesta clínica observada mediante la realización del correspondiente análisis de correlación. Este tipo de análisis puede plantearse con carácter retrospectivo o prospectivo y en base a modelos de respuesta lineales o de efecto máximo; en cualquier caso, la simulación de las curvas de concentraciones plasmáticas correspondientes al régimen posológico administrado proporciona una metodología de fácil aplicación que aporta la información farmacocinética necesaria para calcular los índices de eficacia definidos y la evaluación a priori de la potencial eficacia del tratamiento propuesto. Información adicional sobre la susceptibilidad del patógeno causante de la infección y sobre la respuesta al tratamiento administrado es necesaria para llevar a cabo el análisis que determine cuál de los índices presenta mayor correlación con la eficacia y, por tanto, cuál debe optimizarse para individualizar la posología antibacteriana en cada situación clínica considerada. (AU)

In clinical practice, antimicrobial dosage individualization should be based on the optimization of the efficacy index best correlated with patient response. Although the Cmaxss/MIC ratio is the most recommended index for aminoglycosides, fluoroquinolanes and those antibiotics showing a postantibiotic effect (EPA), and the tsupraMlC is the one for antimicrobials with no EPA, such as the betalactams, it is also true that other indices based on the area under the curve are well correlated to clinical response. Accordingly, it seems appropriate to establish the degree of correlation among the different efficacy indices and the clinical response by clinicians in their own patients by means of the corresponding correlation analysis. This type of analysis can be either retrospective or prospective and may be based on linear or maximum response models. In any case, simulation of the plasma concentrations curves obtained with the dosage schedule administered offers a methodology that is easy to apply and that provides the pharmacokinetic information necessary to calculate the different efficacy indices defined. Information about the susceptibility of the pathogen responsible and concerning the response to the treatment supplied is also necessary to conduct the correlation analysis. This type of analysis determines which of the indices is best correlated with efficacy and hence the one to be optimized when attempting to individualize antibacterial closing in each situation (AU)

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