Pharmacokinetic/Pharmacodynamic Analysis of Oral Calcium Fosfomycin: Are Urine Levels Sufficient to Ensure Efficacy for Urinary Tract Infections?

Urinary tract infections (UTIs) are extremely common and a major driver for the use of antimicrobials. Calcium fosfomycin is an old antibiotic indicated for the treatment of UTIs; however, data about its urine pharmacokinetic profile are scarce. In this work, we have evaluated the pharmacokinetics of fosfomycin from urine concentrations after oral administration of calcium fosfomycin to healthy women. Moreover, we have assessed, by pharmacokinetic/pharmacodynamic (PK/PD) analysis and Monte Carlo simulations, its effectiveness considering the susceptibility profile of Escherichia coli, the main pathogen involved in UTIs. The accumulated fraction of fosfomycin excreted in urine was around 18%, consistent with its low oral bioavailability and its almost exclusively renal clearance by glomerular filtration as unchanged drug. PK/PD breakpoints resulted to be 8, 16, and 32 mg/L for a single dose of 500 mg, a single dose of 1000 mg, and 1000 mg q8h for 3 days, respectively. For empiric treatment, the estimated probability of treatment success was very high (>95%) with the three dose regimens, considering the susceptibility profile of E. coli reported by EUCAST. Our results show that oral calcium fosfomycin at a dose level of 1000 mg every 8 h provides urine concentrations sufficient to ensure efficacy for the treatment of UTIs in women.

Ceftaroline and Avibactam Removal by Continuous Renal Replacement Therapies: An in vitro Study.

INTRODUCTION: Continuous renal replacement therapies (CRRTs) are frequently used in critically ill patients; however, there are scarce in vitro and in vivo studies showing the extracorporeal elimination of ceftaroline and avibactam. The aim of this study was to assess, through an in vitro model, the extracorporeal elimination of ceftaroline and avibactam by continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodiafiltration (CVVHDF), and continuous veno-venous hemodialysis (CVVHD), using a polysulfone hemofilter. METHODS: Simulated in vitro experiments were performed using a multiFiltrate machine with a 1.4 m2 Ultraflux® AV600S polysulfone hemofilter. Isofundin® without or with bovine serum albumin was circulated as vehicle for ceftaroline or avibactam. Pre-filter, post-filter, and effluent samples were taken over a period of 60 min, and they were immediately stored at 4°C until processed in the same day. The quantification of ceftaroline and avibactam in the samples was performed by high-performance liquid chromatography with ultraviolet detection. Protein binding, extraction coefficient (EC), and extracorporeal clearance (CLCRRT) were calculated. RESULTS: The elimination of both ceftaroline and avibactam during the three extracorporeal modalities followed first-order pharmacokinetics. Regardless of the CRRT technique, EC values for both molecules were around 1, similar to the unbound fraction of avibactam (0.96) and higher than the unbound fraction of ceftaroline (0.79). CLCRRT of ceftaroline ranged from 15.63 to 17.66 mL/min when CVVH and CVVHD were used with a flow rate of 1,000 mL/h, and from 29.25 to 32.95 mL/min for the CVVHDF modality with a flow rate of 2,000 mL/h. For avibactam, CLCRRT ranged from 15.07 to 18.82 mL/min for CVVH and CVVHD, and from 33.74 to 34.13 mL/min for CVVHDF. DISCUSSION: Avibactam and ceftaroline are extensively removed through the polysulfone membrane, and a dose adjustment may be recommended for patients under CRRT to ensure pharmacodynamic target achievement.

Key Factors in Effective Patient-Tailored Dosing of Fluoroquinolones in Urological Infections: Interindividual Pharmacokinetic and Pharmacodynamic Variability.

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

Pseudomonas aeruginosa Susceptibility in Spain: Antimicrobial Activity and Resistance Suppression Evaluation by PK/PD Analysis.

Pseudomonas aeruginosa remains one of the major causes of healthcare-associated infection in Europe; in 2019, 12.5% of invasive isolates of P. aeruginosa in Spain presented combined resistance to ≥3 antimicrobial groups. The Spanish nationwide survey on P. aeruginosa antimicrobial resistance mechanisms and molecular epidemiology was published in 2019. Based on the information from this survey, the objective of this work was to analyze the overall antimicrobial activity of the antipseudomonal antibiotics considering pharmacokinetic/pharmacodynamic (PK/PD) analysis. The role of PK/PD to prevent or minimize resistance emergence was also evaluated. A 10,000-subject Monte Carlo simulation was executed to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) considering the minimum inhibitory concentration (MIC) distribution of bacteria isolated in ICU or medical wards, and distinguishing between sample types (respiratory and non-respiratory). Ceftazidime/avibactam followed by ceftolozane/tazobactam and colistin, categorized as the Reserve by the Access, Watch, Reserve (AWaRe) classification of the World Health Organization, were the most active antimicrobials, with differences depending on the admission service, sample type, and dose regimen. Discrepancies between EUCAST-susceptibility breakpoints for P. aeruginosa and those estimated by PK/PD analysis were detected. Only standard doses of ceftazidime/avibactam and ceftolozane/tazobactam provided drug concentrations associated with resistance suppression.

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function.

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials.

Pharmacokinetic/pharmacodynamic (PK/PD) analysis has proved to be very useful to establish rational dosage regimens of antimicrobial agents in human and veterinary medicine. Actually, PK/PD studies are included in the European Medicines Agency (EMA) guidelines for the evaluation of medicinal products. The PK/PD approach implies the use of in vitro, ex vivo, and in vivo models, as well as mathematical models to describe the relationship between the kinetics and the dynamic to determine the optimal dosing regimens of antimicrobials, but also to establish susceptibility breakpoints, and prevention of resistance. The final goal is to optimize therapy in order to maximize efficacy and minimize side effects and emergence of resistance. In this review, we revise the PK/PD principles and the models to investigate the relationship between the PK and the PD of antibiotics. Additionally, we highlight the outstanding role of the PK/PD analysis at different levels, from the development and evaluation of new antibiotics to the optimization of the dosage regimens of currently available drugs, both for human and animal use.

Evaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspective / Evaluación de la adecuación del tratamiento antimicrobiano de las infecciones invasivas por Haemophilus influenzae: perspectiva farmacocinética/farmacodinámica

Introduction: In Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. Methods: Pharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. Results: Regardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL− and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. Conclusions: Our study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.(AU)

Introducción: H. influenzae no tipable (NTHi) es la principal causa de enfermedad invasiva por H. influenzae en adultos en Europa, y frecuentemente está asociada a una alta mortalidad. El principal objetivo de nuestro estudio fue determinar si el tratamiento antibiótico actual es adecuado para tratar infecciones invasivas por H. influenzae en España, teniendo en cuenta la probabilidad de alcanzar el objetivo farmacocinético/farmacodinámico (PK/PD). Métodos: Los parámetros farmacocinéticos de los antibióticos (ampicilina, amoxicilina, amoxicilina/clavulanato, ceftriaxona, cefotaxima, imipenem y ciprofloxacino) y los datos de sensibilidad de H. influenzae se obtuvieron de la literatura. Mediante simulación de Montecarlo, se estimó la probabilidad de alcanzar el objetivo farmacodinámico (PTA) y la fracción de respuesta acumulada (CFR), ambas indicativas de la probabilidad de éxito del tratamiento. Resultados: Independientemente del régimen de dosificación, todos los antibióticos proporcionaron valores de CFR del 100% o cerca del 100% para todas las cepas, incluidas BL+, BL− y BLNAR, excepto amoxicilina y ampicilina para BL+. Si la infección se debe a cepas BL+, el tratamiento con amoxicilina y ampicilina tiene una baja probabilidad de éxito (CFR≤8%). Los puntos de corte PK/PD de la dosis estándar de amoxicilina, amoxicilina/clavulanato e imipenem concuerdan con los puntos de corte clínicos de EUCAST. Para el resto, los puntos de corte PK/PD son más altos que los puntos de corte EUCAST. Conclusiones: Nuestro estudio ha demostrado, mediante análisis PK/PD, que los antibióticos utilizados para el tratamiento de la enfermedad invasiva de H. influenzae proporcionan una probabilidad de éxito elevada.(AU)

Evaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspective.

INTRODUCTION: In Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. METHODS: Pharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. RESULTS: Regardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL- and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. CONCLUSIONS: Our study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.

Pharmacotherapeutic management of Parkinson's disease inpatients: how about asking hospital pharmacists?

INTRODUCTION: Parkinson's disease (PD) is considered to be the fastest growing neurological disorder in the world. Patients with PD are hospitalised more frequently, have longer admissions and experience more complications during hospitalisation than age-matched control groups. The incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs are the most important risk factors for motor function deterioration during hospital admission, and have been associated with longer hospital stays and even increased mortality. Despite their crucial role in pharmacotherapy, little attention has been paid to the perspective of hospital pharmacists. The objective of this study was to identify key issues in the pharmacotherapeutic management of inpatients with PD by the implementation of a national Spanish survey specifically designed to analyse the perspective of hospital pharmacists. METHODS: An internet-based questionnaire covering the following areas was designed: hospital and participant characteristics, drug formulary, medication compliance and reconciliation, protocols and contraindicated drugs and areas for improvement. RESULTS: A total of 76 pharmacists from 59 hospitals answered the survey. Some weaknesses were identified in the availability of drugs: (1) pharmacy services closed at certain times (86.4%); (2) low variety of antiparkinsonian drugs (18.4% store >21 different drugs); (3) delay in antiparkinsonian drug administration if unavailable (>12 hours in 39.5% of cases); (4) lack of flexibility in administration times; (5) low availability of transdermal rotigotine and subcutaneous apomorphine (<50%). The participants ranked highly the designing of specific protocols for patients with PD and implementation of concrete actions to optimise PD inpatient pharmacotherapy. CONCLUSIONS: The participants detected some improvement opportunities and proposed realistic and applicable recommendations and strategies aiming to enhance the safety of patients with PD. Protocols for antiparkinsonian drug interchange, administration timing and nil by mouth status, medication reconciliation, and handling nausea/vomiting or psychotic symptoms are considered the main improvement areas.

Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study / Sensibilidad de Pseudomonas aeruginosa y análisis PK/PD de su actividad antimicrobiana: estudio de vigilancia de 18 años

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 < 70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR > 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

INTRODUCCIÓN: Para evaluar la terapia antimicrobiana frente a Pseudomonas aeruginosa (P. aeruginosa) en pacientes ingresados en un hospital terciario español (excluida Unidad de Cuidados Intensivos), se analizaron los cambios en la sensibilidad a los antimicrobianos durante 18 años (2000-2017). También se evaluó la actividad antimicrobiana utilizando criterios farmacocinéticos/farmacodinámicos (PK/PD) como herramienta de vigilancia microbiológica. MÉTODOS: La sensibilidad se estudió utilizando los puntos de corte del CLSI. Se realizaron simulaciones de Monte Carlo para calcular la fracción de respuesta acumulada (CFR). Se llevó a cabo un análisis de tendencia de sensibilidad y CFR mediante regresión lineal. RESULTADOS: En 2017, la sensibilidad a amikacina, penicilinas y cefalosporinas fue ≥ 85%; tobramicina 76%, meropenem 75% y para gentamicina, imipenem y fluoroquinolonas < 70%. El análisis PK/PD fue capaz de identificar cambios en la actividad antimicrobiana no detectados mediante la evaluación únicamente de las concentraciones mínimas inhibitorias; meropenem administrado en forma de infusión extendida alcanzó una CFR > 90%, ceftazidima, piperacilina/tazobactam e imipenem proporcionaron CFR entre 80 y 90%, todos ellos administrados a las dosis más altas. CONCLUSIÓN: La evaluación de la sensibilidad y el análisis PK/PD deben considerarse conjuntamente para seleccionar el tratamiento antimicrobiano más apropiado: fármaco y régimen de dosificación. La terapia empírica frente a P. aeruginosa variaría considerablemente si se consideraran ambas herramientas de vigilancia microbiológica. En este estudio, el análisis PK/PD ha permitido preservar el valor terapéutico de antimicrobianos con bajos valores de sensibilidad, como los carbapenems, y la selección de los antimicrobianos de mayor eficacia, entre aquellos que presentaban altos valores de sensibilidad

Pharmacokinetic/pharmacodynamic analysis as a tool for surveillance of the activity of antimicrobials against Pseudomonas aeruginosa strains isolated in critically ill patients / Análisis farmacocinético/farmacodinámico como herramienta para la vigilancia de la actividad de los antimicrobianos frente a Pseudomonas aeruginosa en pacientes críticos

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 (2g/8h) 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

INTRODUCCIÓN: Evaluar los cambios en la sensibilidad de Pseudomonas aeruginosa (2000-2017) a los antimicrobianos utilizados en una unidad de cuidados intensivos en España, y compararlos con la actividad antimicrobiana considerando criterios f armacocinéticos/farmacodinámicos (PK/PD) teóricos. También se comparan los diferentes métodos para el manejo de aislados duplicados utilizados para cuantificar la sensibilidad. MÉTODOS: La sensibilidad se determinó siguiendo los puntos de corte del Clinical and Laboratory Standards Institute (CLSI). Se realizaron simulaciones de Monte Carlo para calcular la fracción de respuesta acumulada (CFR). Se analizó la tendencia en la sensibilidad microbiana y la CFR a lo largo del tiempo mediante regresión lineal. RESULTADOS: En el análisis de tendencias se observó un descenso significativo en la sensibilidad a gentamicina e imipenem, y una disminución significativa de la CFR para ciprofloxacino, imipenem y levofloxacino. En los últimos años, amikacina, cefalosporinas y piperacilina/tazobactam presentaron los mayores valores de sensibilidad (>80%). La CFR para la mayoría de los antimicrobianos fue inferior al 70% durante el último periodo estudiado. Solo meropenem proporcionó altas probabilidades (> 90%) de alcanzar el objetivo PK/PD. Las cefalosporinas proporcionaron probabilidades moderadas (> 80%), siendo necesarias dosis elevadas de ceftazidima (2 g/8 h). CONCLUSIONES: Los datos de sensibilidad antimicrobiana y los valores de CFR deben considerarse herramientas complementarias y, por tanto, evaluarse conjuntamente tanto en actividades de vigilancia como en la evaluación de la eficacia terapéutica de los regímenes de dosificación. De hecho, los datos de sensibilidad no siempre son útiles para detectar cambios en la CFR. Finalmente, no se observaron diferencias relevantes entre los métodos para el manejo de aislados duplicados empleados

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

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 <70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR >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 / Aplicación del análisis farmacocinético/farmacodinámico en la evaluación de la adecuación de la terapia antimicrobiana de la otitis media aguda en niños en España antes y después de la implantación de la vacuna antineumocócica heptavalente

Objetivo: Evaluar mediante análisis farmacocinético/farmadocinámico (PK/PD) si el cambio en la sensibilidad antimicrobiana tras la introducción en España de la vacuna anti-neumocócica heptavalente (VNC7) ha implicado cambios en la adecuación del tratamiento antibiótico de la otitis media aguda (OMA) en niños. Materiales y métodos: Los parámetros PK y datos de sensibilidad de Streptococcus pneumoniae y Haemophilus influenzae fueron obtenidos de la bibliografía. Mediante simulación de Montecarlo, calculamos la probabilidad de éxito del tratamiento antibiótico, expresada como fracción de respuesta acumulada (CFR). Para amoxicilina y amoxicilina/ácido clavulánico, el objetivo farmacodinámico considerado fue el tiempo durante el cual las concentraciones libres en sangre permanecen por encima de la concentración mínima inhibitoria (CMI), expresado como porcentaje del intervalo de dosificación (fT>CMI≥50%). Para cefuroxima axetilo y cefotaxima, el objetivo fue fT>CMI≥60%. Valores de CFR≥90% se consideraron indicativos de éxito. Resultados: Si se tienen en cuenta todos los serotipos de S. pneumoniae, amoxicilina y cefotaxima proporcionaron una alta probabilidad de éxito, sin apenas diferencia entre ambos periodos. En el caso de H. influenzae, los valores de CFR fueron más altos con amoxicilina/ácido clavulánico que con amoxicilina. Para ambos microorganismos, las probabilidades de éxito de cefuroxima axetilo fueron bajas en ambos periodos de estudio. Conclusiones: La introducción de la vacuna PCV7 no ha implicado cambios en la probabilidad de éxito del tratamiento antibiótico empírico de la OMA. Hemos demostrado la utilidad del análisis PK/PD para detectar cambios en la adecuación del tratamiento antibiótico tras la implantación de una vacuna, proporcionando información complementaria al seguimiento de los valores de CMI

Objetivo: Evaluar mediante análisis farmacocinético/farmadocinámico (PK/PD) si el cambio en la sensibilidad antimicrobiana tras la introducción en España de la vacuna anti-neumocócica heptavalente (VNC7) ha implicado cambios en la adecuación del tratamiento antibiótico de la otitis media aguda (OMA) en niños. Materiales y métodos: Los parámetros PK y datos de sensibilidad de Streptococcus pneumoniae y Haemophilus influenzae fueron obtenidos de la bibliografía. Mediante simulación de Montecarlo, calculamos la probabilidad de éxito del tratamiento antibiótico, expresada como fracción de respuesta acumulada (CFR). Para amoxicilina y amoxicilina/ácido clavulánico, el objetivo farmacodinámico considerado fue el tiempo durante el cual las concentraciones libres en sangre permanecen por encima de la concentración mínima inhibitoria (CMI), expresado como porcentaje del intervalo de dosificación (fT>CMI≥50%). Para cefuroxima axetilo y cefotaxima, el objetivo fue fT>CMI≥60%. Valores de CFR≥90% se consideraron indicativos de éxito. Resultados: Si se tienen en cuenta todos los serotipos de S. pneumoniae, amoxicilina y cefotaxima proporcionaron una alta probabilidad de éxito, sin apenas diferencia entre ambos periodos. En el caso de H. influenzae, los valores de CFR fueron más altos con amoxicilina/ácido clavulánico que con amoxicilina. Para ambos microorganismos, las probabilidades de éxito de cefuroxima axetilo fueron bajas en ambos periodos de estudio. Conclusiones: La introducción de la vacuna PCV7 no ha implicado cambios en la probabilidad de éxito del tratamiento antibiótico empírico de la OMA. Hemos demostrado la utilidad del análisis PK/PD para detectar cambios en la adecuación del tratamiento antibiótico tras la implantación de una vacuna, proporcionando información complementaria al seguimiento de los valores de CMI

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

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 (2g/8h) 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.

Medication errors in Parkinson's disease inpatients in the Basque Country.

INTRODUCTION: Parkinson's disease (PD) medication errors, including both missing dopaminergic drug doses and antidopaminergic usage, have been suggested as risk factors for prolonged hospital stays. The objective of this study was to evaluate the prevalence of such errors in PD patients admitted to public acute-care hospitals in the Basque Country over a two year period and their association with clinically relevant adverse health outcomes, such as length of hospital stay and mortality. METHODS: All PD patients admitted to any of the 11 public acute-care hospitals in the Basque Country in 2011-2012 were included. Medication errors involved incorrect timing or the complete omission of administration for dopaminergic drugs, and the administration of centrally acting antidopaminergics. A logistic regression and a competing risk analysis were applied to verify whether those errors affected intrahospital mortality and length of stay. RESULTS: The study included 1628 patients admitted 2546 times. Medication errors, affecting almost one third of admissions and half of patients, were associated with higher mortality: inappropriately omitted dopaminergic drug doses OR = 1.92 CI 95% (1.34-2.76); inappropriate antiemetic administration OR = 2.15 CI 95% (1.36-3.39); and inappropriate antipsychotic administration OR = 1.91 CI 95% (1.33-1.73). Inappropriately omitted doses and both inappropriate antipsychotic and antiemetic administration were associated with a significant 4-day increase in median hospital stay. CONCLUSION: Medication errors (missing dopaminergic drug doses and centrally acting antidopaminergic use) are not only associated with increased length of hospital stays in PD patients, but also with a higher mortality rate.

[Challenges in the pharmacotherapeutic management of the hospitalised patient with Parkinson's disease]. / Desafíos en el manejo farmacoterapéutico del paciente ingresado con enfermedad de Parkinson.

Patients with Parkinson's disease (PD) are admitted to hospital more frequently and for a longer time than other patients from the same age group. The reason they are hospitalised is often different from their underlying baseline disease and they are usually attended in services with little knowledge of the disease. Both the errors made when administering levodopa and the inappropriate use of pharmacological agents with a central antidopaminergic action are relatively common during their stay in hospital. This study reports on an analysis of the literature available on the challenges and complications that patients with PD have to deal with when they are admitted to hospital, especially those that have to do with pharmacotherapy. Likewise, the authors also propose a series of strategies that lead to better care of the patients during the time they are in hospital, including aspects such as controlling the supplies of antiparkinsonian medication and establishing protocols for the therapeutic exchange of antiparkinsonian agents, as well as protocols for a suitable management of comorbidities in this kind of patients. Other strategies involve encouraging self-management of the antiparkinsonian treatment by the hospitalised patients, conducting follow-up studies to monitor inappropriate prescriptions or creating the figure of 'specialist in PD'. To do so, it will be necessary to raise the awareness of the healthcare staff at the hospital, as well as that of both patients and their relatives, about the problems derived from an inappropriate management of pharmacotherapy in PD.

TITLE: Desafios en el manejo farmacoterapeutico del paciente ingresado con enfermedad de Parkinson.Los pacientes con enfermedad de Parkinson (EP) ingresan en el hospital con mayor frecuencia y durante mas tiempo que los pacientes del mismo grupo etario. El motivo del ingreso es a menudo diferente de su enfermedad de base, y son habitualmente atendidos en servicios con un conocimiento pobre de la enfermedad. Tanto los errores en el momento de la administracion de levodopa como el uso inapropiado de farmacos con accion antidopaminergica central son relativamente comunes durante su estancia hospitalaria. En este estudio se lleva a cabo un analisis de la bibliografia disponible sobre los desafios y las complicaciones a los que se enfrentan los pacientes con EP cuando ingresan en el hospital, principalmente en aquellos relacionados con la farmacoterapia. Asimismo, se proponen una serie de estrategias que redunden en una atencion a los pacientes durante su ingreso hospitalario, que incluyen aspectos como el control de las existencias de medicamentos antiparkinsonianos y el establecimiento de protocolos de intercambio terapeutico de antiparkinsonianos, asi como de protocolos para el manejo adecuado de comorbilidades en este tipo de pacientes; el fomento de la autogestion del tratamiento antiparkinsoniano por parte de los pacientes ingresados; la realizacion de estudios de seguimiento de prescripciones inapropiadas o la creacion de la figura de 'especialista en EP'. Para ello sera necesario impulsar la concienciacion del personal sanitario del hospital, asi como de los pacientes y sus familiares, sobre los problemas derivados del manejo inapropiado de la farmacoterapia en EP.

Desafíos en el manejo farmacoterapéutico del paciente ingresado con enfermedad de Parkinson / Challenges in the pharmacotherapeutic management of the hospitalised patient with Parkinson’s disease

Los pacientes con enfermedad de Parkinson (EP) ingresan en el hospital con mayor frecuencia y durante más tiempo que los pacientes del mismo grupo etario. El motivo del ingreso es a menudo diferente de su enfermedad de base, y son habitualmente atendidos en servicios con un conocimiento pobre de la enfermedad. Tanto los errores en el momento de la administración de levodopa como el uso inapropiado de fármacos con acción antidopaminérgica central son relativamente comunes durante su estancia hospitalaria. En este estudio se lleva a cabo un análisis de la bibliografía disponible sobre los desafíos y las complicaciones a los que se enfrentan los pacientes con EP cuando ingresan en el hospital, principalmente en aquellos relacionados con la farmacoterapia. Asimismo, se proponen una serie de estrategias que redunden en una atención a los pacientes durante su ingreso hospitalario, que incluyen aspectos como el control de las existencias de medicamentos antiparkinsonianos y el establecimiento de protocolos de intercambio terapéutico de antiparkinsonianos, así como de protocolos para el manejo adecuado de comorbilidades en este tipo de pacientes; el fomento de la autogestión del tratamiento antiparkinsoniano por parte de los pacientes ingresados; la realización de estudios de seguimiento de prescripciones inapropiadas o la creación de la figura de ‘especialista en EP’. Para ello será necesario impulsar la concienciación del personal sanitario del hospital, así como de los pacientes y sus familiares, sobre los problemas derivados del manejo inapropiado de la farmacoterapia en EP (AU)

Patients with Parkinson’s disease (PD) are admitted to hospital more frequently and for a longer time than other patients from the same age group. The reason they are hospitalised is often different from their underlying baseline disease and they are usually attended in services with little knowledge of the disease. Both the errors made when administering levodopa and the inappropriate use of pharmacological agents with a central antidopaminergic action are relatively common during their stay in hospital. This study reports on an analysis of the literature available on the challenges and complications that patients with PD have to deal with when they are admitted to hospital, especially those that have to do with pharmacotherapy. Likewise, the authors also propose a series of strategies that lead to better care of the patients during the time they are in hospital, including aspects such as controlling the supplies of antiparkinsonian medication and establishing protocols for the therapeutic exchange of antiparkinsonian agents, as well as protocols for a suitable management of comorbidities in this kind of patients. Other strategies involve encouraging self-management of the antiparkinsonian treatment by the hospitalised patients, conducting follow-up studies to monitor inappropriate prescriptions or creating the figure of ‘specialist in PD’. To do so, it will be necessary to raise the awareness of the healthcare staff at the hospital, as well as that of both patients and their relatives, about the problems derived from an inappropriate management of pharmacotherapy in PD (AU)

Pharmacokinetic/pharmacodynamic evaluation of antimicrobial treatments of orofacial odontogenic infections.

OBJECTIVE: To evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards' (NCCLS) breakpoints. STUDY DESIGN: Retrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). METHODS: For antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters. RESULTS: Only amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints. CONCLUSION: Owing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.