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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.

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 (

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.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.In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses.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.

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.

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.

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) &gt, 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.

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. This research was funded by the Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU 17/32).

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.

Azken urteotan infekzioen tratamendua mundu mailako osasun publi-koko arazo bilakatu da, erresistentzien garapenaren ondorioz, bakterio multirresisten-teen agerpena izugarri igo baita. Antibiotiko berrien gabeziak merkatuan daudenen do-sifikazioen optimizazioaren premia areagotzen du. Zenbait pazientetan, gaixo larrietan esaterako, aipatutakoa egitea bereziki zaila suerta daiteke. Izan ere, beraien egoera fi-siopatologikoa dela eta, medikamentuen farmakozinetika eta farmakodinamia eralda-tuta daukate. Analisi farmakozinetiko/farmakodinamikoak, Monte Carlo simulazioekin batera, dosifikazio-erregimenen optimizazioa ahalbidetzen du. Horrela, tratamenduaren arrakasta bermatu eta erresistentzien agerpena ekiditen da.; Nowadays, the treatment of infectious diseases has become a global health issue, due to multi-resistant antibiotic bacteria. The lack of new antibiotics enhances urgent need for current antimicrobials’ dosing regimens optimization. This could be-come an extremely challenging duty when treating some kind of patients, such as the critically ill; as due to their physiophatological situation, both pharmacokinetics and pharmacodynamics might be altered. PK/PD analysis, together with Monte Carlo Sim-ulation, might be a useful tool in order to optimize dosing regimens of antibiotic agents and, therefore, improve clinical outcome and diminish emergence of resistances.

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.

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.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.

Background The antibiotics used for prophylaxis in colorectal surgery (CS) must maintain appropriate plasma concentrations (PC) throughout surgery to avoid surgical site infections (SSI). Purpose To determine the suitability of a single dose of metronidazole and cefuroxime for prophylaxis of CS, assessing the relation between antibiotic PC and the minimum inhibition concentration (MIC) of the microorganisms often isolated in SSI. Materials and methods Prospective study involving 64 patients undergoing CS in a tertiary hospital. Each patient was given a single dose of 1.5 g metronidazole and 1.5 g cefuroxime by intravenous infusion over 20–60 min during induction of anaesthesia. 4–5 blood samples were taken; the first at the time of starting the infusion and one of them at the end of surgery. Mean duration of the operation was 2.68 h (range 0.75–6.83 h). We checked whether the dosing regimens used ensured concentrations of both drugs above the MIC of the microorganisms commonly isolated in SSI, during the whole intervention. The target concentration was 8 mg/L, the highest susceptibility breakpoint for bacteria expected to be found in these procedures. Results Metronidazole PC at the time of closure of the peritoneal cavity ranged from 8.6 mg/L to 49 mg/L, all values above 8 mg/L. Cefuroxime PC at the time of closing ranged from 2.7 mg/L to 72 6 mg/L. In 6 cases, where surgery was prolonged over 2.6 h, the cefuroxime concentrations at closing time were less than 8 mg/L. Considering that the elimination half-life of cefuroxime is 1.3 h and after 2.6 h (two elimination half-lives) plasma levels fall below the target value, a second dose of 1.5 g of cefuroxime should be recommended in operations that extend over 2 h to ensure the target concentration throughout the intervention. Conclusions A single dose of 1.5 g of metronidazole is able to maintain suitable levels of drug in the plasma for the entire surgery. In the case of cefuroxime, additional doses should be administered if the surgery is extended beyond 2 h. No conflict of interest.