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.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)

Augmented Renal Clearance in Critically Ill Patients: A Systematic Review

Background Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well-studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. Objective The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes. Method A systematic review was conducted to include all the original studies that provided information on ARC in critically ill patients, and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Augmented renal clearance, defined as a creatinine clearance (CrCl)[130 mL/min/1.73 m2, preferably measured in urine, is present in 20–65% of critically ill patients. Younger age, polytrauma and lower severity illness have been identified as risk factors. An influence of ARC on antimicrobial pharmacokinetics has been observed, with ARC consistently being associated with subtherapeutic antibiotic plasma concentrations. Conclusion ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.This study was financially supported by the University of the Basque Country (UPV/EHU) (PPG17/65)

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 overtime (2000–2017) against antimicrobials used in an intensive care unit of a Spanish tertiaryhospital, and to compare them with the antimicrobial activity considering theoretical pharmacoki-netic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolatesto 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 morerecently the highest percentages of susceptible strains were found for amikacin, cephalosporins andpiperacillin/tazobactam (>80%). The probability of success of an empiric treatment or CFR for most of theevaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem providedhigh 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 decreasein the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed.Conclusions: Both susceptibility rates and CFR values have to be considered together to optimize theantimicrobial dose regimen for clinical making-decisions. They are complementary tools and, theyshould be used jointly in surveillance programmes. In fact, susceptibility data are not always usefulto detect changes in the CFR. No relevant differences were observed among the methods for handlingrepeated isolates.This work was supported by the UPV/EHU (PPG17/65,GIU17/032). A Valero thanks Universia Foundation for her grant

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

Population pharmacokinetics of daptomycin in critically ill patients

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.This study was supported by the University of the Basque Country UPV/EHU (PPG17/65)

Quantification of Ceftaroline in Human Plasma Using High-Performance Liquid Chromatography with Ultraviolet Detection: Application to Pharmacokinetic Studies

This study was conducted to develop a rapid, simple and reproducible method for the quantification of ceftaroline in plasma samples by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Sample processing consisted of methanol precipitation and then, after centrifugation, the supernatant was injected into the HPLC system, working in isocratic mode. Ceftaroline was detected at 238 nm at a short acquisition time (less than 5 min). The calibration curve was linear over the concentration range from 0.25 to 40 µg/mL, and the method appeared to be selective, precise and accurate. Ceftaroline in plasma samples was stable at −80 °C for at least 3 months. The method was successfully applied to characterize the pharmacokinetic profile of ceftaroline in two critically ill patients and to evaluate whether the pharmacokinetic/pharmacodynamic (PK/PD) target was reached or not with the dose regimen administered.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU 17/32)

Impact of augmented renal clearance on the pharmacokinetics of linezolid: Advantages of continuous infusion from a pharmacokinetic/pharmacodynamic perspective

Objectives: The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). Results: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations >= 2 mg/l in 70% of the ARC patients. MCS revealed that concentrations >= 2 mg/l would be reached in >90% of patients receiving 75 mg/h. Conclusions: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations >= 2 mg/ml.This work was supported by the University of the Basque Country UPV/EHU (PPG17/65, GIU17/32), Spain

Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study

[EN] Background Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. Methods Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. Results According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. Conclusions Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU20/048)

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.This research was funded by the UPV/EHU (GIU 20/048)

Farmazia-zerbitzu profesional asistentzialak Euskal Autonomia Erkidegoko (EAE) farmazietan

Throughout history, the pharmacy has undergone major transformations. Previously, pharmacy was based on the preparation and dispensing of medicines, but due to the changes in society, the pharmaceutical profession has taken a more care path. Thus, in recent decades the development of pharmaceutical care and healthcare pharmacy has been prompted. Pharmaceutical care can be defined as the pharmac ist’s professional practice of caring for the patient’s needs by detecting, preventing, and resolving drug-related problems in a continu ous, systematic, and documented manner, in collaboration with the patient and other health care professionals to achieve accurate patient quality of life. Related to pharmaceutical care and healthcare pharmacy, Professional Pharmaceutical Care Services (PPCS) have been developed; so that community pharmacies offer a wide range of services to all citizens. Nowadays, in almost every country in the world, new services are being designing and implementing with the aim to also integrate them into the activity of community pharmacy. PPCSs fall currently into two groups. On the one hand, the Pharmaceutical Care Services and on the other hand, the Services related to Community Health. A few years ago, and in conjunction with the Basque Pharmacists’ Council, Basque pharmacies began offering PPCSs. These services, as important tools for change in the profession, do not only benefit patients, but also the collective of pharmacists and pharmacists themselves. However, an important ch allenge in promoting healthcare pharmacy is to make patients and other health professionals aware of the benefits of such clinical interventions, and thus to integrate community pharmacy into public health systems.; Historian zehar, farmaziak eraldaketa handiak izan ditu. Aurretik, farmaziak sendagaien prestaketa eta dispentsazioa zituen oinarri nagusitzat, baina, gizartearen aldaketa dela eta, lanbide horrek bide asistentzialagoa hartu du. Horrela, azken hamarkadetan arreta farmazeutikoaren eta farmazia asistentzialaren garapena sustatu da. Arreta farmazeutikoa pazientearen beharrak artatzeko farmazialariaren praktika profesional gisa defini daiteke, sendagaiekin loturiko arazoak modu jarraituan, sistematizatuan eta dokumentatuan detektatuz, prebenituz eta konponduz, pazientearekiko berarekiko eta osasun-taldeko gainerako profesionalekiko lankidetzan, pazientearen bizi-kalitatea hobetuko duten emaitza zehatzak lortzeko. Arreta farmazeutikoarekin eta farmazia asistentzialarekin lotuak, Farmazia-Zerbitzu Profesional Asistentzialak (FZPAk) sortu dira; farmazia komunitarioak herritar guztiei zerbitzu aukera zabala eskaintzen die. Gaur egun, munduko ia herrialde guztietan zerbitzu berriak diseinatzen eta ezartzen ari dira, eta, aldi berean, farmazia komunitarioaren jardueran txertatu nahi dira. FZPAk bi taldetan sailkatzen dira. Alde batetik, Arreta Farmazeutikoaren Zerbitzuak eta, beste alde batetik, Komunitateko Osasunarekin erlazionaturiko Zerbitzuak. Duela urte batzuk, eta Euskal Autonomia Erkidegoko (EAE) Farmazialarien Kontseiluarekin bat eginez, EAEko farmaziak FZPAk eskaintzen hasi ziren. Zerbitzu horiek, lanbidearen aldaketarako tresna garrantzitsua izanik, pazienteei ez ezik, farmazialarien kolektiboari eta farmazialariei eurei ere onurak ekartzen dizkiete. Hala ere, farmazia asistentziala sustatzeko erronka garrantzitsua da pazienteek eta gainerako osasun-profesionalek farmazialarien esku-hartze kliniko horien onurak ezagutzea, eta, farmazia komunitarioa, osasun-sistema publikoetan era sakonago batean integratzea