Although inappropriate therapy has been consistently associated with adverse outcomes, the magnitude and consistency of the benefit associated with appropriate empiric therapy in critically ill patients remain uncertain. We aimed to quantify the prevalence of appropriate empiric antimicrobial therapy and evaluate its association with outcomes and antimicrobial exposure in a large international ICU cohort. This predefined sub-analysis of the DIANA study included adult ICU patients receiving empirical antimicrobials for suspected or confirmed bacterial infection. Only patients with microbiologically confirmed infections were analyzed, and therapy was classified as appropriate if at least one agent demonstrated in vitro activity against the identified pathogen. Associations with 28-day mortality and antimicrobial-free days were assessed using multivariable logistic and Cox regression models. Pre-specified interaction analyses explored effect modification by disease severity and diagnostic certainty. Of 845 patients with microbiologically confirmed infections, 87.7

The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (fUNB_PIP). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life. Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations. The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L−1, the PIP values for V1, CL, V2 and Q2 were 10.4 L, 10.6 L h−1, 11.6 L and 15.2 L h−1, respectively, and the TAZ values were 10.5 L, 9.58 L h−1, 13.7 L and 16.8 L h−1, respectively. The CL for both drugs show maturation in early life, reaching 50

The optimal approach to prevent stroke and systemic embolism in patients with advanced chronic kidney disease (CKD) and atrial fibrillation remains unresolved. We conducted a narrative review to explore areas of uncertainty and opportunities for future research. First, the relationship between atrial fibrillation and stroke is more complex in patients with advanced CKD than in the general population. The currently employed risk stratification tools do not adequately discriminate between patients deriving a net benefit and those suffering a net harm from oral anticoagulation. Anticoagulation initiation should probably be more restrictive than is currently advocated by official guidelines. Recent evidence reveals that the superior benefit-risk profile of non–vitamin K antagonist oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) observed in the general population and in moderate CKD can be extended to advanced CKD. The NOACs yield better protection against stroke, cause less major bleeding, are associated with less acute kidney injury and a slower decline of CKD, and are associated with a lower incidence of cardiovascular events than VKAs. The VKAs may be harmful in CKD patients, in particular in patients with a high bleeding risk and labile international normalized ratio. The better safety and efficacy of NOACs as opposed to VKAs may be particularly evident in advanced CKD as a result of better on-target anticoagulation with NOACs, harmful off-target vascular effects of VKAs, and beneficial off-target vascular effects of NOACs. The intrinsic vasculoprotective effects of NOACs are supported by animal experimental evidence as well as by findings of large clinical trials and may result in use of NOACs beyond their anticoagulant properties.

Background Several studies have indicated that commonly used piperacillin-tazobactam (TZP) and meropenem (MEM) dosing regimens lead to suboptimal plasma concentrations for a range of pharmacokinetic/pharmacodynamic (PK/PD) targets in intensive care unit (ICU) patients. These targets are often based on a hypothetical worst-case scenario, possibly overestimating the percentage of suboptimal concentrations. We aimed to evaluate the pathogen-based clinically relevant target attainment (CRTA) and therapeutic range attainment (TRA) of optimized continuous infusion dosing regimens of TZP and MEM in surgical ICU patients. Methods A single center prospective observational study was conducted between March 2016 and April 2019. Free plasma concentrations were calculated by correcting total plasma concentrations, determined on remnants of blood gas samples by ultra-performance liquid chromatography with tandem mass spectrometry, for their protein binding. Break points (BP) of identified pathogens were derived from epidemiological cut-off values. CRTA was defined as a corrected measured total serum concentration above the BP and calculated for increasing BP multiplications up to 6 × BP. The upper limit of the therapeutic range was set at 157.2 mg/L for TZP and 45 mg/L for MEM. As a worst-case scenario, a BP of 16 mg/L for TZP and 2 mg/L for MEM was used. Results 781 unique patients were included with 1036 distinctive beta-lactam antimicrobial prescriptions (731 TZP, 305 MEM) for 1003 unique infections/prophylactic regimens (750 TZP, 323 MEM). 2810 samples were available (1892 TZP, 918 MEM). The median corrected plasma concentration for TZP was 86.4 mg/L [IQR 56.2–148] and 16.2 mg/L [10.2–25.5] for MEM. CRTA and TRA was consistently higher for the pathogen-based scenario than for the worst-case scenario, but nonetheless, a substantial proportion of samples did not attain commonly used PK/PD targets. Conclusion Despite these pathogen-based data demonstrating that CRTA and TRA is higher than in the often-used theoretical worst-case scenario, a substantial proportion of samples did not attain commonly used PK/PD targets when using optimised continuous infusion dosing regimens. Therefore, more dosing optimization research seems warranted. At the same time, a ‘pathogen-based analysis’ approach might prove to be more sensible than a worst-case scenario approach when evaluating target attainment and linked clinical outcomes.

Abstract Background Beta-lactam antimicrobial concentrations are frequently suboptimal in critically ill patients. Population pharmacokinetic (PopPK) modeling is the golden standard to predict drug concentrations. However, currently available PopPK models often lack predictive accuracy, making them less suited to guide dosing regimen adaptations. Furthermore, many currently developed models for clinical applications often lack uncertainty quantification. We, therefore, aimed to develop machine learning (ML) models for the prediction of piperacillin plasma concentrations while also providing uncertainty quantification with the aim of clinical practice. Methods Blood samples for piperacillin analysis were prospectively collected from critically ill patients receiving continuous infusion of piperacillin/tazobactam. Interpretable ML models for the prediction of piperacillin concentrations were designed using CatBoost and Gaussian processes. Distribution-based Uncertainty Quantification was added to the CatBoost model using a proposed Quantile Ensemble method, useable for any model optimizing a quantile function. These models are subsequently evaluated using the distribution coverage error, a proposed interpretable uncertainty quantification calibration metric. Development and internal evaluation of the ML models were performed on the Ghent University Hospital database (752 piperacillin concentrations from 282 patients). Ensuing, ML models were compared with a published PopPK model on a database from the University Medical Centre of Groningen where a different dosing regimen is used (46 piperacillin concentrations from 15 patients.). Results The best performing model was the Catboost model with an RMSE and $$R^2$$ R 2 of 31.94–0.64 and 33.53–0.60 for internal evaluation with and without previous concentration. Furthermore, the results prove the added value of the proposed Quantile Ensemble model in providing clinically useful individualized uncertainty predictions and show the limits of homoscedastic methods like Gaussian Processes in clinical applications. Conclusions Our results show that ML models can consistently estimate piperacillin concentrations with acceptable and high predictive accuracy when identical dosing regimens as in the training data are used while providing highly relevant uncertainty predictions. However, generalization capabilities to other dosing schemes are limited. Notwithstanding, incorporating ML models in therapeutic drug monitoring programs seems definitely promising and the current work provides a basis for validating the model in clinical practice.

The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.

Background: Therapeutic drug monitoring (TDM) of beta-lactam antibiotics may be used to optimize dosing for patients in the intensive care unit (ICU). A noninvasive matrix such as oral fluid may be interesting in selected patient groups. We compared the oral fluid concentrations of piperacillin and meropenem with the respective unbound and total concentrations in plasma. A secondary objective was to evaluate feasibility of the collection of oral fluid samples in this specific patient population. Methods: The study included 20 non-intubated ICU patients, age 22 to 77 y, receiving piperacillin or meropenem via continuous intravenous infusion. The standard protocol consisted of collecting a paired plasma-oral fluid sample for 3 consecutive days. Oral fluid was obtained from the patients using a standardized procedure by spitting in a plastic container after 2 min of gathering oral fluid in the mouth. Results: Antibiotic concentrations of piperacillin and meropenem are measurable, albeit very low, in unstimulated oral fluid of ICU patients. For piperacillin, a poor correlation was found between oral fluid and both total and unbound plasma concentrations (Spearman's correlation coefficients (Rs) 0.46 and 0.48 respectively). For meropenem this correlation was better (Rs for oral fluid versus total and unbound plasma meropenem concentration 0.92 and 0.93 respectively). Dispersion of antibiotic concentrations was greater in oral fluid than in blood. Collecting oral fluid samples was difficult in non-intubated ICU patients. Conclusions: Oral fluid from non-intubated ICU patients, obtained through a standardized procedure, cannot be recommended as an alternative matrix for quantitative meropenem or piperacillin TDM.

INTRODUCTION:Individualizing antibiotic therapy is paramount to improve clinical outcomes while minimizing the risk of toxicity and antimicrobial therapy. β-lactam antibiotics are amongst the drugs most commonly prescribed in the Intensive Care Unit (ICU). The pharmacokinetics of β-lactam antibiotics are profoundly altered in critically ill patients, leading to the failure of standard drug dosing regimens to result in adequate drug concentrations. Therapeutic Drug Monitoring (TDM) of β-lactam antibiotics is a promising tool to help optimize β-lactam antibiotic therapy.AREAS COVERED:The rationale behind TDM for β-lactam antibiotics is explained, as well as some more practical aspects such as when to sample, what concentrations to strive for and how to use it in clinical practice. We also discuss microbiological and analytical considerations, knowledge gaps, and future perspectives of β-lactam antibiotics TDM in ICU patients.EXPERT OPINION:TDM of β-lactam antibiotics has been studied intensively in recent years. While TDM may not yet be widely available, and targets need to be further refined, TDM of β-lactam antibiotics will help to optimize antibiotic therapy in the critically ill patient, as an integrated part of an antimicrobial stewardship program.

The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60–1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14–1.64). ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely.

Purpose: Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative. Materials and methods: We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath (R) device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma. Results: Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg!filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate. Conclusions: Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs. (C) 2019 Published by Elsevier Inc.

The authors regret that in the manuscript under the section 2.3 Study Protocol, the following is written: “This dose was either decreased or increased based on the patient's kidney function ( 200 mL/min: 24/3 g/24h)” This should read instead: “This dose was adapted based on the patient's kidney function ( 30 mL/min: 16/2 g/24 h) The authors would like to apologise for any inconvenience caused.

The authors regret an error in section 2.3 Study Protocol. The sentence: “This dose was either decreased or increased based on the patient's kidney function ( 200mL/min: 24/3 g/24h)” Should instead read: “This dose was adapted based on the patient's kidney function ( 30 mL/min: 16/2 g/24h) The authors would like to apologise for any inconvenience caused.

PurposeIncreased renal elimination is the leading cause for subtherapeutic concentrations of renally cleared antibiotics and it has been hypothesized that brain damaged patients in the intensive care unit (ICU) are particularly at risk. The objective of this study is to determine the prevalence of subtherapeutic piperacillin concentrations in neurocritical patients and to investigate if having a neurocritical diagnosis is a risk factor for this.Materials and methodsSingle center retrospective analysis of a prospective cohort study of adult ICU patients receiving continuous infusion piperacillin/tazobactam. Patients were categorized as either having a neurocritical diagnosis or not. An unbound piperacillin concentration > 4× the epidemiologic cut-off value (ECOFF) of Pseudomonas aeruginosa was selected as the PKPD target of choice. Multivariable logistic regression was performed to identify risk factors for subtherapeutic piperacillin concentrations.Results356 patients had a measured creatinine clearance (mCrCl) and matched piperacillin concentration, 52 of which had a neurocritical diagnosis. Subtherapeutic piperacillin concentrations were reported significantly more frequent in neurocritical patients. In multivariate analysis, the only risk factor identified for subtherapeutic piperacillin concentration was an increasing mCrCl.ConclusionSubtherapeutic piperacillin concentrations are common in neurocritical patients yet having a neurocritical admission diagnosis was not identified as an independent risk factor.

INTRODUCTION:Severe infections in critically ill patients carry a high morbidity and mortality rate. Given the impact of early and broad-spectrum empirical therapy in several studies and the emphasis on this in international guidelines, there is a low threshold for initiating antibiotics in many patients with suspected infection. This has led to the widespread use of antibiotics in critically ill patients, which is often unnecessary or inappropriate. Areas covered: Antimicrobial stewardship (AMS) attempts to reduce antibiotic exposure while improving outcomes and may intuitively contrast with current antibiotic prescription practices. The challenge for critical care physicians is thus to correctly diagnose infection and improve outcome while reducing antibiotic use. This can be done by adhering to local guidelines for empirical therapy, better risk for multidrug resistance assessment, optimized antibiotic dosing, and integration of rapid diagnostic techniques in the decision-making process. Watchful waiting, or withholding antibiotics until infection is confirmed, is justified in non-severely ill patients in whom the clinical picture is not clear. Expert opinion: Integrating AMS strategies in clinical practice can help upholding the best antibiotic empirical therapy while reducing antibiotic consumption. AMS is a multidisciplinary policy and should be embraced by critical care physicians as a solution for balanced antibiotic use.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (V-p) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (K-m) and the maximum elimination rate for Michaelis-Menten elimination (V-max) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for K-m and V-max were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for K-m lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration-time data. The mean +/- standard deviation parameter estimates were 8.38 +/- 9.91 L/h for drug clearance and 25.54 +/- 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m(2), a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT(>4xMIC)) against susceptible Pseudomonas aerginosa isolates (MIC <= 16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance. (c) 2017 Elsevier B. V. and International Society of Chemotherapy. All rights reserved.