Oral Anticoagulation in Patients With Advanced Chronic Kidney Disease and Atrial Fibrillation: Beyond Anticoagulation.

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.

Pathogen-based target attainment of optimized continuous infusion dosing regimens of piperacillin-tazobactam and meropenem in surgical ICU patients: a prospective single center observational study.

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.

Development and evaluation of uncertainty quantifying machine learning models to predict piperacillin plasma concentrations in critically ill patients.

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 [Formula: see text] 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.

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the 'Maximum Tolerable Dose'.

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.

Pilot study of oral fluid and plasma meropenem and piperacillin concentrations in the intensive care unit.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-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.

Prolonged Versus Intermittent Infusion of ß-Lactam Antibiotics: A Systematic Review and Meta-Regression of Bacterial Killing in Preclinical Infection Models.

BACKGROUND: Administering ß-lactam antibiotics via prolonged infusions for critically ill patients is mainly based on preclinical evidence. Preclinical data on this topic have not been systematically reviewed before. OBJECTIVES: The aim of this study was to describe the pharmacokinetic/pharmacodynamic (PK/PD) indices and targets reported in preclinical models and to compare the bactericidal efficacy of intermittent and prolonged infusions of ß-lactam antibiotics. METHODS: The MEDLINE and EMBASE databases were searched. To compare the bactericidal action of ß-lactam antibiotics across different modes of infusion, the reported PK/PD outcomes, expressed as the percentage of time (T) that free (f) ß-lactam antibiotic concentrations remain above the minimal inhibitory concentration (MIC) (%fT>MIC) or trough concentration (Cmin)/MIC of individual studies, were recomputed relative to the area under the curve of free drug to MIC ratio (fAUC24/MIC). A linear mixed-effects meta-regression was performed to evaluate the impact of the ß-lactam class, initial inoculum, Gram stain, in vivo or in vitro experiment and mode of infusion on the reduction of bacterial cells (in colony-forming units/mL). RESULTS: Overall, 33 articles were included for review, 11 of which were eligible for meta-regression. For maximal bactericidal activity, intermittent experiments reported a PK/PD target of 40-70% fT>MIC, while continuous experiments reported a steady-state concentration to MIC ratio of 4-8. The adjusted effect of a prolonged as opposed to intermittent infusion on bacterial killing was small (coefficient 0.66, 95% confidence interval - 0.78 to 2.11). CONCLUSIONS: Intermittent and prolonged infusions of ß-lactam antibiotics require different PK/PD targets to obtain the same level of bacterial cell kill. The additional effect of a prolonged infusion for enhancing bacterial killing could not be demonstrated.

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Therapeutic drug monitoring of ß-lactam antibiotics in the ICU.

INTRODUCTION: Individualizing antibiotic therapy is paramount to improve clinical outcomes while minimizing the risk of toxicity and antimicrobial therapy. ß-lactam antibiotics are amongst the drugs most commonly prescribed in the Intensive Care Unit (ICU). The pharmacokinetics of ß-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 ß-lactam antibiotics is a promising tool to help optimize ß-lactam antibiotic therapy. AREAS COVERED: The rationale behind TDM for ß-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 ß-lactam antibiotics TDM in ICU patients. EXPERT OPINION: TDM of ß-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 ß-lactam antibiotics will help to optimize antibiotic therapy in the critically ill patient, as an integrated part of an antimicrobial stewardship program.

Subtherapeutic piperacillin concentrations in neurocritical patients.

PURPOSE: Increased 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 METHODS: Single 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. RESULTS: 356 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. CONCLUSION: Subtherapeutic piperacillin concentrations are common in neurocritical patients yet having a neurocritical admission diagnosis was not identified as an independent risk factor.

Early target attainment of continuous infusion piperacillin/tazobactam and meropenem in critically ill patients: A prospective observational study.

PURPOSE: To evaluate target attainment of empirically dosed continuous infusion piperacillin/tazobactam (TZP) and meropenem (MER) in critically ill patients. PATIENTS AND METHODS: Patients were sampled on a daily basis. TZP or MER concentrations were evaluated during the first two days antibiotic therapy. The lower limit of the target range was defined as unbound concentrations equaling 4 times the epidemiological cutoff value of P. aeruginosa. The upper limit of the target range was based on the risk of toxicity, i.e. unbound concentrations >160 mg/L for TZP and > 45 mg/L for MER. Multivariable logistic regression was used to evaluate factors associated with target attainment. RESULTS: Data from 253 patients were analyzed. Overall, 76/205 (37.1%) and 36/48 (75%) of the patients receiving TZP or MER respectively, attained target concentrations. In multivariable analysis, estimated creatinine clearance was identified as a risk factor for target non-attainment (OR 0.988, 95%CI [0.982;0.994]). Patients receiving MER were more likely to attain target concentrations compared with patients receiving TZP (OR 6.02, 95%CI [2.12;18.4]). CONCLUSION: Target attainment of empiric antibiotic therapy in critically ill patients was low (37%) for TZP and moderate (75%) for MER, despite the use of a loading dose and despite optimization of the mode of infusion.

Antibiotic stewardship in sepsis management: toward a balanced use of antibiotics for the severely ill patient.

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.

Population pharmacokinetics and evaluation of the predictive performance of pharmacokinetic models in critically ill patients receiving continuous infusion meropenem: a comparison of eight pharmacokinetic models.

Background: Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem concentrations in an independent validation dataset when meropenem is infused continuously. Patients and methods: A PopPK model was developed with concentration-time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted. Results: A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ±âŸ3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from -8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L. Conclusions: Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing.

Emergence of antimicrobial resistance to piperacillin/tazobactam or meropenem in the ICU: Intermittent versus continuous infusion. A retrospective cohort study.

BACKGROUND: Prolonged infusion of beta-lactam antibiotics is broadly recognized as a strategy to optimize antibiotic therapy by achieving a higher percentage of time that concentrations remain above the minimal inhibitory concentration (% fT>MIC), i.e. the pharmacokinetic/pharmacodynamic (PK/PD) index. However, %fT>MIC may not be the PK/PD index of choice for inhibition of resistance emergence and it is therefore unsure what impact prolonged infusion of beta-lactam antibiotics may have on the emergence of resistance. METHODS: A retrospective cohort study including 205 patients receiving either intermittent (101 patients) or continuous (104 patients) infusion of piperacillin/tazobactam or meropenem was conducted in the ICU of the Ghent University Hospital. Logistic regression analysis was used to develop a prediction model and to determine whether the mode of infusion was a predictor of emergence of antimicrobial resistance. RESULTS: Resistant strains emerged in 24 out of the 205 patients (11.7%). The mode of infusion was no predictor of emergence of antimicrobial resistance. Infection with Pseudomonas aeruginosa was associated with a significantly higher risk for emergence of resistance. CONCLUSIONS: In this retrospective cohort study, the emergence of antimicrobial resistance to piperacillin/tazobactam or meropenem was not related to the mode of infusion.

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients.

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 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) 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.

Student participation: to the benefit of both the student and the faculty.

Students who actively participate in the evaluation of their undergraduate medical curriculum become important stakeholders in decisions related to the design of the school's curriculum. Research and reports on student participation in curriculum change are scarce, and not much is known about how students personally benefit. We describe the structure and activities of engaging students in designing and improving the curriculum at the Faculty of Medicine and Health Sciences of Ghent University (Belgium). We present an example of a major curriculum change led by students, and we assess the perceptions of the students on how engagement in student curriculum committees strengthened their leadership skills. We encourage students at other schools to become active participants in the curriculum design and improvement processes of their institutions as a way to improve medical education.