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TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics of Drugs".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 34022

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Prof. Dr. Alexander Brinkmann

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Klinikum Heidenheim, Klinik für Anästhesie, operative Intensivmedizin und spezielle, Schmerztherapie, Heidenheim, Germany
Interests: antibiotic therapy; PK/PD; sepsis; TDM; individual dosing and application

Dr. Stefan Hagel

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Institute for Infectious Diseases and Infection Control, Universitätsklinikum Jena, Jena, Germany
Interests: antibiotic therapy; sepsis; TDM; difficult to treat infections

Dr. Otto Roman Frey

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Klinikum Heidenheim, Apotheke, Heidenheim, Germany
Interests: Antibiotic therapy; therapeutic drug monitoring of antiinfective drugs; HPLC with UV-detection

Special Issue Information

Dear colleague,

Inadequate empirical antimicrobial therapy, which does not cover the causative microorganism and starts with relevant delay, is associated with a substantial increase in morbidity and mortality in patients with sepsis and septic shock.

Emerging evidence suggests that an insufficient antimicrobial exposure, i.e., when the pharmacokinetic/pharmacodynamic (PK/PD) target to kill or inhibit the growth of a pathogen is not attained, adversely affects clinical outcome as well. Antibiotic concentration at the site of infection may be particularly unpredictable in critically ill patients due to substance-specific PK alterations compared to healthy humans. Pathophysiological changes in volume of distribution, drug clearance, and protein-binding can be significantly different in critically ill patients compared to what is observed in other patient groups. There is a growing body of evidence demonstrating that current dosing strategies result in suboptimal plasma concentrations (p.c.) leading to either inadequate antimicrobial exposure at the site of infection or potential toxic side effects in a relevant number of critically ill patients. Diverse antibiotic drugs including beta-lactam antibiotics have the potential to evoke drug-induced toxicity, which is increasingly apparent but likely remains underestimated in the clinical practice of sepsis therapy. Dose-induced toxicity may particularly manifest in the form of neurological deterioration and acute kidney injury (AKI).

Personalized dosing approaches, including the use of dosing software and therapeutic drug monitoring, may be required to ensure optimal antibiotic exposure and better therapeutic outcomes in patients with severe infection and sepsis. This Special Issue seeks manuscript submissions that refine our understanding of adequate dosing and application of antibiotics in critically ill patients. Submissions on clinical aspects and recommendations are especially encouraged.

Prof. Dr. Alexander Brinkmann
Dr. Stefan Hagel
Dr. Otto Roman Frey
Guest Editors

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Keywords

Sepsis therapy
individual dosing
Individual application
dosing softwares
therapeutic drug monitoring,
drug induced toxicity
pharmacokinetic and pharmacodynamic of antibiotics

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Published Papers (10 papers)

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Research

17 pages, 1062 KiB

Open AccessArticle

Evaluation of a Meropenem and Piperacillin Monitoring Program in Intensive Care Unit Patients Calls for the Regular Assessment of Empirical Targets and Easy-to-Use Dosing Decision Tools

by Ferdinand Anton Weinelt, Miriam Songa Stegemann, Anja Theloe, Frieder Pfäfflin, Stephan Achterberg, Franz Weber, Lucas Dübel, Agata Mikolajewska, Alexander Uhrig, Peggy Kiessling, Wilhelm Huisinga, Robin Michelet, Stefanie Hennig and Charlotte Kloft

Antibiotics 2022, 11(6), 758; https://doi.org/10.3390/antibiotics11060758 - 2 Jun 2022

Cited by 3 | Viewed by 3155

Abstract

The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1–5 × MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8–40 mg/L and 16–80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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10 pages, 965 KiB

Open AccessArticle

The Serum Concentration of Vancomycin as a Diagnostic Predictor of Nephrotoxic Acute Kidney Injury in Critically Ill Patients

by Welder Zamoner, Karina Zanchetta Cardoso Eid, Lais Maria Bellaver de Almeida, Isabella Gonçalves Pierri, Adriano dos Santos, André Luis Balbi and Daniela Ponce

Antibiotics 2022, 11(1), 112; https://doi.org/10.3390/antibiotics11010112 - 15 Jan 2022

Cited by 4 | Viewed by 2394

Abstract

The impact of serum concentrations of vancomycin is a controversial topic. Results: 182 critically ill patients were evaluated using vancomycin and 63 patients were included in the study. AKI occurred in 44.4% of patients on the sixth day of vancomycin use. Vancomycin higher than 17.53 mg/L between the second and the fourth days of use was a predictor of AKI, preceding AKI diagnosis for at least two days, with an area under the curve of 0.806 (IC 95% 0.624–0.987, p = 0.011). Altogether, 46.03% of patients died, and in the Cox analysis, the associated factors were age, estimated GFR, CPR, and vancomycin between the second and the fourth days. Discussion: The current 2020 guidelines recommend using Bayesian-derived AUC monitoring rather than trough concentrations. However, due to the higher number of laboratory analyses and the need for an application to calculate the AUC, many centers still use therapeutic trough levels between 15 and 20 mg/L. Conclusion: The results of this study suggest that a narrower range of serum concentration of vancomycin was a predictor of AKI in critically ill septic patients, preceding the diagnosis of AKI by at least 48 h, and it can be a useful monitoring tool when AUC cannot be used. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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13 pages, 1592 KiB

Open AccessArticle

Personalized Antibiotic Therapy for the Critically Ill: Implementation Strategies and Effects on Clinical Outcome of Piperacillin Therapeutic Drug Monitoring—A Descriptive Retrospective Analysis

by Schrader Nikolas, Riese Thorsten, Kurlbaum Max, Meybohm Patrick, Kredel Markus, Surat Güzin, Scherf-Clavel Oliver, Strate Alexander, Pospiech Andreas and Hoppe Kerstin

Antibiotics 2021, 10(12), 1452; https://doi.org/10.3390/antibiotics10121452 - 26 Nov 2021

Cited by 4 | Viewed by 2711

Abstract

Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m²) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians’ alertness. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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11 pages, 1457 KiB

Open AccessArticle

Cerebrospinal Fluid Concentrations of Meropenem and Vancomycin in Ventriculitis Patients Obtained by TDM-Guided Continuous Infusion

by Christoph Tiede, Ute Chiriac, Daniel Dubinski, Florian J. Raimann, Otto R. Frey, Anka C. Röhr, Anna Wieduwilt, Michael Eibach, Natalie Filmann, Christian Senft, Kai Zacharowski, Volker Seifert and Jan Mersmann

Antibiotics 2021, 10(11), 1421; https://doi.org/10.3390/antibiotics10111421 - 20 Nov 2021

Cited by 8 | Viewed by 3753

Abstract

Effective antibiotic therapy of cerebral infections such as meningitis or ventriculitis is hindered by low penetration into the cerebrospinal fluid (CSF). Because continuous infusion of meropenem and vancomycin and routine therapeutic drug monitoring (TDM) have been proposed to optimize antimicrobial exposure in ventriculitis patients, an individualized dosing strategy was implemented in our department. We present a retrospective analysis of meropenem and vancomycin concentrations in serum and CSF in the first nine ventriculitis patients treated with continuous infusion and TDM-guided dose optimization aiming at 20–30 mg/L. Median initial dosing was 8.8 g/24 h meropenem and 4.25 g/24 h vancomycin, respectively, resulting in median serum concentrations of 21.3 mg/L for meropenem and 24.5 mg/L for vancomycin and CSF concentrations of 3.4 mg/L for meropenem and 1.7 mg/L for vancomycin. Median CSF penetration was 15% for meropenem and 7% for vancomycin. With initial dosing, all but one patient achieved CSF concentrations above 1 mg/L. Dose adjustment according to TDM ensured sufficient CSF concentrations in all patients within 48 h of treatment. Given the limited penetration, continuous infusion of meropenem and vancomycin based on renal function and TDM-guided dose optimization appears a reasonable approach to attain sufficient CSF concentrations in ventriculitis patients. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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17 pages, 440 KiB

Open AccessArticle

Clinically Relevant Interactions with Anti-Infectives on Intensive Care Units—A Multicenter Delphi Study

by Joachim Andreas Koeck, Heike Hilgarth, Andreas von Ameln-Mayerhofer, Damaris Meyn, Ruediger Warlich, Andreas Münstedt, Dagmar Horn and Christina König

Antibiotics 2021, 10(11), 1330; https://doi.org/10.3390/antibiotics10111330 - 31 Oct 2021

Cited by 4 | Viewed by 3001

Abstract

Patients in intensive care units (ICUs) are at high risk of drug–drug interactions (DDIs) due to polypharmacy. Little is known about type and frequency of DDIs within German ICUs. Clinical pharmacists’ interventions (PI) recorded in a national database (ADKA-DokuPIK) were filtered for ICU patients. Binary DDIs involving ≥1 anti-infective agent with >1 database entry were selected. A modified two-step Delphi process with a group of senior hospital pharmacists was employed to evaluate selected DDIs for clinical relevance by using a five-point scale and to develop guidance for clinical practice. In total, 16,173 PI were recorded, including 1836 (11%) DDIs in the ICU setting. Of the latter, 41% (756/1836) included ≥1 anti-infective agent, 32% (590/1836) were binary DDIs, and 25% (455/1836) were listed at least twice. This translates into 88 different DDIs, 74% (65/88) of which were rated as being clinically relevant by our expert panel. The majority of DDIs (76% [67/88]) included macrolides, antifungals, or fluoroquinolones. This percentage was even higher in DDIs being rated as clinically relevant by the experts (85% [55/65]). It is noted that an inter-professional discussion and approach is needed in the individual patient management of DDIs. The guidance developed might be a tool for decision support. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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13 pages, 1331 KiB

Open AccessArticle

Prolonged Infusion of β-Lactams Decreases Mortality in Patients with Septic Shock: A Retrospective before-and-after Study

by Daniel Christoph Richter, Maximilian Dietrich, Lazar Detelinov Lalev, Felix C. F. Schmitt, Mascha Onida Fiedler, Thomas Bruckner, Dominic Stoerzinger, Ute Chiriac, Sabrina Klein, Thilo Hackert, Thorsten Brenner, Alexander Brinkmann and Markus A. Weigand

Antibiotics 2021, 10(6), 687; https://doi.org/10.3390/antibiotics10060687 - 8 Jun 2021

Cited by 12 | Viewed by 3667

Abstract

Septic shock substantially alters the pharmacokinetic properties of β-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of β-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft _>MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with β-lactams. Patients of the years 2015–2017 received intermittent bolus application whereas patients of 2017–2020 received PI of β-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n = 119/290 vs. IB: 54.8%, n = 68/114; p = 0.0097) and day 90 (PI: 47.9%, n = 139/290 vs. IB: 62.9%, n = 78/124; p = 0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (−10%, p = 0.14). PI was further associated with a reduction in the duration of invasive ventilation and a stronger decrease in SOFA scores within a 14 day-observation period. PI of β-lactams was associated with a significant reduction of mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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13 pages, 1098 KiB

Open AccessArticle

Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing

by Ute Chiriac, Daniel C. Richter, Otto R. Frey, Anka C. Röhr, Sophia Helbig, Judit Preisenberger, Stefan Hagel, Jason A. Roberts, Markus A. Weigand and Alexander Brinkmann

Antibiotics 2021, 10(6), 667; https://doi.org/10.3390/antibiotics10060667 - 3 Jun 2021

Cited by 15 | Viewed by 3391

Abstract

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (c_PIP) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as c_PIP of 32–64 mg/L (2–4× the ‘MIC breakpoint’ of Pseudomonas aeruginosa). Of the 1544 patients screened, we included 179 patients (335 serum concentrations), of whom 89% achieved the minimum therapeutic exposure of >32 mg/L and 12% achieved potentially harmful c_PIP > 96 mg/L within the first 48 h. Therapeutic exposure was achieved in 40% of the patients. Subsequent TDM-guided dose adjustments significantly enhanced therapeutic exposure to 65%, and significantly reduced c_PIP > 96 mg/L to 5%. Mortality in patients with c_PIP > 96 mg/L (13/21; 62%) (OR 5.257, 95% CI 1.867–14.802, p = 0.001) or 64–96 mg/L (30/76; 45%) (OR 2.696, 95% CI 1.301–5.586, p = 0.007) was significantly higher compared to patients with therapeutic exposure (17/72; 24%). Given the observed variability in critically ill patients, combining the application of dosing software and consecutive TDM increases therapeutic drug exposure of piperacillin in patients with sepsis and septic shock. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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10 pages, 550 KiB

Open AccessArticle

Cefiderocol in Critically Ill Patients with Multi-Drug Resistant Pathogens: Real-Life Data on Pharmacokinetics and Microbiological Surveillance

by Christina König, Anna Both, Holger Rohde, Stefan Kluge, Otto R. Frey, Anka C. Röhr and Dominic Wichmann

Antibiotics 2021, 10(6), 649; https://doi.org/10.3390/antibiotics10060649 - 28 May 2021

Cited by 17 | Viewed by 3785 | Correction

Abstract

Cefiderocol is a new siderophore-cephalosporin for the treatment of multi-drug resistant Gram-negative pathogens. As a reserve agent, it will and should be used primarily in critically ill patients in the upcoming years. Due to the novelty of the substance little data on the pharmacokinetics in critically ill patients with septic shock and renal failure (including continuous renal replacement therapy and cytokine adsorber therapy) is available. We performed therapeutic drug monitoring in a cohort of five patients treated with cefiderocol, to improve the knowledge on pharmacokinetics in this vulnerable patient population. As expected for a cephalosporin with predominantly renal elimination the maintenance dose could be reduced in patients with renal impairment or on continuous renal replacement therapy. The manufacturer’s dosing instructions were sufficient to achieve a drug level well above the MIC. However, the addition of a cytokine adsorber might reduce serum levels substantially, so that in this context therapeutic drug monitoring and dose adjustment are recommended. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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16 pages, 1222 KiB

Open AccessArticle

Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection

by Annabel Werumeus Buning, Caspar J. Hodiamont, Natalia M. Lechner, Margriet Schokkin, Paul W. G. Elbers, Nicole P. Juffermans, Ron A. A. Mathôt, Menno D. de Jong and Reinier M. van Hest

Antibiotics 2021, 10(6), 612; https://doi.org/10.3390/antibiotics10060612 - 21 May 2021

Cited by 10 | Viewed by 2563

Abstract

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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13 pages, 1840 KiB

Open AccessArticle

Evaluation of the MeroRisk Calculator, A User-Friendly Tool to Predict the Risk of Meropenem Target Non-Attainment in Critically Ill Patients

by Uwe Liebchen, Marian Klose, Michael Paal, Michael Vogeser, Michael Zoller, Ines Schroeder, Lisa Schmitt, Wilhelm Huisinga, Robin Michelet, Johannes Zander, Christina Scharf, Ferdinand A. Weinelt and Charlotte Kloft

Antibiotics 2021, 10(4), 468; https://doi.org/10.3390/antibiotics10040468 - 20 Apr 2021

Cited by 5 | Viewed by 3320

Abstract

Background: The MeroRisk-calculator, an easy-to-use tool to determine the risk of meropenem target non-attainment after standard dosing (1000 mg; q8h), uses a patient’s creatinine clearance and the minimum inhibitory concentration (MIC) of the pathogen. In clinical practice, however, the MIC is rarely available. The objectives were to evaluate the MeroRisk-calculator and to extend risk assessment by including general pathogen sensitivity data. Methods: Using a clinical routine dataset (155 patients, 891 samples), a direct data-based evaluation was not feasible. Thus, in step 1, the performance of a pharmacokinetic model was determined for predicting the measured concentrations. In step 2, the PK model was used for a model-based evaluation of the MeroRisk-calculator: risk of target non-attainment was calculated using the PK model and agreement with the MeroRisk-calculator was determined by a visual and statistical (Lin’s concordance correlation coefficient (CCC)) analysis for MIC values 0.125–16 mg/L. The MeroRisk-calculator was extended to include risk assessment based on EUCAST-MIC distributions and cumulative-fraction-of-response analysis. Results: Step 1 showed a negligible bias of the PK model to underpredict concentrations (−0.84 mg/L). Step 2 revealed a high level of agreement between risk of target non-attainment predictions for creatinine clearances >50 mL/min (CCC = 0.990), but considerable deviations for patients <50 mL/min. For 27% of EUCAST-listed pathogens the median cumulative-fraction-of-response for the observed patients receiving standard dosing was < 90%. Conclusions: The MeroRisk-calculator was successfully evaluated: For patients with maintained renal function it allows a reliable and user-friendly risk assessment. The integration of pathogen-based risk assessment substantially increases the applicability of the tool. Full article

(This article belongs to the Special Issue TDM, Individual Dosing and Application of Antibiotics/Antiinfectives in Critically Ill Patients)

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