Myoglobin adsorption and saturation kinetics of the cytokine adsorber Cytosorb® in patients with severe rhabdomyolysis: a prospective trial.

BACKGROUND: Rhabdomyolysis is a serious condition that can lead to acute kidney injury with the need of renal replacement therapy (RRT). The cytokine adsorber Cytosorb® (CS) can be used for extracorporeal myoglobin elimination in patients with rhabdomyolysis. However, data on adsorption capacity and saturation kinetics are still missing. METHODS: The prospective Cyto-SOLVE study (NCT04913298) included 20 intensive care unit patients with severe rhabdomyolysis (plasma myoglobin > 5000 ng/ml), RRT due to acute kidney injury and the use of CS for myoglobin elimination. Myoglobin and creatine kinase (CK) were measured in the patient´s blood and pre- and post-CS at defined time points (ten minutes, one, three, six, and twelve hours after initiation). We calculated Relative Change (RC, %) with: [Formula: see text]. Myoglobin plasma clearances (ml/min) were calculated with: [Formula: see text] RESULTS: There was a significant decrease of the myoglobin plasma concentration six hours after installation of CS (median (IQR) 56,894 ng/ml (11,544; 102,737 ng/ml) vs. 40,125 ng/ml (7879; 75,638 ng/ml) (p < 0.001). No significant change was observed after twelve hours. Significant extracorporeal adsorption of myoglobin can be seen at all time points (p < 0.05) (ten minutes, one, three, six, and twelve hours after initiation). The median (IQR) RC of myoglobin at the above-mentioned time points was - 79.2% (-85.1; -47.1%), -34.7% (-42.7;-18.4%), -16.1% (-22.1; -9.4%), -8.3% (-7.5; -1.3%), and - 3.9% (-3.9; -1.3%), respectively. The median myoglobin plasma clearance ten minutes after starting CS treatment was 64.0 ml/min (58.6; 73.5 ml/min), decreasing rapidly to 29.1 ml/min (26.5; 36.1 ml/min), 16.1 ml/min (11.9; 22.5 ml/min), 7.9 ml/min (5.5; 12.5 ml/min), and 3.7 ml/min (2.4; 6.4 ml/min) after one, three, six, and twelve hours, respectively. CONCLUSION: The Cytosorb® adsorber effectively eliminates myoglobin. However, the adsorption capacity decreased rapidly after about three hours, resulting in reduced effectiveness. Early change of the adsorber in patients with severe rhabdomyolysis might increase the efficacy. The clinical benefit should be investigated in further clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04913298. Registered 07 May 2021, https//clinicaltrials.gov/study/NCT04913298.

Can linezolid be validly measured in endotracheal aspiration in critically ill patients? A proof-of-concept trial.

BACKGROUND: Therapeutic drug monitoring (TDM) of anti-infectives such as linezolid is routinely performed in blood of intensive care unit (ICU) patients to optimize target attainment. However, the concentration at the site of infection is considered more important for a successful therapy. Until now, bronchoalveolar lavage (BAL) is the gold standard to measure intrapulmonary concentrations of anti-infective agents. However, it is an invasive method and unsuitable for regular TDM. The aim of this proof-of-concept study was to investigate whether it is possible to reliably determine the intrapulmonary concentration of linezolid from endotracheal aspiration (ENTA). METHODS: Intubated ICU patients receiving 600 mg intravenous linezolid twice daily were examined in steady state. First, preliminary experiments were performed in six patients to investigate which patients are suitable for linezolid measurement in ENTA. In a second step, trough and peak linezolid concentrations of plasma and ENTA were determined in nine suitable patients. RESULTS: Linezolid can validly be detected in ENTA with viscous texture and > 0.5 mL volume. The mean (SD) linezolid trough concentration was 2.02 (1.27) mg/L in plasma and 1.60 (1.36) mg/L in ENTA, resulting in a median lung penetration rate of 104%. The mean (SD) peak concentration in plasma and ENTA was 10.77 (5.93) and 4.74 (2.66) mg/L. CONCLUSIONS: Linezolid can validly be determined in ENTA with an adequate texture and volume. The penetration rate is comparable to already published BAL concentrations. This method might offer a simple and non-invasive method for TDM at the site of infection "lung". Due to promising results of the feasibility study, comparison of ENTA and BAL in the same patient should be investigated in a further trial.

Determination of glomerular filtration rate "en passant" after high doses of iohexol for computed tomography in intensive care medicine-a proof of concept.

Accurate assessment of renal function is of great clinical and scientific importance, as it is an important pharmacokinetic covariate of pivotal drugs. The iohexol clearance is nearly identical to the glomerular filtration rate, but its determination usually requires an intravenous injection and therefore bears intrinsic risks. This motivates to showcase an "en passant" approach to quantification of renal function without additional risk or blood sampling beyond routine care using real-world data. We enrolled 37 intensive care patients who received high doses of iohexol for computed tomography imaging, and quantified series of iohexol plasma concentrations by high-performance liquid chromatography (HPLC-UV). Iohexol clearance was derived by both log-linear regression and nonlinear least squares fitting and compared to glomerular filtration rate estimated by the CKD-EPI-2021 formulas. Nonlinear fitting not only turned out to be more accurate but also more robust in handling the irregularly timed data points. Concordance of iohexol clearance against estimations based on both creatinine and cystatin C showed a slightly higher bias (-3.44 mL/min/1.73 m2) compared to estimations based on creatinine alone (-0.76 mL/min/1.73 m2), but considerably narrower limits of agreement (±42.8 vs. 56 mL/min/1.73 m2) and higher Lin's correlation (0.84 vs. 0.72). In summary, we have demonstrated the feasibility and performance of the "en passant" variant of the iohexol method in intensive care medicine and described a working protocol for its application in clinical practice and pharmacologic studies.

Extracorporeal adsorption of protective and toxic bile acids and bilirubin in patients with cholestatic liver dysfunction: a prospective study.

BACKGROUND: The release of toxic bile acids (BAs) in the blood of critically ill patients with cholestatic liver dysfunction might lead to the damage of various organs. Their extracorporeal elimination using the cytokine adsorber Cytosorb® (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data proving a potential adsorption are missing so far. METHODS: The prospective Cyto-SOVLE study (NCT04913298) included 20 intensive care patients with cholestatic liver dysfunction, continuous kidney replacement therapy, total bilirubin concentration > 10 mg/dl and the application of CS into the dialysis circuit. Bilirubin and different BAs were measured pre- and post-CS at defined timepoints (10 min, 1, 3, 6, and 12 h after initiation). Relative reduction (RR, %) was calculated with: [Formula: see text]. RESULTS: The median RR for total and conjugated bilirubin after initiation was - 31.8% and - 30.3%, respectively, and decreased to - 4.5% and - 4.8% after 6 h. A high initial RR was observed for the toxic BAs GCA (- 97.4%), TCA (- 94.9%), GCDCA (- 82.5%), and TCDCA (- 86.0%), decreasing after 6 h to - 32.9%, - 32.7%, - 12.8%, and - 14.3%, respectively. The protective hydrophilic BAs showed a comparable RR after initiation (UDCA: - 77.7%, GUDCA: - 83.0%, TUDCA: - 91.3%) dropping after 6 h to - 7.4%, - 8.5%, and - 12.5%, respectively. CONCLUSIONS: Cytosorb® can adsorb bilirubin and toxic as well as protective BAs. However, a fast saturation of the adsorber resulting in a rapid decrease of the RR was observed. Furthermore, no relevant difference between hydrophobic toxic and hydrophilic protective BAs was detected regarding the adsorption amount. The clinical benefit or harm of the BA adsorption needs to be evaluated in the future.

Correlation between Bilirubin Elimination with the Cytokine Adsorber CytoSorb® and Mortality in Critically Ill Patients with Hyperbilirubinemia.

INTRODUCTION: Hyperbilirubinemia is often the first evidence for any kind of liver disorder and over one-third of all patients in intensive care units (ICU) show elevated bilirubin concentrations. In critically ill patients, high concentrations of serum bilirubin are correlated with a poor outcome. Therapies to lower bilirubin concentrations are often just symptomatically and their effect on the patients' outcome is hardly evaluated. Therefore, this study investigates whether the extracorporeal elimination of bilirubin with the cytokine adsorber CytoSorb® (CS) reduces mortality in patients with hyperbilirubinemia. METHODS: Patients with bilirubin concentrations >10 mg/dL at the ICU were screened for evaluation from 2018 to 2020. Patients with kidney replacement therapy and older than 18 years were included. Patients with continuously decreasing bilirubin concentrations after liver transplantation or other liver support systems (i.e., Molecular Adsorbents Recirculating System [MARS®], Advanced Organ Support [ADVOS]) were excluded. CS therapy was used in clinical routine and was indicated by the treating physicians. Statistical analysis was performed with IBM SPSS statistics utilizing a multivariate model. Primary outcome measure was the effect of CS on the 30-day mortality. RESULTS: Data from 82 patients (mean Simplified Acute Physiology Score [SAPS] II: 74 points, mean bilirubin: 18 mg/dL, mean lactate: 3.7 mmol/L) were analyzed. There were no significant differences in patients with and without CS treatment. The multivariate model showed no significant effect of CS therapy (p = 0.402) on the 30-day mortality. In addition, a significant effect of bilirubin concentration (p = 0.274) or Model for End-Stage Liver Disease score (p = 0.928) on the 30-day mortality could not be shown. In contrast, lactate concentration (p = 0.001, b = 0.044) and SAPS II (p = 0.025, b = 0.008) had significant impact on 30-day mortality. CONCLUSION: The use of CS in patients with hyperbilirubinemia did not result in a significant reduction in 30-day mortality. Randomized and controlled studies with mortality as primary outcome measure are needed in the future to justify their use.

The effect of cytosorb® application on kidney recovery in critically ill patients with severe rhabdomyolysis: a propensity score matching analysis.

Severe rhabdomyolysis frequently results in acute kidney injury (AKI) due to myoglobin accumulation with the need of kidney replacement therapy (KRT). The present study investigated whether the application of Cytosorb® (CS) led to an increased rate of kidney recovery in patients with KRT due to severe rhabdomyolysis. Adult patients with a myoglobin-concentration >10,000 ng/ml and KRT were included from 2014 to 2021. Exclusion criteria were chronic kidney disease and CS-treatment before study inclusion. Groups 1 and 2 were defined as KRT with and without CS, respectively. The primary outcome parameter was independence from KRT after 30 days. Propensity score (PS) matching was performed (predictors: myoglobin, SAPS-II, and age), and the chi2-test was used. 35 pairings could be matched (mean age: 57 vs. 56 years; mean myoglobin: 27,218 vs. 26,872 ng/ml; mean SAPS-II: 77 vs. 76). The probability of kidney recovery was significantly (p = .04) higher in group 1 (31.4 vs. 11.4%, mean difference: 20.0%, odds ratio (OR): 3.6). Considering patients who survived 30 days, kidney recovery was also significantly (p = .03) higher in patients treated with CS (61.1 vs. 23.5%, mean difference: 37.6%, OR: 5.1). In conclusion, the use of CS might positively affect renal recovery in patients with severe rhabdomyolysis. A prospective randomized controlled trial is needed to confirm this hypothesis.

Heat-Triggered Release of Dexamethasone from Thermosensitive Liposomes Using Prodrugs or Excipients.

Dexamethasone (DXM) is a potent glucocorticoid with an anti-inflammatory and anti-angiogenic activity which is widely clinically used. Systemic side effects limit the long-term use of DXM in patients requiring formulations which deliver and selectively release the drug to the diseased tissues. This in vitro study compares the suitability of DXM and commonly used prodrugs dexamethasone-21-phosphate (DXMP) and dexamethasone-21-palmitate (DP) as well as DXM complexed by 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) for the use in thermosensitive liposomes (TSL). DXM showed a poor retention and a low final drug:lipid ratio in a 1,2-dipalmitoyl-sn­glycero-3-phosphodiglycerol-based TSL (DPPG2-TSL) and a low-temperature sensitive liposome (LTSL). In contrast to DXM, DXMP and DP were stably retained at 37 °C in TSL in serum and could be encapsulated with high drug:lipid ratios in DPPG2-TSL and LTSL. DXMP showed a rapid release at mild hyperthermia (HT) from both TSL in serum, whereas DP remained incorporated in the TSL bilayer. According to release experiments with carboxyfluorescein (CF), HP-γ-CD and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) are suitable vehicles for the loading of DXM into DPPG2-TSL and LTSL. Complexation of DXM with HP-γ-CD increased the aqueous solubility of the drug leading to approx. ten times higher DXM:lipid ratio in DPPG2-TSL and LTSL in comparison to un-complexed DXM. Both DXM and HP-γ-CD showed increased release at HT in comparison to 37 °C in serum. In conclusion, DXMP and DXM complexed by HP-γ-CD represent promising candidates for TSL delivery.

Systematic Evaluation of Voriconazole Pharmacokinetic Models without Pharmacogenetic Information for Bayesian Forecasting in Critically Ill Patients.

Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from -15.4 to 124.6%/-0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%; rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use.

Serum linezolid concentrations are reduced in critically ill patients with pulmonary infections: A prospective observational study.

RATIONALE: The concentration-time profile of linezolid varies considerably in critically ill patients. Question of interest is, if the site of infection influences linezolid serum concentrations. METHODS: 68 critically ill patients, treated with linezolid, were included. The concentration-time-profile for linezolid was determined using maximum a-posteriori predictions. A trough concentration (Cmin) between 2 and 10 mg/L was defined as the target. A generalized linear model (GLM) was established to evaluate potential covariates. RESULTS: The indications for linezolid therapy were in descending order: peritonitis (38.2%), pneumonia (25.0%), infectious acute respiratory distress syndrome (ARDS) (19.1%), and other non-pulmonary infection (17.7%). 27.2 and 7.9% of Cmin were subtherapeutic and toxic, respectively. In the GLM, ARDS (mean: -2.1 mg/L, CI: -3.0 to -1.2 mg/L) and pneumonia (mean: -2.2 mg/L, CI: -2.8 to -1.6 mg/L) were significant (p < 0.001) determinants of Cmin. Patients with ARDS (mean: 2.3 mg/L, 51.2% subtherapeutic, 0.0% toxic) and pneumonia (mean: 3.5 mg/L, 41.5% subtherapeutic, 7.7% toxic) had significantly (p < 0.001) lower Cmin than those with peritonitis (mean: 5.5 mg/L, 14.4% subtherapeutic, 9.3% toxic) and other non-pulmonary infection (mean: 5.2 mg/L, 3.3% subtherapeutic, 16.5% toxic). CONCLUSION: Linezolid serum concentrations are reduced in patients with pulmonary infections. Future studies should investigate if other linezolid thresholds are needed in those patients due to linezolid pooling in patients´ lung.

Does the cytokine adsorber CytoSorb® reduce vancomycin exposure in critically ill patients with sepsis or septic shock? a prospective observational study.

BACKGROUND: Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb® unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb®. METHODS: Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb® treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb® was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations. RESULTS: 20 CytoSorb® treatments in 7 patients (160 serum samples/24 during CytoSorb®-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb®). Significant adsorption with a linear decrease during CytoSorb® treatment was identified (p < 0.0001) and revealed a maximum increase in vancomycin clearance of 291% (initially after CytoSorb® installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb® treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb® attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24 h. CONCLUSION: We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb® treatment to avoid subtherapeutic concentrations. Trial registration NCT03985605. Registered 14 June 2019, https://clinicaltrials.gov/ct2/show/NCT03985605.

Transport stability profiling - a proposed generic protocol.

OBJECTIVES: Diagnostic samples are exposed to a spectrum of variables during transport to laboratories; therefore, the evaluation of a rather comprehensive stability profile of measurands is warranted. While appropriate testing standards have been established for pharmaceuticals and reagents, this is not the case for diagnostic samples. The aim of our work was to develop and evaluate a protocol applicable to diagnostic samples. METHODS: An isochronous approach with representation of temperature and exposure duration in a two-dimensional matrix was established. The deviations of the measurement results from the baseline associated with the exposure are evaluated with respect to the measurement uncertainty of the analytical measurement procedure applied. Variables of the experiment are documented in a standardized matrix. As a proof-of-concept, we profiled the stability patterns of a number of measurands at four temperature levels over up to 72 h in primary serum sample tubes. RESULTS: The protocol proved to be workable and allowed the description of a comprehensive stability profile of a considerable number of compounds based on 21 small-volume primary samples collected from each volunteer and exposed according to this protocol. CONCLUSIONS: A straightforward and feasible isochronous protocol can be used to investigate in detail the effects of different pre-processing conditions on the stability of measurands in primary samples during transport to diagnostic laboratories. This is of significance as pre-analytical logistics become increasingly important with the centralization of analytical services.

Diminished Short- and Long-Term Antibody Response after SARS-CoV-2 Vaccination in Hemodialysis Patients.

Short-term studies have shown an attenuated immune response in hemodialysis patients after COVID-19-vaccination. The present study examines how antibody response is maintained after vaccination against SARS-CoV-2 in a large population of hemodialysis patients from six outpatient dialysis centers. We retrospectively assessed serum antibody levels against SARS-CoV-2 spike protein and nucleocapsid protein (electrochemiluminescence immunoassays, Roche Diagnostics) after COVID-19-vaccination in 298 hemodialysis and 103 non-dialysis patients (controls), comparing early and late antibody response. Compared to a non-dialysis cohort hemodialysis patients showed a favorable but profoundly lower early antibody response, which decreased substantially during follow-up measurement (median 6 months after vaccination). Significantly more hemodialysis patients had anti-SARS-CoV-2-S antibody titers below 100 U/mL (p < 0.001), which increased during follow-up from 23% to 45% but remained low in the control group (3% vs. 7%). In multivariate analysis, previous COVID-19 infections (p < 0.001) and female gender (p < 0.05) were significantly associated with higher early as well as late antibody vaccine response in hemodialysis patients, while there was a significant inverse correlation between patient age and systemic immunosuppression (p < 0.001). The early and late antibody responses were significantly higher in patients receiving vaccination after a SARS-CoV-2 infection compared to uninfected patients in both groups (p < 0.05). We also note that a higher titer after complete immunization positively affected late antibody response. The observation, that hemodialysis patients showed a significantly stronger decline of SARS-CoV-2 vaccination antibody titers within 6 months, compared to controls, supports the need for booster vaccinations to foster a stronger and more persistent antibody response.

Trough concentrations of meropenem and piperacillin during slow extended dialysis in critically ill patients with intermittent and continuous infusion: A prospective observational study.

Beta-lactam dosing is challenging in critically ill patients with slow extended daily dialysis (SLEDD). This prospective observational study aimed to investigate meropenem and piperacillin concentrations and half-lives during SLEDD and in SLEDD-free intervals. Critically ill patients with SLEDD-therapy and meropenem or piperacillin therapy were included. Breakpoints of target attainment were defined as 2 and 20.8 mg/L for meropenem and piperacillin, respectively. Daily TDM was performed and therapies were adapted based on the measured concentrations. Elimination rate constants were determined by using nonlinear regression analysis. Seventeen patients were included (48 SLEDD intervals; median SLEDD-duration: 7.25 h). The median antibiotic trough concentrations and half-lives were significantly (p < 0.001) lower during and after the SLEDD-therapy compared to SLEDD-free intervals (median meropenem: 22.3 (IQR: 12.8, 25.6) vs. 28.3 mg/L (IQR: 16.9, 37.4); median piperacillin: 55.8 (IQR: 45.1, 84.9) vs. 130 mg/L (IQR: 91.5, 154.5); relative change: -48.0% each, IQR meropenem: -33.3, -58.5%; IQR piperacillin: -36.3, -52.1%). However, none of the measured trough concentrations were subtherapeutic during SLEDD. SLEDD leads to a reduction in meropenem and piperacillin concentrations of approximately 50% independently of the initial concentration. If the concentration is twice as high as the breakpoint of target attainment before SLEDD-therapy, subtherapeutic levels can be avoided.

Isotope dilution LC-MS/MS quantification of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their major metabolites in human serum.

OBJECTIVES: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have revolutionized the therapeutic landscape in CF treatment. These vital drugs are extensively metabolized via CYP3A, so caution must be exercised in multimodal CF therapy because of the risk of adverse drug interactions. Our goal was to develop a highly sensitive assay for the purpose of therapeutic drug monitoring (TDM) in diagnostic laboratories. METHODS: After protein precipitation, the CFTR modulators ivacaftor, lumacaftor, tezacaftor, elexacaftor, and their metabolites ivacaftor-M1, ivacaftor-M6, and tezacaftor-M1 were separated with a two-dimensional chromatography setup within 5 min, and quantified with stable isotope-labeled internal standards. The method was validated according to the European Medicines Agency (EMA) guideline on bioanalytical method validation and applied to CF patient samples. RESULTS: Inaccuracy was ≤7.0% and the imprecision coefficient of variation (CV) was ≤8.3% for all quality controls (QCs). The method consistently compensated for matrix effects, recovery, and process efficiency were 105-115 and 96.5-103%, respectively. Analysis of CF serum samples provided concentrations comparable to the pharmacokinetic profile data reported in the EMA assessment report for the triple combination therapy Kaftrio. CONCLUSIONS: We hereby present a robust and highly selective isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) assay for the simultaneous quantification of the so far approved CFTR modulators and their metabolites in human serum. The assay is suitable for state-of-the-art pharmacovigilance of CFTR modulator therapy in CF patients, in order to maximize safety and efficacy, and also to establish dose-response relationships in clinical trials.

Combination of Pharmacokinetic and Pathogen Susceptibility Information To Optimize Meropenem Treatment of Gram-Negative Infections in Critically Ill Patients.

Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of Gram-negative infections based on intensive care unit (ICU)-specific resistance data. Antimicrobial susceptibility testing of Gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed MIC distribution, stochastic simulations (n = 1,000) of an evaluated pharmacokinetic meropenem model, and a defined pharmacokinetic/pharmacodynamic target (100%T>4×MIC while minimum concentrations were <44.5 mg/L), dosing recommendations for patients with varying renal function were derived. Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR), and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR of >90% was considered adequate. The observed MIC distribution significantly differed from the EUCAST database. Based on the 6,520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii, or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases, dosing needs to be adjusted based on renal function. ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings.