Meropenem plasma concentrations in critically ill patients treated with the novel multi organ replacement therapy ADVOS

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This study aims to provide real life data on meropenem plasma concentrations after prolonged infusion in patients treated with ADVOS and a critically ill control group with and without continuous veno-venous hemodiafiltration (CVVHDF). Methods: We retrospectively analyzed plasma concentrations of meropenem obtained as part of our standard of care therapeutic drug monitoring in the intensive care unit. Meropenem was administered as a prolonged infusion over 3 hours. We measured peak and trough levels, pre-and post-filter levels of meropenem using high performance liquid chromatography. We calculated the meropenem clearance and compared the measured clearance with predicted clearance based on creatinine, calculated by the MeroEasy tool. Results: In total, 171 measurements across 16 patients were analyzed. Meropenem trough concentrations were highest in the CVVHDF group with a median of 23.5 mg/L, followed by the ADVOS (median 9.3 mg/L) and control group (median 7.6 mg/L). No trough levels were below the lower limit of 2 mg/L in the CVVHDF and ADVOS groups. Meropenem machine clearance by CVVHDF was calculated to be 1.8 (± 0.5) L/h and 3.5 (± 1) L/h for ADVOS. Conclusion: Our results suggest that ADVOS treatment in critically ill patients receiving meropenem in standard dosage does not lead to underdosing. Some trough values were even within potentially toxic levels, especially in the CVVHDF group, highlighting the importance of therapeutic drug monitoring. Meropenem TDM therapeutic drug monitoring ADVOS multi organ replacement therapy calculated vs. measured values Figures Figure 1 Figure 2 Figure 3 Main Point We investigated meropenem plasma concentrations in critically ill patients treated with the novel multi-organ-replacement therapy ADVOS. We found no cases of underdosing in the ADVOS treatment group and calculated an ADVOS machine clearance of 3.5 L/h. Introduction Infections are a leading cause of morbidity and mortality among critically ill patients in intensive care units (ICUs). The management of these infections requires timely and effective antibiotic therapy to combat potentially life-threatening pathogens. Beta-lactam antibiotics, particularly meropenem, play a crucial role due to their broad-spectrum activity and favorable safety profile ( 1 ). However, ensuring optimal dosing in this patient population is a persistent challenge due to complex pharmacokinetic changes and variability in clinical conditions ( 2 , 3 ). Meropenem is widely used in ICUs to treat severe bacterial infections, including those caused by more resistant organisms ( 4 ). Its pharmacokinetics are characterized by low protein binding and high renal clearance. As a hydrophilic molecule it has a low volume of distribution of 0.4–0.6 L/kg in critically ill patients, making it effective for bloodstream infections ( 3 ). The efficacy of beta-lactam antibiotics depends on maintaining drug concentrations above the pathogen's minimum inhibitory concentration (fT > MIC) ( 5 ). In ICU patients treated with intermittent meropenem infusions trough levels up to 2–4 times above the MIC are targeted. The MIC for meropenem sensible pathogens is ≤ 2 mg/L, hence meropenem trough levels of 4–8 mg/L are targeted in severely ill patients( 2 ).Underdosing can result in treatment failure, while excessive meropenem concentrations risk neurotoxicity and nephrotoxicity( 6 ). In critically ill patients, pharmacokinetics are often altered by factors such as renal dysfunction, hyperfiltration, fluid overload, and the use of extracorporeal therapies, such as continuous veno-venous hemodiafiltration (CVVHDF) ( 2 , 3 ) or the ADVanced Organ Support (ADVOS) system. The latter is an innovative extracorporeal therapy that integrates albumin dialysis with multi-organ support, effectively removing protein-bound substances like bilirubin and addressing acid-base disorders ( 7 ). It is particularly valuable in patients with multi-organ failure, sepsis, or profound shock due to hepatic or renal dysfunction ( 8 – 10 ). For extracorporeal therapies therapeutic drug monitoring (TDM) is recommended to optimize dosing ( 2 ). The effects of novel systems such as ADVOS on antibiotic clearance remain unclear. While traditional systems like CVVHDF have been studied, limited data exists regarding the clearance of antibiotics like meropenem during ADVOS therapy ( 11 , 12 ). Dosing calculators, such as the MeroEasy tool ( https://www.doseeasy.de/ ) and the Caddy ( https://www.thecaddy.de/caddy/caddy/ ), are not validated for ADVOS, further complicating dose optimization in these patients. This study aims to address the knowledge gap by investigating the pharmacokinetics of meropenem in critically ill patients undergoing ADVOS therapy. Specifically, it seeks to compare meropenem plasma levels in patients treated with ADVOS versus those on CVVHDF or without extracorporeal therapy. These real-world data will help optimize antibiotic treatment strategies and improve outcomes in this complex patient population. Methods Study design This retrospective observational study was conducted in the intensive care unit (ICU) of a tertiary care hospital specialized on infectious diseases. It aimed to evaluate the pharmacokinetics of meropenem in critically ill patients, comparing plasma concentrations and clearance rates across the three patient groups. Plasma concentrations of meropenem, collected as part of standard therapeutic drug monitoring (TDM) between October 2022 and February 2024, were analyzed. Data were extracted from electronic medical records, including demographic and clinical characteristics, renal function, organ support modalities, and antibiotic dosing regimens. All included patients were critically ill and required ICU treatment for several days. Patients were categorized into three groups based on the presence and type of extracorporeal therapy: ( 1 ) patients on ADVOS® therapy (ADVITOS®, Munich, Germany), ( 2 ) patients on continuous veno-venous hemodiafiltration (CVVHDF; Prismaflex®, Baxter®, Deerfield, USA), and ( 3 ) patients without extracorporeal organ replacement therapy. Interventions All patients received meropenem via prolonged infusion over three hours using a perfusion pump. After an initial bolus of 2 g, subsequent dosing was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) high-dose recommendations based on glomerular filtration rate (GFR): 1) GFR > 50 mL/min/1.73m²: 2 g every 8 hours; 2) GFR 30–50 mL/min/1.73m²: 2 g every 12 hours; 3) GFR < 30 mL/min/1.73m²: 1 g every 12 hours (control group without dialysis) ( 18 ). For patients on ADVOS or CVVHDF, the maximum approved dose of 2 g every 8 hours was used with the aim to achieve sufficient plasma levels to cover pathogens with an MIC up to 4 mg/L (i.e., Epidemiological cut-off value - ECOFF for Acinetobacter) ( 18 ). Technical settings of the extracorporeal therapies ADVOS: A blood flow of 100 ml/min and a concentrate flow of 160 ml/min were used in all patients. CVVHD: A blood flow of 100 ml/min was used in all patients. The substitute was re-infused as post-dilution. In most patients the dialysate flow and substitute flow were both 750 ml/min. Citrate was used as anticoagulation method in CVVHDF and ADVOS. Sampling Plasma samples were collected at steady state, after at least one prolonged infusion. Samples were drawn at two time points per dosing interval: 1) Peak levels: 1–20 minutes after the end of the infusion; and 2) trough levels: 1–20 minutes before the next scheduled dose. In patients receiving ADVOS or CVVHDF, both pre- and post-filter samples were obtained simultaneously. Sampling during CVVHDF used Prismaflex ST150 filters (Baxter®, Deerfield, USA), ensuring that therapies remained uninterrupted during the dosing interval. Blood was drawn into EDTA vials via arterial access, immediately centrifuged (10 minutes at 3,000 × g), and plasma aliquoted into vials containing 50 µL stabilizing priming solution (Chromsystems®, Munich, Germany). Samples were mixed, frozen at -20°C, and transported under controlled conditions to the University Hospital Vienna for analysis the next workday. Samples arriving uncooled were discarded. Meropenem plasma concentrations were measured using high-performance liquid chromatography (HPLC) with the CE-IVD-certified reagent kit "Antibiotics in serum/plasma" (Identification number: 61000, Chromsystems®, Munich, Germany). Clearance calculations We defined the following parameters: CL patient : for overall calculated clearance (based on trough values). CL ADVOS : for calculated clearance attributed to ADVOS CL CVVHD : for calculated clearance attributed to CVVHD. CL estimated : for estimated clearance with MeroEasy (based on serum creatinine). CL patient was calculated using the MeroEasy tool, based on the meropenem trough values, taking into consideration the sex, age, body weight, body size and serum creatinine. A detailed description can be found at www.doseeasy.de . CL estimated was calculated using the MeroEasy tool based on the patient’s serum creatinine . The CL ADVOS and CL CVVHDF were calculated using simultaneously measured pre- and post-dialyzer plasma levels and considering the blood flow. Statistical Analysis Descriptive statistics were used to summarize patient characteristics and measured values. Meropenem trough concentrations were compared between groups using the Mann-Whitney test, while clearance values were compared using paired t-tests where applicable. Graphical representations and statistical analyses were performed using GraphPad Prism 9 (Dotmatics, Boston, MA, USA). A p-value < 0.05 was considered statistically significant. Results The patient characteristics are detailed in Table 1 . We included 16 patients (11 male/5 female) in our analysis. Two patients had measurements in both the ADVOS and CVVHDF group, resulting in a total of 8 patients in the control group without dialysis, 5 in the CVVHDF group and 5 in the ADVOS group. Creatinine at baseline was lower in the control group with 0.9 mg/dl vs. 1.2 mg/dl in CVVHDF and ADVOS patients. Bilirubin at baseline was highest in the ADVOS group with 7.7 ± 6.5 mg/dl. All patients groups were critically ill with mean APACHE II score > 20 ( 13 ). Patients in the ADVOS group were most ill with a mean APACHE II score of 29.2 ± 12. Table 1 Patient characteristics: all values: mean with standard deviation Control CVVHDF ADVOS Number of patients 8 5 5 Number of measurements 81 33 57 Gender (Male/Female) 6/2 4/1 2/3 Age (years) 59.1 (± 18) 61.2 (± 14.2) 56.4 (± 8.7) Weight (kg) 77.5 (± 2 6) 88.6 (± 13.5) 83.4 (± 22) Height (cm) 170.9 (± 9.3) 175.4 (± 8.9) 166.6 (± 9.6) Creatinine at baseline (mg/dL) 0.9 (± 0.9) 1.2 (± 0.5) 1.2 (± 0.5) Bilirubin at baseline (mg/dL) 1.3 (± 1.7) 5.1 (± 6.2) 7.7 (± 6.5) Albumin at baseline (g/L) 23.1 (± 2.7) 22.9 (± 3.9) 24.2 (± 3.6) APACHE II Score 20.1 (± 11.3) 27.2 (± 9.1) 29.2 (± 12.3) Table 2 Measured meropenem plasma-levels, all values median with interquartile range, the unit is mg/L. Post-dialyzer values are not applicable (= n. a. in the control group. Meropenem levels (mg/L) Control (n = 81) CVVHDF (n = 33) ADVOS (n = 57) Peak levels: Pre-dialyzer 45 (18.2) 43.3 (24.6) 37.9 (30.7) Post-dialyzer n.a. 25.5 ( 17 ) 11 (6.9) Trough levels : Pre-dialyzer 7.6 (6.6) 23.5 (19.1) 9.3 (9.8) Post-dialyzer n.a. 14.9 (15.1) 3.5 (0.8) Meropenem trough levels in the CVVHDF group (median 23.5 mg/L, IQR: 19.1) were higher than those in the ADVOS (median 9.3 mg/L, IQR: 12.8) and control groups (median 7.6 mg/L, IQR: 7) ( Graph 1 A ). The difference was only significant between the CVVHDF and control groups (p = 0.0017), but not between CVVHDF and ADVOS (p = 0.12). Trough levels in the ADVOS group varied strongly from 2.1 to 62.8 mg/L. In the control group 47.5% of trough levels were within the optimal range – with 3 levels below the optimal range ( Graph 1 B ). Similarly, 42.8% of the patients in the ADVOS group were within the target zone. In the CVVHDF group only 22.2% were within the target zone. Next, we analyzed the meropenem clearance in our patients ( Graph 2). The meropenem clearance calculated based on the trough values was highest in the control group with a mean of 8L/h (± 2), followed by the ADVOS (6.6 ± 2.9) and CVVHDF (6.3 ± 2.7) group ( Graph 2 A ). Furthermore, we calculated the machine clearance by using pre- and post-dialyzer values and found a mean clearance of 1.8 L/h (± 0.5) in the CVVHDF group and 3.5 L/h (± 1) in the ADVOS group ( Graph 2 B ). Graph 2 C shows a combination of the previous graphs, highlighting the fraction of total clearance achieved by the machine. Finally, we examined whether estimated clearance values using creatinine could be used as a surrogate marker for meropenem levels, potentially foregoing therapeutic drug monitoring. Graph 3B shows estimated meropenem clearance values calculated with the MeroEasy tool based on the creatinine values measured in routine laboratory examinations on the day of the corresponding meropenem measurement. The estimated clearance based on creatinine levels was significantly higher than the estimated clearance based on measured plasma trough values, with a mean difference of 3.7 L/h (p = 0.0001) for the control group, 4.1 L/h (p = 0.003) for the CVVHDF group and 3.6 L/h (p = 0.0003) for the ADVOS group. Correlation between the estimated and measured values was weak, with a pearson r of 0.46 (p = 0.0004) ( Graph 3 C ). Discussion This study provides the first real-life pharmacokinetic analysis of meropenem in critically ill patients undergoing ADVOS therapy and compares it with CVVHDF and non-extracorporeal treatments. It is also the first study to measure pre- and post-filter levels of meropenem to calculate machine-specific clearance in these patient groups. The key findings indicate that ADVOS therapy is safe for critically ill patients treated with meropenem, as meropenem clearance by ADVOS was lower than anticipated, and no trough levels fell below the therapeutic target of 2–8 mg/L. The ADVOS machine clearance of 3.5 L/h, measured in this study, is comparable to the documented in vitro values (3.4 ml/h) ( 12 ). This is only approximately 30% of the normal intrinsic meropenem clearance in healthy adults (12.5 L/h ( 14 )) or 40% of the clearance observed by Jaruratanasirikul et al. in non-renal insufficient intensive care patients (7.8 L/h) ( 15 ). This clearance in critically ill patients is consistent to the clearance of 8 L/h measured in our control group. Importantly, only 3 trough levels below 2 mg/L were observed, all in the control group without extracorporeal therapy. However, a significant number of trough levels exceeded the optimal range of 2–8 mg/L, particularly in the CVVHDF group (77.8%), compared to the ADVOS (57.2%) and control groups (52.5%).These results align with previous in vitro studies and case reports on ADVOS, which shows that the limited ADVOS machine clearance of 3.5 L/h cannot compensate for the complete loss of renal function with an assumed renal meropenem clearance in ICU patients of approximately 8 L/h. Hence, meropenem underdosing in patients with renal failure on ADVOS therapy receiving standard meropenem doses (2 g q8h) is unlikely. Nonetheless, the ADVOS clearance is much more effective than the CVVHDF clearance (3.5 vs 1.8 L/h) and this must be considered in dosing. In CVVHDF, higher trough levels are consistent with existing studies that show impaired intrinsic clearance in patients with renal failure, even with extracorporeal therapy ( 16 ). Prior studies on CVVHDF also highlight the unpredictability of antibiotic clearance due to variability in flow rates, membrane permeability, and patient-specific factors ( 16 , 17 ). The findings from this study further underscore the necessity of therapeutic drug monitoring (TDM) in CVVHDF to avoid overdosing, as the use of tools like MeroEasy , which relies on population estimates, may overestimate clearance without accounting for real-world machine maintenance pauses or individual variations. The safety of the dosing regimen employed (2 g q8h) in ADVOS and CVVHDF was supported by the absence of levels below therapeutic thresholds. However, a substantial proportion of trough levels exceeded 8 mg/L, raising concerns about potential toxicity. Neurotoxic and nephrotoxic effects have been reported at meropenem trough levels exceeding 44.45 mg/L and 64.2 mg/L, respectively ( 6 ), which was exceeded by one of our measurements in the ADVOS group. This high proportion of supra-therapeutic levels warrants further evaluation, especially in patients with limited residual renal function. Generalizability is supported by the inclusion of a significant number of measurements (171), covering a range of clinical conditions, but caution is warranted in extrapolating the findings to antibiotics with different pharmacokinetic profiles, such as high protein binding or low intrinsic clearance agents (e.g. ceftriaxone, daptomycin). This study has several limitations. First, the retrospective, single-center design limits its external validity. Second, the small sample size within subgroups, particularly for ADVOS therapy, reduces the power to detect subtle differences in meropenem clearance. Third, the study did not account for interindividual variability in patient factors such as fluid status, inflammation, and other pharmacokinetic modifiers, which may influence meropenem levels. Moreover, the reliance on TDM performed under routine clinical conditions introduces potential inconsistencies in sample timing and handling. Since only values after dosing intervals without ADVOS interruptions were included, the total daily clearance may be overestimated since the daily pause to set up and exchange the ADVOS machine is not accounted for. Future studies should investigate the pharmacokinetics of antibiotics with high protein binding and low intrinsic clearance during ADVOS therapy. Prospective, multicenter studies could provide more robust data and validate these findings across different ICUs. Moreover, detailed analyses of the impact of therapy interruptions and machine configurations on drug clearance are necessary to refine dosing strategies. Pharmacokinetic modeling incorporating real-world TDM data could improve tools like MeroEasy to account for individual variations and therapy-specific factors. Additionally, studies comparing ADVOS with other extracorporeal modalities in critically ill patients with different organ dysfunction profiles (e.g., liver failure, intoxication) could help optimize dosing protocols for a broader range of clinical scenarios. In conclusion, this study shows that patients with renal failure on ADVOS therapy receiving standard meropenem doses (2 g q8h) have no risk of antibiotic underdosing and ADVOS therapy is safe for patients with severe infections. The study highlights the importance of TDM in extracorporeal therapies and critically ill patients, as the ideal dosing is unpredictable due to variable factors influencing drug levels. Our findings emphasize the need for personalized dosing regimens to balance therapeutic efficacy and safety and to impede overdosing. Declarations Ethics Approval and Consent to Participate: Ethics approval was obtained (EK 24-066-VK), consent to participate is not applicable since we only performed a retrospective data analysis. Availability of data and materials: The data referred to during the study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. AP was employed by ADVITOS GmbH at the time of writing this manuscript. DT, SN and OF received lecture fees by ADVITOS GmbH. Funding: No funding was received for conducting this study. Authors’ contributions: DT, AP, MT: conceptualization and writing. DT, AP, TS, SN, OF, MT: methodology. DT, TM, KB, CG, DS, EF, JH, MD, TR, ML, CO, WH: investigation. DT, TS, SN, CW, AZ: resources. OF, SN, CW, AZ, WH, MT: supervision. 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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. AP was employed by ADVITOS GmbH at the time of writing this manuscript. Cite Share Download PDF Status: Published Journal Publication published 21 May, 2025 Read the published version in Infection → Version 1 posted Editorial decision: Revision requested 19 Apr, 2025 Reviews received at journal 18 Apr, 2025 Reviews received at journal 17 Apr, 2025 Reviews received at journal 10 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviewers invited by journal 27 Mar, 2025 Editor assigned by journal 27 Mar, 2025 Submission checks completed at journal 27 Mar, 2025 First submitted to journal 26 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Group","correspondingAuthor":false,"prefix":"","firstName":"Wolfgang","middleName":"","lastName":"Hoepler","suffix":""},{"id":442710024,"identity":"177c4704-3a97-457d-a7b7-5516388952ce","order_by":14,"name":"Aritz Perez","email":"","orcid":"","institution":"ADVITOS GmbH","correspondingAuthor":false,"prefix":"","firstName":"Aritz","middleName":"","lastName":"Perez","suffix":""},{"id":442710025,"identity":"290797f2-a092-49e2-9a01-3e74ccca7d5b","order_by":15,"name":"Christoph Wenisch","email":"","orcid":"","institution":"Vienna Healthcare Group","correspondingAuthor":false,"prefix":"","firstName":"Christoph","middleName":"","lastName":"Wenisch","suffix":""},{"id":442710026,"identity":"ac51ef64-3a6e-4051-8b82-806a3ec98efe","order_by":16,"name":"Otto Frey","email":"","orcid":"","institution":"Apotheke Kliniken Landkreis Heidenheim gGmbH, Regionales Arzneimittelinformationszentrum","correspondingAuthor":false,"prefix":"","firstName":"Otto","middleName":"","lastName":"Frey","suffix":""},{"id":442710027,"identity":"63d71e7c-d572-4765-92be-07af39e20265","order_by":17,"name":"Alexander Zoufaly","email":"","orcid":"","institution":"Sigmund Freud Private University Vienna","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Zoufaly","suffix":""},{"id":442710028,"identity":"3cf171a6-0ba5-403c-8d4e-9a216c375361","order_by":18,"name":"Marianna Traugott","email":"data:image/png;base64,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","orcid":"","institution":"Vienna Healthcare Group","correspondingAuthor":true,"prefix":"","firstName":"Marianna","middleName":"","lastName":"Traugott","suffix":""}],"badges":[],"createdAt":"2025-03-26 19:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6314993/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6314993/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s15010-025-02554-4","type":"published","date":"2025-05-21T15:58:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80815661,"identity":"7b5328a1-fe3c-4e8c-8607-e4ef6c184491","added_by":"auto","created_at":"2025-04-17 11:01:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":128610,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraph 1:\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/em\u003e\u003cem\u003eAnalysis of meropenem trough levels, \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e: Min to max Boxplot of trough levels in the control, CVVHDF- and ADVOS group. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e: Scatterplot of all trough levels. The green area highlights the target range of trough levels of 2 – 8 mg/L (18), the red line shows nephrotoxic levels of 44 mg/L \u003c/em\u003e(6)\u003cem\u003e. The percentages\u003c/em\u003e\u003cu\u003e\u003cem\u003e \u003c/em\u003e\u003c/u\u003e\u003cem\u003eat the top show the fraction of values in the target range area. Abbreviations: CVVHDF: continuous veno-venous hemodiafiltration; ADVOS: ADVanced Organ Support.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6314993/v1/cdcddb525b004d404d39cf17.png"},{"id":80816264,"identity":"4a9f39ef-418f-4761-ae72-6151a0612caa","added_by":"auto","created_at":"2025-04-17 11:09:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":98003,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraph 2: \u003c/strong\u003e\u003cem\u003eAnalysis of meropenem clearance, \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eA:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Bar graph of calculated meropenem clearance, based on trough levels. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eB:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003eBar graph of calculated machine clearance, based on measured pre- and post-dialyzer levels. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eC:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Bar graph showing the fraction of total clearance achieved by the respective machine clearance. Striped areas represent the machine clearance. Estimated values by subtracting the machine clearance (B) from the total clearance (A). Abbreviations: CVVHDF: continuous veno-venous hemodiafiltration; ADVOS: ADVanced Organ Support.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6314993/v1/3b1bf637cc49d838ed632a23.png"},{"id":80816501,"identity":"d76bd72a-fc6b-4e72-bf9e-6b6af2f79bfd","added_by":"auto","created_at":"2025-04-17 11:17:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":91482,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraph 3: \u003c/strong\u003e\u003cem\u003eAnalysis of creatinine as a surrogate marker, \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eA:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Bar graph of calculated meropenem clearance, based on trough levels. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eB:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003eBar graph of estimated meropenem clearance, based on creatinine values. \u003c/em\u003e\u003cem\u003e\u003cstrong\u003eC:\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Correlation plot of the measured meropenem clearance (A) and estimated meropenem clearance (B). Abbreviations: CVVHDF: continuous veno-venous hemodiafiltration; ADVOS: ADVanced Organ Support.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6314993/v1/b51860abca184eecafb6a757.png"},{"id":83460168,"identity":"8605635c-bb98-4267-aca7-168226396fc3","added_by":"auto","created_at":"2025-05-26 16:11:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1086990,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6314993/v1/9e18321f-3b95-4516-aeca-a7488edfcc8c.pdf"}],"financialInterests":"Competing interest reported. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAP was employed by ADVITOS GmbH at the time of writing this manuscript.","formattedTitle":"Meropenem plasma concentrations in critically ill patients treated with the novel multi organ replacement therapy ADVOS","fulltext":[{"header":"Main Point","content":"\u003cp\u003eWe investigated meropenem plasma concentrations in critically ill patients treated with the novel multi-organ-replacement therapy ADVOS. We found no cases of underdosing in the ADVOS treatment group and calculated an ADVOS machine clearance of 3.5 L/h.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eInfections are a leading cause of morbidity and mortality among critically ill patients in intensive care units (ICUs). The management of these infections requires timely and effective antibiotic therapy to combat potentially life-threatening pathogens. Beta-lactam antibiotics, particularly meropenem, play a crucial role due to their broad-spectrum activity and favorable safety profile (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, ensuring optimal dosing in this patient population is a persistent challenge due to complex pharmacokinetic changes and variability in clinical conditions (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMeropenem is widely used in ICUs to treat severe bacterial infections, including those caused by more resistant organisms (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Its pharmacokinetics are characterized by low protein binding and high renal clearance. As a hydrophilic molecule it has a low volume of distribution of 0.4–0.6 L/kg in critically ill patients, making it effective for bloodstream infections (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The efficacy of beta-lactam antibiotics depends on maintaining drug concentrations above the pathogen's minimum inhibitory concentration (fT \u0026gt; MIC) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In ICU patients treated with intermittent meropenem infusions trough levels up to 2–4 times above the MIC are targeted. The MIC for meropenem sensible pathogens is ≤ 2 mg/L, hence meropenem trough levels of 4–8 mg/L are targeted in severely ill patients(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).Underdosing can result in treatment failure, while excessive meropenem concentrations risk neurotoxicity and nephrotoxicity(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In critically ill patients, pharmacokinetics are often altered by factors such as renal dysfunction, hyperfiltration, fluid overload, and the use of extracorporeal therapies, such as continuous veno-venous hemodiafiltration (CVVHDF) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) or the ADVanced Organ Support (ADVOS) system. The latter is an innovative extracorporeal therapy that integrates albumin dialysis with multi-organ support, effectively removing protein-bound substances like bilirubin and addressing acid-base disorders (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). It is particularly valuable in patients with multi-organ failure, sepsis, or profound shock due to hepatic or renal dysfunction (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). For extracorporeal therapies therapeutic drug monitoring (TDM) is recommended to optimize dosing (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe effects of novel systems such as ADVOS on antibiotic clearance remain unclear. While traditional systems like CVVHDF have been studied, limited data exists regarding the clearance of antibiotics like meropenem during ADVOS therapy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Dosing calculators, such as the \u003cem\u003eMeroEasy\u003c/em\u003e tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.doseeasy.de/\u003c/span\u003e\u003cspan address=\"https://www.doseeasy.de/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and \u003cem\u003ethe Caddy\u003c/em\u003e (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.thecaddy.de/caddy/caddy/\u003c/span\u003e\u003cspan address=\"https://www.thecaddy.de/caddy/caddy/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), are not validated for ADVOS, further complicating dose optimization in these patients.\u003c/p\u003e \u003cp\u003eThis study aims to address the knowledge gap by investigating the pharmacokinetics of meropenem in critically ill patients undergoing ADVOS therapy. Specifically, it seeks to compare meropenem plasma levels in patients treated with ADVOS versus those on CVVHDF or without extracorporeal therapy. These real-world data will help optimize antibiotic treatment strategies and improve outcomes in this complex patient population.\u003c/p\u003e \n\n \n\n \n\n \n\n "},{"header":"Methods","content":"\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis retrospective observational study was conducted in the intensive care unit (ICU) of a tertiary care hospital specialized on infectious diseases. It aimed to evaluate the pharmacokinetics of meropenem in critically ill patients, comparing plasma concentrations and clearance rates across the three patient groups. Plasma concentrations of meropenem, collected as part of standard therapeutic drug monitoring (TDM) between October 2022 and February 2024, were analyzed. Data were extracted from electronic medical records, including demographic and clinical characteristics, renal function, organ support modalities, and antibiotic dosing regimens.\u003c/p\u003e\n\u003cp\u003eAll included patients were critically ill and required ICU treatment for several days. Patients were categorized into three groups based on the presence and type of extracorporeal therapy: (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) patients on ADVOS\u0026reg; therapy (ADVITOS\u0026reg;, Munich, Germany), (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) patients on continuous veno-venous hemodiafiltration (CVVHDF; Prismaflex\u0026reg;, Baxter\u0026reg;, Deerfield, USA), and (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) patients without extracorporeal organ replacement therapy.\u003c/p\u003e\n\u003ch2\u003eInterventions\u003c/h2\u003e\n\u003cp\u003eAll patients received meropenem via prolonged infusion over three hours using a perfusion pump. After an initial bolus of 2 g, subsequent dosing was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) high-dose recommendations based on glomerular filtration rate (GFR): 1) GFR\u0026thinsp;\u0026gt;\u0026thinsp;50 mL/min/1.73m\u0026sup2;: 2 g every 8 hours; 2) GFR 30\u0026ndash;50 mL/min/1.73m\u0026sup2;: 2 g every 12 hours; 3) GFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73m\u0026sup2;: 1 g every 12 hours (control group without dialysis) (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFor patients on ADVOS or CVVHDF, the maximum approved dose of 2 g every 8 hours was used with the aim to achieve sufficient plasma levels to cover pathogens with an MIC up to 4 mg/L (i.e., Epidemiological cut-off value - ECOFF for Acinetobacter) (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eTechnical settings of the extracorporeal therapies\u003c/h3\u003e\n\u003cp\u003eADVOS: A blood flow of 100 ml/min and a concentrate flow of 160 ml/min were used in all patients.\u003c/p\u003e\n\u003cp\u003eCVVHD: A blood flow of 100 ml/min was used in all patients. The substitute was re-infused as post-dilution. In most patients the dialysate flow and substitute flow were both 750 ml/min.\u003c/p\u003e\n\u003cp\u003eCitrate was used as anticoagulation method in CVVHDF and ADVOS.\u003c/p\u003e\n\u003ch3\u003eSampling\u003c/h3\u003e\n\u003cp\u003ePlasma samples were collected at steady state, after at least one prolonged infusion. Samples were drawn at two time points per dosing interval: 1) Peak levels: 1\u0026ndash;20 minutes after the end of the infusion; and 2) trough levels: 1\u0026ndash;20 minutes before the next scheduled dose.\u003c/p\u003e\n\u003cp\u003eIn patients receiving ADVOS or CVVHDF, both pre- and post-filter samples were obtained simultaneously. Sampling during CVVHDF used Prismaflex ST150 filters (Baxter\u0026reg;, Deerfield, USA), ensuring that therapies remained uninterrupted during the dosing interval. Blood was drawn into EDTA vials via arterial access, immediately centrifuged (10 minutes at 3,000 \u0026times; g), and plasma aliquoted into vials containing 50 \u0026micro;L stabilizing priming solution (Chromsystems\u0026reg;, Munich, Germany). Samples were mixed, frozen at -20\u0026deg;C, and transported under controlled conditions to the University Hospital Vienna for analysis the next workday. Samples arriving uncooled were discarded.\u003c/p\u003e\n\u003cp\u003eMeropenem plasma concentrations were measured using high-performance liquid chromatography (HPLC) with the CE-IVD-certified reagent kit \"Antibiotics in serum/plasma\" (Identification number: 61000, Chromsystems\u0026reg;, Munich, Germany).\u003c/p\u003e\n\u003ch3\u003eClearance calculations\u003c/h3\u003e\n\u003cp\u003eWe defined the following parameters:\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003epatient\u003c/sub\u003e: for overall calculated clearance (based on trough values).\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003eADVOS\u003c/sub\u003e: for calculated clearance attributed to ADVOS\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003eCVVHD\u003c/sub\u003e: for calculated clearance attributed to CVVHD.\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003eestimated\u003c/sub\u003e: for estimated clearance with \u003cem\u003eMeroEasy\u003c/em\u003e (based on serum creatinine).\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003epatient\u003c/sub\u003e was calculated using the \u003cem\u003eMeroEasy\u003c/em\u003e tool, based on the meropenem trough values, taking into consideration the sex, age, body weight, body size and serum creatinine. A detailed description can be found at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.doseeasy.de\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eCL\u003csub\u003eestimated was calculated using the MeroEasy tool based on the patient\u0026rsquo;s serum creatinine\u003c/sub\u003e.\u003c/p\u003e\n\u003cp\u003eThe CL\u003csub\u003eADVOS\u003c/sub\u003e and CL\u003csub\u003eCVVHDF\u003c/sub\u003e were calculated using simultaneously measured pre- and post-dialyzer plasma levels and considering the blood flow.\u003c/p\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eDescriptive statistics were used to summarize patient characteristics and measured values. Meropenem trough concentrations were compared between groups using the Mann-Whitney test, while clearance values were compared using paired t-tests where applicable. Graphical representations and statistical analyses were performed using GraphPad Prism 9 (Dotmatics, Boston, MA, USA). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe patient characteristics are detailed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. We included 16 patients (11 male/5 female) in our analysis. Two patients had measurements in both the ADVOS and CVVHDF group, resulting in a total of 8 patients in the control group without dialysis, 5 in the CVVHDF group and 5 in the ADVOS group. Creatinine at baseline was lower in the control group with 0.9 mg/dl vs. 1.2 mg/dl in CVVHDF and ADVOS patients. Bilirubin at baseline was highest in the ADVOS group with 7.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5 mg/dl. All patients groups were critically ill with mean APACHE II score\u0026thinsp;\u0026gt;\u0026thinsp;20 (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). Patients in the ADVOS group were most ill with a mean APACHE II score of 29.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cem\u003ePatient characteristics: all values: mean with standard deviation\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCVVHDF\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADVOS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of measurements\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender (Male/Female)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59.1 (\u0026plusmn;\u0026thinsp;18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.2 (\u0026plusmn;\u0026thinsp;14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56.4 (\u0026plusmn;\u0026thinsp;8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.5 (\u0026plusmn;\u0026thinsp;2 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.6 (\u0026plusmn;\u0026thinsp;13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.4 (\u0026plusmn;\u0026thinsp;22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight (cm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e170.9 (\u0026plusmn;\u0026thinsp;9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e175.4 (\u0026plusmn;\u0026thinsp;8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e166.6 (\u0026plusmn;\u0026thinsp;9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCreatinine at baseline (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9 (\u0026plusmn;\u0026thinsp;0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2 (\u0026plusmn;\u0026thinsp;0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2 (\u0026plusmn;\u0026thinsp;0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBilirubin at baseline (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3 (\u0026plusmn;\u0026thinsp;1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1 (\u0026plusmn;\u0026thinsp;6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.7 (\u0026plusmn;\u0026thinsp;6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlbumin at baseline (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.1 (\u0026plusmn;\u0026thinsp;2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.9 (\u0026plusmn;\u0026thinsp;3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.2 (\u0026plusmn;\u0026thinsp;3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAPACHE II Score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.1 (\u0026plusmn;\u0026thinsp;11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.2 (\u0026plusmn;\u0026thinsp;9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.2 (\u0026plusmn;\u0026thinsp;12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cem\u003eMeasured meropenem plasma-levels, all values median with interquartile range, the unit is mg/L. Post-dialyzer values are not applicable (=\u0026thinsp;n. a. in the control group.\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMeropenem levels (mg/L)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCVVHDF (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADVOS (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePeak levels:\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-dialyzer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.3 (24.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.9 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-dialyzer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.5 (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrough levels\u003c/strong\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePre-dialyzer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.6 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.5 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.3 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-dialyzer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.9 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.5 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eMeropenem trough levels in the CVVHDF group (median 23.5 mg/L, IQR: 19.1) were higher than those in the ADVOS (median 9.3 mg/L, IQR: 12.8) and control groups (median 7.6 mg/L, IQR: 7) (\u003cem\u003eGraph 1 A\u003c/em\u003e). The difference was only significant between the CVVHDF and control groups (p\u0026thinsp;=\u0026thinsp;0.0017), but not between CVVHDF and ADVOS (p\u0026thinsp;=\u0026thinsp;0.12). Trough levels in the ADVOS group varied strongly from 2.1 to 62.8 mg/L. In the control group 47.5% of trough levels were within the optimal range \u0026ndash; with 3 levels below the optimal range (\u003cem\u003eGraph 1 B\u003c/em\u003e). Similarly, 42.8% of the patients in the ADVOS group were within the target zone. In the CVVHDF group only 22.2% were within the target zone.\u003c/p\u003e\n\u003cp\u003eNext, we analyzed the meropenem clearance in our patients (\u003cem\u003eGraph\u003c/em\u003e 2). The meropenem clearance calculated based on the trough values was highest in the control group with a mean of 8L/h (\u0026plusmn;\u0026thinsp;2), followed by the ADVOS (6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9) and CVVHDF (6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7) group (\u003cem\u003eGraph 2 A\u003c/em\u003e). Furthermore, we calculated the machine clearance by using pre- and post-dialyzer values and found a mean clearance of 1.8 L/h (\u0026plusmn;\u0026thinsp;0.5) in the CVVHDF group and 3.5 L/h (\u0026plusmn;\u0026thinsp;1) in the ADVOS group (\u003cem\u003eGraph 2 B\u003c/em\u003e). Graph 2 C shows a combination of the previous graphs, highlighting the fraction of total clearance achieved by the machine.\u003c/p\u003e\n\u003cp\u003eFinally, we examined whether estimated clearance values using creatinine could be used as a surrogate marker for meropenem levels, potentially foregoing therapeutic drug monitoring. Graph 3B shows estimated meropenem clearance values calculated with the \u003cem\u003eMeroEasy\u003c/em\u003e tool based on the creatinine values measured in routine laboratory examinations on the day of the corresponding meropenem measurement. The estimated clearance based on creatinine levels was significantly higher than the estimated clearance based on measured plasma trough values, with a mean difference of 3.7 L/h (p\u0026thinsp;=\u0026thinsp;0.0001) for the control group, 4.1 L/h (p\u0026thinsp;=\u0026thinsp;0.003) for the CVVHDF group and 3.6 L/h (p\u0026thinsp;=\u0026thinsp;0.0003) for the ADVOS group. Correlation between the estimated and measured values was weak, with a pearson r of 0.46 (p\u0026thinsp;=\u0026thinsp;0.0004) (\u003cem\u003eGraph 3 C\u003c/em\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides the first real-life pharmacokinetic analysis of meropenem in critically ill patients undergoing ADVOS therapy and compares it with CVVHDF and non-extracorporeal treatments. It is also the first study to measure pre- and post-filter levels of meropenem to calculate machine-specific clearance in these patient groups.\u003c/p\u003e \u003cp\u003eThe key findings indicate that ADVOS therapy is safe for critically ill patients treated with meropenem, as meropenem clearance by ADVOS was lower than anticipated, and no trough levels fell below the therapeutic target of 2\u0026ndash;8 mg/L. The ADVOS machine clearance of 3.5 L/h, measured in this study, is comparable to the documented in vitro values (3.4 ml/h) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This is only approximately 30% of the normal intrinsic meropenem clearance in healthy adults (12.5 L/h (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)) or 40% of the clearance observed by Jaruratanasirikul et al. in non-renal insufficient intensive care patients (7.8 L/h) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This clearance in critically ill patients is consistent to the clearance of 8 L/h measured in our control group. Importantly, only 3 trough levels below 2 mg/L were observed, all in the control group without extracorporeal therapy. However, a significant number of trough levels exceeded the optimal range of 2\u0026ndash;8 mg/L, particularly in the CVVHDF group (77.8%), compared to the ADVOS (57.2%) and control groups (52.5%).These results align with previous in vitro studies and case reports on ADVOS, which shows that the limited ADVOS machine clearance of 3.5 L/h cannot compensate for the complete loss of renal function with an assumed renal meropenem clearance in ICU patients of approximately 8 L/h. Hence, meropenem underdosing in patients with renal failure on ADVOS therapy receiving standard meropenem doses (2 g q8h) is unlikely. Nonetheless, the ADVOS clearance is much more effective than the CVVHDF clearance (3.5 vs 1.8 L/h) and this must be considered in dosing. In CVVHDF, higher trough levels are consistent with existing studies that show impaired intrinsic clearance in patients with renal failure, even with extracorporeal therapy (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Prior studies on CVVHDF also highlight the unpredictability of antibiotic clearance due to variability in flow rates, membrane permeability, and patient-specific factors (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The findings from this study further underscore the necessity of therapeutic drug monitoring (TDM) in CVVHDF to avoid overdosing, as the use of tools like \u003cem\u003eMeroEasy\u003c/em\u003e, which relies on population estimates, may overestimate clearance without accounting for real-world machine maintenance pauses or individual variations.\u003c/p\u003e \u003cp\u003eThe safety of the dosing regimen employed (2 g q8h) in ADVOS and CVVHDF was supported by the absence of levels below therapeutic thresholds. However, a substantial proportion of trough levels exceeded 8 mg/L, raising concerns about potential toxicity. Neurotoxic and nephrotoxic effects have been reported at meropenem trough levels exceeding 44.45 mg/L and 64.2 mg/L, respectively (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), which was exceeded by one of our measurements in the ADVOS group. This high proportion of supra-therapeutic levels warrants further evaluation, especially in patients with limited residual renal function. Generalizability is supported by the inclusion of a significant number of measurements (171), covering a range of clinical conditions, but caution is warranted in extrapolating the findings to antibiotics with different pharmacokinetic profiles, such as high protein binding or low intrinsic clearance agents (e.g. ceftriaxone, daptomycin).\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the retrospective, single-center design limits its external validity. Second, the small sample size within subgroups, particularly for ADVOS therapy, reduces the power to detect subtle differences in meropenem clearance. Third, the study did not account for interindividual variability in patient factors such as fluid status, inflammation, and other pharmacokinetic modifiers, which may influence meropenem levels.\u003c/p\u003e \u003cp\u003eMoreover, the reliance on TDM performed under routine clinical conditions introduces potential inconsistencies in sample timing and handling. Since only values after dosing intervals without ADVOS interruptions were included, the total daily clearance may be overestimated since the daily pause to set up and exchange the ADVOS machine is not accounted for.\u003c/p\u003e \u003cp\u003eFuture studies should investigate the pharmacokinetics of antibiotics with high protein binding and low intrinsic clearance during ADVOS therapy. Prospective, multicenter studies could provide more robust data and validate these findings across different ICUs. Moreover, detailed analyses of the impact of therapy interruptions and machine configurations on drug clearance are necessary to refine dosing strategies.\u003c/p\u003e \u003cp\u003ePharmacokinetic modeling incorporating real-world TDM data could improve tools like \u003cem\u003eMeroEasy\u003c/em\u003e to account for individual variations and therapy-specific factors. Additionally, studies comparing ADVOS with other extracorporeal modalities in critically ill patients with different organ dysfunction profiles (e.g., liver failure, intoxication) could help optimize dosing protocols for a broader range of clinical scenarios.\u003c/p\u003e \u003cp\u003eIn conclusion, this study shows that patients with renal failure on ADVOS therapy receiving standard meropenem doses (2 g q8h) have no risk of antibiotic underdosing and ADVOS therapy is safe for patients with severe infections. The study highlights the importance of TDM in extracorporeal therapies and critically ill patients, as the ideal dosing is unpredictable due to variable factors influencing drug levels. Our findings emphasize the need for personalized dosing regimens to balance therapeutic efficacy and safety and to impede overdosing.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate: \u003c/strong\u003eEthics approval was obtained (EK 24-066-VK), consent to participate is not applicable since we only performed a retrospective data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The data referred to during the study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003eAP was employed by ADVITOS GmbH at the time of writing this manuscript.\u003c/p\u003e\n\u003cp\u003eDT, SN and OF received lecture fees by ADVITOS GmbH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions: \u003c/strong\u003eDT, AP, MT: conceptualization and writing. DT, AP, TS, SN, OF, MT: methodology. DT, TM, KB, CG, DS, EF, JH, MD, TR, ML, CO, WH: investigation. DT, TS, SN, CW, AZ: resources. OF, SN, CW, AZ, WH, MT: supervision. All authors contributed to the article and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBush K, Bradford PA. β-Lactams and β-Lactamase Inhibitors: An Overview. Cold Spring Harb Perspect Med. 2016;6(8):a025247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdul-Aziz MH, Alffenaar JWC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Med. 2020;46(6):1127\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteffens NA, Zimmermann ES, Nichelle SM, Brucker N. Meropenem use and therapeutic drug monitoring in clinical practice: a literature review. J Clin Pharm Ther. 2021;46(3):610\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHellinger WC, Brewer NS. Carbapenems and monobactams: imipenem, meropenem, and aztreonam. Mayo Clin Proc. 1999;74(4):420\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGon\u0026ccedil;alves-Pereira J, P\u0026oacute;voa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams. Crit Care. 2011;15(5):1\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImani S, Buscher H, Marriott D, Gentili S, Sandaradura I. Too much of a good thing: a retrospective study of β-lactam concentration-toxicity relationships. J Antimicrob Chemother. 2017;72(10):2891\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcharya M, Berger R, Popov AF. The role of the ADVanced Organ Support (ADVOS) system in critically ill patients with multiple organ failure. Artif Organs. 2022;46(5):735\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Chalabi A, Matevossian E, von Thaden A, Schreiber C, Radermacher P, Huber W, et al. Evaluation of an ADVanced Organ Support (ADVOS) system in a two-hit porcine model of liver failure plus endotoxemia. Intensive Care Med Exp. 2017;5:31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuhrmann V, Weber T, Roedl K, Motaabbed J, Tariparast A, Jarczak D, et al. Advanced organ support (ADVOS) in the critically ill: first clinical experience in patients with multiple organ failure. Ann Intensive Care. 2020;10:96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuhrmann V, Perez Ruiz de Garibay A, Faltlhauser A, Tyczynski B, Jarczak D, Lutz J, et al. Registry on extracorporeal multiple organ support with the advanced organ support (ADVOS) system. Med (Baltim). 2021;100(7):e24653.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026ouml;nig C, Kluge S, Fuhrmann V, Jarczak D. Pharmacokinetics of meropenem during advanced organ support (ADVOS\u0026reg;) and continuous renal replacement therapy. Int J Artif Organs. 2021;44(10):783\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026ouml;nig C, Frey O, Himmelein S, Mulack L, Brinkmann A, Perez Ruiz de Garibay A et al. In vitro elimination of antimicrobials during Advanced Organ Support (ADVOS) hemodialysis. Front Pharmacol [Internet]. 2024 Nov 22 [cited 2024 Nov 28];15. 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Precision Dosing of Meropenem in Adults with Normal Renal Function: Insights from a Population Pharmacokinetic and Monte Carlo Simulation Study. Antibiotics. 2024;13(9):849.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaruratanasirikul S, Thengyai S, Wongpoowarak W, Wattanavijitkul T, Tangkitwanitjaroen K, Sukarnjanaset W, et al. Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units. Antimicrob Agents Chemother. 2015;59(6):2995\u0026ndash;3001.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValtonen M, Tiula E, Backman JT, Neuvonen PJ. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2000;45(5):701\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ele Noble JLML, Meenks SD, Foudraine N, Janssen PKC. Alterations in transmembrane pressures during continuous venovenous haemofiltration significantly contribute to the pharmacokinetic variability of meropenem: a case series of three patients. J Antimicrob Chemother. 2019;74(1):271\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDosages used to define breakpoints [Internet]. 2023. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.eucast.org\u003c/span\u003e\u003cspan address=\"http://www.eucast.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"infection","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infe","sideBox":"Learn more about [Infection](http://link.springer.com/journal/15010)","snPcode":"15010","submissionUrl":"https://submission.nature.com/new-submission/15010/3","title":"Infection","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Meropenem, TDM, therapeutic drug monitoring, ADVOS, multi organ replacement therapy, calculated vs. measured values","lastPublishedDoi":"10.21203/rs.3.rs-6314993/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6314993/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eOptimal dosing of antibiotics in critically ill patients treated with the novel multi organ replacement therapy ADVOS (ADVanced Organ Support) based on albumin dialysis is unclear. This study aims to provide real life data on meropenem plasma concentrations after prolonged infusion in patients treated with ADVOS and a critically ill control group with and without continuous veno-venous hemodiafiltration (CVVHDF).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed plasma concentrations of meropenem obtained as part of our standard of care therapeutic drug monitoring in the intensive care unit. Meropenem was administered as a prolonged infusion over 3 hours. We measured peak and trough levels, pre-and post-filter levels of meropenem using high performance liquid chromatography. We calculated the meropenem clearance and compared the measured clearance with predicted clearance based on creatinine, calculated by the MeroEasy tool.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 171 measurements across 16 patients were analyzed. Meropenem trough concentrations were highest in the CVVHDF group with a median of 23.5 mg/L, followed by the ADVOS (median 9.3 mg/L) and control group (median 7.6 mg/L). No trough levels were below the lower limit of 2 mg/L in the CVVHDF and ADVOS groups. Meropenem machine clearance by CVVHDF was calculated to be 1.8 (± 0.5) L/h and 3.5 (± 1) L/h for ADVOS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur results suggest that ADVOS treatment in critically ill patients receiving meropenem in standard dosage does not lead to underdosing. Some trough values were even within potentially toxic levels, especially in the CVVHDF group, highlighting the importance of therapeutic drug monitoring.\u003c/p\u003e","manuscriptTitle":"Meropenem plasma concentrations in critically ill patients treated with the novel multi organ replacement therapy ADVOS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 11:01:38","doi":"10.21203/rs.3.rs-6314993/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-19T08:11:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-18T11:54:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-17T07:21:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-10T04:57:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184981614293972634990572466739670831469","date":"2025-04-08T15:49:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"253494292247566921568496309845146109706","date":"2025-04-07T16:52:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312411740602326070886503369060193951248","date":"2025-04-07T06:50:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306126526605288055668534069213539246726","date":"2025-04-03T07:50:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-27T12:11:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-27T12:07:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-27T06:40:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Infection","date":"2025-03-26T19:22:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"infection","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infe","sideBox":"Learn more about [Infection](http://link.springer.com/journal/15010)","snPcode":"15010","submissionUrl":"https://submission.nature.com/new-submission/15010/3","title":"Infection","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"37e09490-4eea-4da2-a7ec-ef0a439eac63","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:05:10+00:00","versionOfRecord":{"articleIdentity":"rs-6314993","link":"https://doi.org/10.1007/s15010-025-02554-4","journal":{"identity":"infection","isVorOnly":false,"title":"Infection"},"publishedOn":"2025-05-21 15:58:39","publishedOnDateReadable":"May 21st, 2025"},"versionCreatedAt":"2025-04-17 11:01:38","video":"","vorDoi":"10.1007/s15010-025-02554-4","vorDoiUrl":"https://doi.org/10.1007/s15010-025-02554-4","workflowStages":[]},"version":"v1","identity":"rs-6314993","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6314993","identity":"rs-6314993","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}