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Estimated glomerular filtration rate (eGFR) based on creatinine (eGFR Creatinine ) or cystatin C (eGFR CystatinC ) require steady-state conditions and thus have limitations in intensive care unit (ICU) patients. Gentamicin is a potential exogenous marker for eGFR but poorly investigated. This retrospective study included adult ICU patients ( ≥  18 years) treated with gentamicin and not on renal replacement therapy (RRT) at admission. eGFR Creatinine and eGFR CystatinC were calculated using the LM-rev and CAPA equations, respectively. Gentamicin clearance was estimated using a population pharmacokinetic model and used as eGFR Gentamicin . Agreement between eGFRs vs. eGFR Gentamicin and prediction of RRT and mortality for each eGFR were assessed. 254 patients were included of whom 11% ( n  = 28) received RRT later and 19% ( n  = 49) were dead at 30 days. The bias was 12 mL/min/1.73 m 2 and 8 mL/min/1.73 m 2 , respectively, and the limits of agreement − 31–55 mL/min/1.73m 2 and − 46–62 mL/min/1.73m 2 for the agreement between eGFR Gentamicin vs. eGFR Creatinine , and for eGFR Gentamicin vs. eGFR CystatinC , respectively. The c-indexes for predicting RRT during ICU stay were 0.75 (0.64–0.86), 0.77 (0.66–0.88) and 0.80 (0.69–0.90) for eGFR Creatinine , eGFR CystatinC and eGFR Gentamicin respectively, and for 30-day mortality 0.61 (0.52–0.70), 0.61 (0.52–0.70) and 0.63 (0.54–0.72) respectively. In ICU patients already receiving gentamicin, eGFR Gentamicin derived from population PK models can be used to assess renal function and could potentially help improve dosing of other renally cleared drugs like the β-lactams during early phase of infections in the ICU.

Background Standard dosing regimens of meropenem and piperacillin-tazobactam frequently fail to achieve targeted plasma concentrations in critically ill patients. Extended or continuous regimens are often used to improve target attainment. Although prompt antibiotic initiation is a major determinant of survival, few studies have reported systemic concentrations early after treatment initiation. No prior study has reported concentrations immediately after the loading dose and first extended infusion. This study aimed to evaluate plasma target attainment during the first dosing interval with an extended infusion regimen in a general intensive care unit (ICU). Methods Adult ICU patients were prospectively included in conjunction with the first administration of meropenem or piperacillin-tazobactam. Treatment was initiated with a 0.5 h loading dose immediately followed by a 3 h extended infusion; typically 4 + 4 g piperacillin or 1(− 2)g + 1(− 2)g meropenem, in line with the local ICU protocol. Patients requiring renal replacement therapy were excluded. Plasma concentrations were measured post-loading dose (C max ), near the end of the first extended infusion, and at the end of the first dosing interval (C min ). Samples were analyzed using validated tandem mass spectrometry (UHPLC-MS/MS) methods. The primary endpoint was the proportion of patients achieving 100% time above minimum inhibitory concentrations ( f T > MIC) during the first dosing interval. This was evaluated using observed C min above 2 mg/L (meropenem) and 20 mg/L (piperacillin). Additionally, published pharmacokinetic models were applied to the observed data for %fT > MIC estimation, using an a posteriori Bayesian approach. Results We included 65 meropenem and 142 piperacillin measurements from 22 and 48 patients, respectively. Many patients (45% meropenem, 38% piperacillin) failed to reach 100% f T > MIC with the standard regimens used. Target non-attainment was associated with high estimated glomerular filtration rates (eGFR) and suspected augmented renal clearance (ARC). All meropenem patients that failed to reach target had eGFR > 90 mL/min/1.73 m 2 , as did 76% of corresponding piperacillin patients. Patients with suspected ARC frequently exhibited a tenfold or greater peak-to-trough decline (C min /C max  < 0.1). Conclusions Despite aggressive dosing, plasma concentrations often fail to reach 100% f T > MIC during the first dosing interval. Alternative regimens and early plasma concentration measurements followed by adaptive dose adjustments should be considered to improve target attainment.

Antibiotics are life-saving medications, and optimal dosing for each individual is critical to effective and safe treatment. Dose individualisation is needed when routine dosing results in concentrations that vary more than accepted between individuals from an efficacy or safety point of view. A tool for individualisation is model-informed precision dosing (MIPD), which uses software with integrated population pharmacokinetic (PK) models to interpret measured antibiotic concentrations and to optimise dosing.This thesis aimed to improve antibiotic treatment by evaluating pharmacokinetic/pharmacodynamic (PK/PD) target attainment for alternative dosing strategies, assessing PK variability between individuals, and developing processes for MIPD in clinical practice.One way to improve target attainment for beta-lactams without increasing the daily dose is to prolong the infusions. Different beta-lactam infusion durations were evaluated for adult intensive care patients. The predicted attainment of PK/PD targets recommended for critically ill was high for primary pathogen scenarios regardless of infusion strategy, indicating that short infusions (15 min) can be used. In situations when worst-case scenario pathogens are suspected, e.g., hospital-acquired infection, short infusions were insufficient, and 3h extended or continuous infusions improved target attainment. However, when evaluating the implemented routine use of extended infusions in critically ill, a large proportion of individuals was still below target. The large PK variability between individuals suggests a need for early monitoring to identify under and over-treated patients. In patients with sub-optimal exposure, MIPD can provide an added value.This thesis has brought MIPD closer to clinical implementation and the benefit of patients. Barriers to implementation were addressed, including an assessment of how documentation errors can impact dosing decisions based on concentration monitoring. For vancomycin, simulations indicate that target attainment evaluations are robust with respect to locally observed errors in dose administration time. For meropenem, the impact of errors was evident already at normal renal function and pronounced in augmented renal clearance. Extra measures to promote correct documentation are needed when monitoring beta-lactams like meropenem, particularly in intensive care. Further, a novel MIPD workflow and an implementation plan for vancomycin dosing were developed. This work defined a new role for physicians or pharmacists as MIPD consultants and new tasks for clinical pharmacists. The pragmatic development process can guide other institutions aiming to initiate MIPD, and the developed workflow provides an opportunity to expand MIPD to other treatments.

Background Current guidelines recommend dosing vancomycin based on the area under the concentration time curve (AUC) to maximise efficacy and minimise the risk of nephrotoxicity. The preferred approach to AUC-guided therapy is to apply model-informed precision dosing (MIPD). However, the adoption in clinical practice has been slow. Aim We aimed to develop an intervention, including a standardised MIPD workflow and an implementation plan for vancomycin AUC-guided dosing, in a Swedish tertiary hospital. Method The intervention was developed in a framework-guided process. The design phase included stakeholder feedback (nurses, pharmacists, physicians), local data collection and feasibility testing of intervention components with parallel consideration of implementation aspects. The hypothesised relationships between the different components, implementation strategies and the mechanism of action resulting in expected outcomes were represented by a logic model. Results The final intervention consisted of a workflow for MIPD, with defined roles and responsibilities, as well as processes for data and information transfer. Details were provided in supportive documents; an instruction on therapeutic drug monitoring (TDM) sampling and documentation for nurses, and a detailed dosing software instruction for MIPD consultants and clinical pharmacists. Activities to facilitate implementation included the development of a local clinical routine for vancomycin dosing, staff training and recurring MIPD rounds. Conclusion An intervention for MIPD, with an implementation plan for AUC-guided dosing of vancomycin, was developed for a tertiary hospital setting. The process can be used as guidance for other institutions with similar context wishing to initiate MIPD.

PurposeTo characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.MethodsThis work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.ResultsA two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.ConclusionA population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

This paper presents a heat transfer study, based on the actual conditions of the hearth of Blast Furnace 2 at SSAB Oxelosund in Sweden. Initially, an experimental study was carried out. The temperature of the cold surfaces of the bottom and wall lining were measured with a hand-held thermocouple. The aim of the overall study was to find a method to determine the outer surface temperature, based on lining temperature readings from permanently installed thermocouples. A heat transfer model was developed, using the established correlations from the experimental study as boundary conditions. With the model, it is possible to calculate a complete two-dimensional temperature profile of the hearth lining at any given time. The permanently installed thermocouples are used to validate the model, by comparing calculated and measured temperatures; the accuracy of the model is plus/minus 3 degrees difference.

Background After medical center implementation of 2009 ASHP/IDSA guidelines, we evaluated the appropriateness of vancomycin dosing and TDM. Objective Our primary objectives were to assess short term effects on (1) appropriateness of initial vancomycin dosing, (2) appropriateness of sampling of plasma levels, before and after implementation of guidelines. Method The study was conducted in two phases, pre-guideline and post-guideline implementation. The interventions included (1) Nurses and phlebotomist education regarding the appropriate timing of vancomycin sampling, (2) A nomogram for appropriate initial dosing that was distributed to medical staff. Patient demographics, dosing and timing of sampling were collected in eligible patients and assessed for appropriateness. Results The appropriateness of the prescribed dose increased from 51% (128/253) of patients during the pre period to 78% (155/200) ( p  < 0.0001) during the post period. Similarly, overall appropriateness of sampling of vancomycin troughs at steady state improved from 36% (63/173) pre to 55% (106/191) ( p  < 0.03) post. Specifically, the appropriate timing of troughs (within 30 min of the next dose) increased from 37% (64/173) during the pre period to 78% (149/191) during the post period ( p  < 0.0001). Conclusion Adoption of the guidelines with associated training resulted in significant short term improvement in vancomycin dosing and TDM

Earlier we used a glioma model to identify loci in the mouse genome, which were repeatedly targeted by platelet-derived growth factor (PDGF)-containing Moloney murine leukemia viruses. The gene Prkg2 , encoding cyclic guanosine monophosphate (cGMP)-dependent protein kinase II, cGKII, was tagged by retroviral insertions in two brain tumors. The insertions were both situated upstream of the kinase domain and suggested creating a truncated form of the cGKII protein. We transfected different human glioma cell lines with Prkg2 and found an overall reduction in colony formation and cell proliferation compared with controls transfected with truncated Prkg2 (lacking the kinase domain) or empty vector. All glioma cells transfected with the cGKII phosphorylate vasodilator-stimulated phosphoprotein, VASP, after cGMP analog treatment. Glioma cell lines positive for the Sox9 transcription factor showed reduced Sox9 expression when Prkg2 was stably transfected. When cGKII was activated by cGMP analog treatment, Sox9 was phosphorylated, Sox9 protein expression was suppressed and the glioma cell lines displayed loss of cell adhesion, inhibition of Akt phosphorylation and G1 arrest. Sox9 repression by siRNA was similarly shown to reduce glioma cell proliferation. Expression analysis of stem and glial lineage cell markers also suggests that cGKII induces differentiation of glioma cell lines. These findings describe an anti-proliferative role of cGKII in human glioma biology and would further explain the retroviral tagging of the cGKII gene during brain tumor formation in PDGF-induced tumors.

Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells is the ubiquitin–proteasome system (UPS). Oncoproteins that drive tumor development and tumor maintenance are often deregulated and stabilized in malignant cells. This can occur when oncoproteins escape degradation by the UPS because of mutations in either the oncoprotein itself or in the UPS components responsible for recognition and ubiquitylation of the oncoprotein. As the pathogenic accumulation of an oncoprotein can lead to effectively sustained cell growth, viability and tumor progression, it is an indisputable target for cancer treatment. The most common types of malignant brain tumors in children and adults are medulloblastoma and glioma, respectively. Here, we review different ways of how deregulated proteolysis of oncoproteins involved in major signaling cancer pathways contributes to medulloblastoma and glioma development. We also describe means of targeting relevant oncoproteins in brain tumors with treatments affecting their stability or therapeutic strategies directed against the UPS itself.

Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC -amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN -expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC -expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN -expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma. CDKN2A loss and p53 mutations are rare in MYC-driven Group 3 medulloblastomas (MBs). Here the authors generated a transgenic mouse model of Group 3 MB by MYC overexpression and show that MYC suppresses ARF to drive tumorigenesis.