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Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. EU AIDA grant Health-F3-2011-278348.

Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed‐effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology. CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e113; doi:10.1038/psp.2014.12; advance online publication 7 May 2014

A variety of interventions aiming to influence physicians' sickness certification practice have been conducted, most are, however, not evaluated scientifically. The aim of this systematic literature review was to obtain updated knowledge about interventions regarding physicians' sickness certification practice and to summarize their possible effects, in terms of sickness absence (SA) or return to work (RTW) among patients. We searched PubMed and Web of Science up through 15 June 2020 and selected peer-reviewed studies that reported effects of controlled interventions that aimed to improve physicians' sickness certification practice and used SA or RTW among patients as outcome measures. Meta-analyses were conducted using random-effect models. Of the 1399 identified publications, 12 studies covering 9 interventions were assessed as relevant and included in the review. Most (70%) were from the Netherlands, two had a controlled, and seven a randomized controlled study design. All interventions included some type of training of physicians, and two interventions also included IT-support. Regarding the outcomes of SA/RTW, 30 different effect measures were used. In the meta-analyses, no statistically significant effect in favor of the interventions was observed for having any RTW (i.e. first, partial, or full) nor full RTW. The individual studies showed that physicians' sickness certification practice might be influenced by interventions in both the intended and non-intended direction, however, no statistically significant effect was indicated by the meta-analysis. The included studies varied considerably concerning intervention content and effect measures. KEY POINTS The knowledge is very limited regarding the content of interventions directed to physician's sickness certification practice The identified interventions included some type of training of physicians, and some of them also included IT-support for physicians There was a great heterogeneity among the interventions concerning effect measures used regarding return to work among patients The individual studies showed that physicians' sickness certification practice might be influenced by interventions in both intended and non-intended directions, however, the overall meta-analysis did not indicate an effect.

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 μg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-α production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-α, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-α and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

Tyrosine-kinase inhibitors (TKIs) demonstrate high inter-individual variability with respect to safety and efficacy and would therefore benefit from dose or schedule adjustments. This study investigated the efficacy, safety, and economical aspects of alternative dosing options for sunitinib in gastro-intestinal stromal tumors (GIST) and axitinib in metastatic renal cell carcinoma (mRCC). Dose individualization based on drug concentration, adverse effects, and sVEGFR-3 was explored using a modeling framework connecting pharmacokinetic and pharmacodynamic models, as well as overall survival. Model-based simulations were performed to investigate four different scenarios: (I) the predicted value of high-dose pulsatile schedules to improve clinical outcomes as compared to regular daily dosing, (II) the potential of biomarkers for dose individualizations, such as drug concentrations, toxicity measurements, and the biomarker sVEGFR-3, (III) the cost-effectiveness of biomarker-guided dose-individualizations, and (IV) model-based dosing approaches versus standard sample-based methods to guide dose adjustments in clinical practice. Simulations from the axitinib and sunitinib frameworks suggest that weekly or once every two weeks high-dosing result in lower overall survival in patients with mRCC and GIST, compared to continuous daily dosing. Moreover, sVEGFR-3 appears a safe and cost-effective biomarker to guide dose adjustments and improve overall survival (€36 784.- per QALY). Model-based estimations were for biomarkers in general found to correctly predict dose adjustments similar to or more accurately than single clinical measurements and might therefore guide dose adjustments. A simulation framework represents a rapid and resource saving method to explore various propositions for dose and schedule adjustments of TKIs, while accounting for complicating factors such as circulating biomarker dynamics and inter-or intra-individual variability.

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

In recent decades, many countries have implemented return-to-work coordinators to combat high rates of sickness absence and insufficient collaboration in the return-to-work process. The coordinators should improve communication and collaboration between stakeholders in the return-to-work process for people on sickness absence. How they perform their daily work remains unexplored, and we know little about to what extent they collaborate and perform other work tasks to support people on sickness absence. This study examines which work models return-to-work coordinators use in primary healthcare, psychiatry and orthopaedics in Sweden. A questionnaire was sent to all 82 coordinators in one region (89% response rate) with questions about the selection of patients, individual patient support, healthcare collaboration, and external collaboration. Random forest classification analysis was used to identify the models. Three work models were identified. In model A, coordinators were more likely to select certain groups of patients, spend more time in telephone than in face-to-face meetings, and collaborate fairly much. In Model B there was less patient selection and much collaboration and face-to-face meetings. Model C involved little patient selection, much telephone contact and very little collaboration. Model A was more common in primary healthcare, model C in orthopaedics, while model B was distributed equally between primary healthcare and psychiatry. The work models correspond differently to the coordinator's assignments of supporting patients and collaborating with healthcare and other stakeholders. The differences lie in how much they actively select patients, how much they collaborate, and with whom. Their different distribution across clinical contexts indicates that organisational demands influence how work models evolve in practice.

Ibrutinib, a Bruton's tyrosine kinase (Btk) inhibitor, is a key therapy for chronic lymphocytic leukemia (CLL). In clinical practice, adverse events, such as hypertension, frequently necessitate dose reductions or treatment discontinuation. Emerging evidence suggests that reduced doses may retain clinical efficacy while mitigating toxicity. The synergistic ibrutinib–venetoclax combination remains understudied at low doses, particularly for ibrutinib. This study aimed to explore dose optimization strategies, with/without venetoclax, in treatment‐naïve (TN) and relapsed/refractory (R/R) CLL using mechanism‐based, model‐informed approaches to characterize the relationship between systemic ibrutinib exposure and efficacy and safety biomarkers. We leveraged data from phase 1b/2 and 3 studies, including plasma concentrations, leukocyte and lymphocyte counts, lymph node and spleen size measurements, and blood pressure. A previously developed semi‐mechanistic population pharmacokinetic‐pharmacodynamic (PKPD) framework was re‐evaluated, extended by integrating additional biomarkers and identifying differences between TN and R/R patients, and used to simulate alternative dosing strategies. The model successfully captured the temporal dynamics of all biomarkers simultaneously. We quantified a 76% longer phospho‐Btk half‐life and a 43% shorter peripheral CLL cell half‐life in TN versus R/R patients, with no evidence of ibrutinib resistance in TN patients. Dose reductions based on response depth or toxicity preserved comparable response rates and progression‐free survival to standard dosing. Ibrutinib de‐escalation schedules with venetoclax resulted in a ≤ 5% reduction in peripheral blood measurable residual disease compared to standard dosing at 2 years. This PKPD framework supports dose individualization to improve tolerability without sacrificing treatment outcomes, offering a path toward more personalized, effective CLL management.

Quantitative characterization of evolving tumor resistance under targeted treatment could help identify novel treatment schedules, which may improve the outcome of anti-cancer treatment. In this study, a mathematical model which considers various clonal populations and evolving treatment resistance was developed. With parameter values fitted to the data or informed by literature data, the model could capture previously reported tumor burden dynamics and mutant KRAS levels in circulating tumor DNA (ctDNA) of patients with metastatic colorectal cancer treated with panitumumab. Treatment schedules, including a continuous schedule, intermittent schedules incorporating treatment holidays, and adaptive schedules guided by ctDNA measurements were evaluated using simulations. Compared with the continuous regimen, the simulated intermittent regimen which consisted of 8-week treatment and 4-week suspension prolonged median progression-free survival (PFS) of the simulated population from 36 to 44 weeks. The median time period in which the tumor size stayed below the baseline level (T TS

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