| 1. |
|
|
| 2. |
- Khan, David D., et al.
(författare)
-
A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants
- 2015
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 70:11, s. 3051-3060
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting. Methods: In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations. Results: The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill curves for both WT and the six E. coli mutants. Conclusions: The model-derived mutant-specific EC50 estimates were highly correlated (r(2) = 0.99) with the experimentally determined MICs, implying that the in vitro time-kill profile of a mutant strain is reasonably well predictable by the MIC alone based on the model.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Khan, David, et al.
(författare)
-
Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli
- 2018
-
Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 51:3, s. 399-406
-
Tidskriftsartikel (refereegranskat)abstract
- Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.
|
|
| 6. |
|
|
| 7. |
- Nielsen, Elisabet I., 1973-, et al.
(författare)
-
Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains? : External evaluation of a PKPD model describing longitudinal in vitro data
- 2017
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 72:11, s. 3108-3116
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains. Methods: A PKPD model describing the efficacy of ciprofloxacin on Escherichia coli was evaluated. The predictive performance of the model was evaluated across several experimental conditions with respect to: (i) bacterial start inoculum ranging from the standard of similar to 10(6) cfu/mL up to late stationary-phase cultures; and (ii) efficacy for seven additional strains (three laboratory and four clinical strains), not included during the model development process, based only on information regarding their MIC. Model predictions were performed according to the intended experimental protocol and later compared with observed bacterial counts. Results: The mechanism-based PKPD model structure developed based on data from standard start inoculum experiments was able to accurately describe the inoculum effect. The model successfully predicted the time course of drug efficacy for additional laboratory and clinical strains based on only the MIC values. The model structure was further developed to better describe the stationary phase data. Conclusions: This study supports the use of mechanism-based PKPD models based on preclinical data for predictions of untested scenarios.
|
|
| 8. |
- Nielsen, Sara, et al.
(författare)
-
Effects of autism spectrum disorders on outcome in teenage-onset anorexia nervosa evaluated by the Morgan-Russell outcome assessment schedule: a controlled community-based study
- 2015
-
Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 6:14
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of the study was to evaluate time trends and effects of co-existing autism spectrum disorders (ASD) on outcome in an ongoing long-term follow-up study of anorexia nervosa (AN). Methods: The Morgan-Russell Outcome Assessment Schedule (MROAS) was used at 6-, 10- and 18-year follow-up of a representative sample of 51 individuals with teenage-onset AN and a matched group of 51 healthy comparison cases. The full multinomial distribution of responses for the full scale and each of the subscales was evaluated using exact nonparametric statistical methods. The impact of diagnostic stability of ASD on outcome in AN was evaluated in a dose–response model. Results: There were no deaths in either group. Food intake and menstrual pattern were initially poor in the AN group but normalised over time. MROAS ‘mental state’ was much poorer in the AN group and did not improve over time. The psychosexual MROAS domains ‘attitudes’ and ‘aims’ showed persistent problems in the AN group. In the MROAS socioeconomic domain, the subscales ‘personal contacts’, ‘social activities’ and ‘employment record’ all showed highly significant between-group differences at all three follow-ups. A statistically significant negative dose–response relationship was found between a stable diagnosis of ASD over time and the results on the subscales ‘mental state’, ‘psychosexual state’ and ‘socio-economic state’. Conclusions: Outcome of teenage-onset AN is favourable with respect to mortality and persisting eating disorder, but serious problems remain in the domains ‘mental state’, ‘psychosexual function’ and ‘socioeconomic state’. Outcome is considerably worse if ASD is present. Treatment programmes for AN need to be modified so as to accommodate co-existing ASD.
|
|
| 9. |
- Zhao, Chenyan, et al.
(författare)
-
Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model
- 2024
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MICCIP 0.023–1 mg/L and MICCST 0.5–0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC50) in combination was 160% of the EC50 in monodrug experiments, while for colistin, the change in EC50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.
|
|
| 10. |
- Abrantes, João A., et al.
(författare)
-
Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
- 2019
-
Ingår i: CPT. - : Wiley. - 2163-8306. ; 8:12, s. 894-903
-
Tidskriftsartikel (refereegranskat)abstract
- Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.
|
|
| 11. |
- Abrantes, João A., et al.
(författare)
-
Elucidation of Factor VIII Activity Pharmacokinetics : A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
- 2017
-
Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 102:6, s. 977-988
-
Tidskriftsartikel (refereegranskat)abstract
- This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.
|
|
| 12. |
- Abrantes, João A., et al.
(författare)
-
Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
- 2019
-
Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 85:6, s. 1326-1336
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.
|
|
| 13. |
- Abrantes, João A.
(författare)
-
Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.
|
|
| 14. |
- Abrantes, João A., et al.
(författare)
-
Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
- 2020
-
Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 105:5, s. 1443-1453
-
Tidskriftsartikel (refereegranskat)abstract
- Pharmacokinetic-based prophylaxis of replacement factor VIII products has been encouraged in the past years, but the exposure (factor VIII activity)-response (bleeding frequency) relationship remains unclear. The aim of this study was to characterize the relationship between factor VIII dose, plasma factor VIII activity, bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of factor VIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using nonlinear mixed effects modelling in NONMEM. In total, 183 patients (median age 22 years [range, 1-61]; weight 60 kg [11-124]) contributed with 1535 plasma factor VIII activity observations, 633 bleeds and 11 patient/study characteristics (median observation period 12 months [3.1-13.1]). A parametric repeated time-to-categorical bleed model, guided by plasma factor VIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability for the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research based on a post-hoc analysis of the LEOPOLD studies (ClinicalTrials.gov identifiers NCT01029340, NCT01233258 and NCT01311648).
|
|
| 15. |
|
|
| 16. |
- Bahnasawy, Salma M., et al.
(författare)
-
Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli
- 2023
-
Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 169
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios.Methods: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant.Results: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETXcytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release.Conclusion: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.
|
|
| 17. |
- Brekkan, Ari, et al.
(författare)
-
Population Pharmacokinetics of Plasma-Derived Factor IX : Procedures for Dose Individualization
- 2016
-
Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 14:4, s. 724-732
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B. Objectives: The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization. Methods: The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL(-1). Results and conclusions: A three-compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg(-1) dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma-derived FIX products.
|
|
| 18. |
- Brem, Jürgen, et al.
(författare)
-
Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
-
Ingår i: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
-
Tidskriftsartikel (refereegranskat)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
|
|
| 19. |
- Brill, Margreke J. E., et al.
(författare)
-
Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations
- 2018
-
Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 24:7, s. 697-706
-
Forskningsöversikt (refereegranskat)abstract
- Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.
|
|
| 20. |
- Buchner, F. L., et al.
(författare)
-
Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2010
-
Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 21:3, s. 357-371
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study. Methods Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. Results During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. Conclusion We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.
|
|
| 21. |
- Bulman, Zackery P., et al.
(författare)
-
Research priorities towards precision antibiotic therapy to improve patient care
- 2022
-
Ingår i: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802
-
Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.
|
|
| 22. |
- Cam, Henrik, et al.
(författare)
-
Failure to Involve Older Hospitalised Patients in Medication Decisions : A Change of Approach is Called For
- 2024
-
Ingår i: Research in Social and Administrative Pharmacy. - : Elsevier. - 1551-7411 .- 1934-8150. ; 20:2, s. 216-217
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Patient involvement in medical-decision making is linked to improved patient outcomes and increased patient satisfaction.Objectives: The aim was to explore how hospitalised older patients are and wish to be involved in medication decisions affecting their medication therapy after hospital discharge.Methods: Naturalistic observations of consultations between healthcare professionals and hospitalised older patients who were about to be discharged were performed at in total three medical wards at two hospitals in Sweden. Subsequent semi-structured interviews with the patients were conducted within one week after discharge. The data were thematically analysed, guided by systematic text condensation.Results: Twenty patients were included (mean age: 81 (SD 8) years, 45 % female). Three themes were identified: 1) Predetermined authoritarian structures; describes that neither patients nor healthcare professionals expected patients to be involved in medication decisions. The medication decisions were frequently already taken by the healthcare professionals prior to the consultations, 2) Difficulties in finding the right time and setting; displays inhibitory factors in patient involvement in medication decisions when the consultations occur in hospital, and 3) Communication focusing on benefits over side-effects; demonstrates that newly prescribed medications were rarely accompanied with information about side-effects. Patients felt they lacked sufficient knowledge to take informed decisions about medications.Conclusions: There are structures limiting involvement of older patients in medication decisions prior to hospital discharge. A change in approach to consultations from both the patients and healthcare professionals is needed to provide patients with the knowledge they feel is needed to be sufficiently involved.
|
|
| 23. |
- Cam, Henrik, et al.
(författare)
-
The complexities of communication at hospital discharge of older patients : a qualitative study of healthcare professionals' views
- 2023
-
Ingår i: BMC Health Services Research. - : BioMed Central (BMC). - 1472-6963. ; 23
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Hospital discharge of older patients is a high-risk situation in terms of patient safety. Due to the fragmentation of the healthcare system, communication and coordination between stakeholders are required at discharge. The aim of this study was to explore communication in general and medication information transfer in particular at hospital discharge of older patients from the perspective of healthcare professionals (HCPs) across different organisations within the healthcare system.Methods: We conducted a qualitative study using focus group and individual or group interviews with HCPs (physicians, nurses and pharmacists) across different healthcare organisations in Sweden. Data were collected from September to October 2021. A semi-structured interview guide including questions on current medication communication practices, possible improvements and feedback on suggestions for alternative processes was used. The data were analysed thematically, guided by the systematic text condensation method.Results: In total, four focus group and three semi-structured interviews were conducted with 23 HCPs. Three main themes were identified: 1) Support systems that help and hinder describes the use of support systems in the discharge process to compensate for the fragmentation of the healthcare system and the impact of these systems on HCPs' communication; 2) Communication between two separate worlds depicts the difficulties in communication experienced by HCPs in different healthcare organisations and how they cope with them; and 3) The large number of medically complex patients disrupts the communication reveals how the highly pressurised healthcare system impacts on HCPs' communication at hospital discharge.Conclusions: Communication at hospital discharge is hindered by the fragmented, highly pressurised healthcare system. HCPs are at risk of moral distress when coping with communication difficulties. Improved communication methods at hospital discharge are needed for the benefit of both patients and HCPs.
|
|
| 24. |
- Damgaard, Tobias, et al.
(författare)
-
Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units
- 2024
-
Ingår i: Infectious Diseases. - : Taylor & Francis Group. - 2374-4235 .- 2374-4243.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Only about 50% of intensive care unit (ICU) patients reach a free trough concentration above MIC (100% fT > MIC) of beta-lactam antibiotics. Although dose adjustments based on therapeutic drug monitoring (TDM) could be beneficial, TDM is not widely available. We investigated serum creatinine-based estimated GFR (eGFR) as a rapid screening tool to identify ICU patients at risk of insufficient exposure. Method: Ninety-three adult patients admitted to four ICUs in southeast Sweden treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Beta-lactam trough concentrations were measured. The concentration target was set to 100% fT > MICECOFF (2, 4, and 16 mg/L based on calculated free levels for meropenem, cefotaxime, and piperacillin, respectively). eGFR was primarily determined via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and compared to three other eGFR equations. Data was analysed using logistic regression and receiver operative characteristic (ROC) curves. Results: With intermittent standard dosing, insufficient exposure was common in patients with a relative eGFR >= 48mL/min/1.73m(2) [85%, (45/53)], particularly when treated with cefotaxime [96%, (24/25)]. This eGFR cut-off had a sensitivity of 92% and specificity of 82% (AUC 0.871, p < 0.001) in identifying insufficient exposure. In contrast, patients with eGFR <48mL/min/1.73m(2) had high target attainment [90%, (36/40)] with a wide variability in drug exposure. There was no difference between the four eGFR equations (AUC 0.866-0.872, cut-offs 44-51 ml/min/1.73m(2)). Conclusion: Serum creatinine-based eGFR is a simple and widely available surrogate marker with potential for early identification of ICU patients at risk of insufficient exposure to piperacillin, meropenem, and cefotaxime.
|
|
| 25. |
- De Cock, Roosmarijn F W, et al.
(författare)
-
A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates
- 2014
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 31:3, s. 754-767
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSERecently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs.METHODSFive different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis.RESULTSThe descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models.CONCLUSIONSThis study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children.
|
|
