| 1. |
- Zhao, Chenyan, et al.
(författare)
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Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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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.
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| 2. |
- Abrantes, João A., et al.
(författare)
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Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 105:5, s. 1443-1453
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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).
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| 3. |
- Bahnasawy, Salma M., et al.
(författare)
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Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli
- 2023
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 169
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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.
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| 4. |
- Brem, Jürgen, et al.
(författare)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
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Ingår i: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
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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.
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| 5. |
- Bulman, Zackery P., et al.
(författare)
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Research priorities towards precision antibiotic therapy to improve patient care
- 2022
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Ingår i: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802
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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.
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| 6. |
- Cam, Henrik, et al.
(författare)
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Failure to Involve Older Hospitalised Patients in Medication Decisions : A Change of Approach is Called For
- 2024
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Ingår i: Research in Social and Administrative Pharmacy. - : Elsevier. - 1551-7411 .- 1934-8150. ; 20:2, s. 216-217
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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.
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| 7. |
- Cam, Henrik, et al.
(författare)
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The complexities of communication at hospital discharge of older patients : a qualitative study of healthcare professionals' views
- 2023
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Ingår i: BMC Health Services Research. - : BioMed Central (BMC). - 1472-6963. ; 23
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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.
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| 8. |
- Damgaard, Tobias, et al.
(författare)
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Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units
- 2024
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Ingår i: Infectious Diseases. - : Taylor & Francis Group. - 2374-4235 .- 2374-4243.
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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.
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| 9. |
- Johansson, Anna, et al.
(författare)
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Quantitation of seven sedative and analgesic drugs in whole blood from intensive care patients using liquid chromatography mass spectrometry
- 2021
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Ingår i: TOXICOLOGIE ANALYTIQUE ET CLINIQUE. - : Elsevier. - 2352-0078 .- 2352-0086. ; 33:4, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- We present the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of clonidine, dexmedetomidine, fentanyl, ketamine, ketobemidone, midazolam and morphine in whole blood. These are drugs predominately used in intensive care units (ICUs) but they are also encountered in forensic investigations. The analytes were recovered from 0.25 g of blood by protein precipitation with a mixture of acetonitrile and ethanol. Separation was performed on a BEH phenyl column. Mobile phases consisted of 0.05% formic acid in 10 mM ammonium formate and 0.05% formic acid in methanol, respectively, and the flow rate was 600 mu L/min. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring. Validation included selectivity, qualitative matrix effects, calibration model, limit of detection, lower limit of quantification, within- and between-day accuracy and precision, process efficiency, dilution integrity, carry over and stability. Selectivity was high and no ion suppression or enhancementwas observed in the areas were the analytes eluted. Calibration curves were linear over arange of 0.25-50 ng/g for dexmedetomidine, 0.05-50 ng/g for fentanyl and 5.0-500 ng/g formorphine and quadratic over a range of 0.5-50 ng/g for clonidine, 50-5000 ng/g for ketamine, 5.0-500 ng/g for ketobemidone and midazolam. The method showed acceptable within- and betweenday accuracies and precisions. All analytes were stable in whole blood for three weeksat 4. C. Concentrations in patient samples ranged between 42-760 ng/g for midazolam (n = 15), 0.3-1.5 ng/g for dexmedetomidine (n = 13), 0.6-6.4 ng/g for clonidine (n = 13), 8-62 ng/g for morphine (n = 16), 5-19 ng/g for ketobemidone (n = 5), 0.07-3.1 ng/g for fentanyl (n = 43), and 562000 ng/g for ketamine (n = 10). We conclude that the method was successfully validatedand applied to ante-mortem and post-mortem blood samples from critically ill adult patientsin a general ICU.
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| 10. |
- Kempen, Thomas, et al.
(författare)
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Effects of Hospital-Based Comprehensive Medication Reviews Including Postdischarge Follow-up on Older Patients' Use of Health Care : A Cluster Randomized Clinical Trial
- 2021
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Suboptimal use of medications is a leading cause of health care–related harm. Medication reviews improve medication use, but evidence of the possible benefit of inpatient medication review for hard clinical outcomes after discharge is scarce.Objective: To study the effects of hospital-based comprehensive medication reviews (CMRs), including postdischarge follow-up of older patients’ use of health care resources, compared with only hospital-based reviews and usual care.Design, Setting, and Participants: The Medication Reviews Bridging Healthcare trial is a cluster randomized crossover trial that was conducted in 8 wards with multiprofessional teams at 4 hospitals in Sweden from February 6, 2017, to October 19, 2018, with 12 months of follow-up completed December 6, 2019. The study was prespecified in the trial protocol. Outcome assessors were blinded to treatment allocation. In total, 2644 patients aged 65 years or older who had been admitted to 1 of the study wards for at least 1 day were included. Data from the modified intention-to-treat population were analyzed from December 10, 2019, to September 9, 2020.Interventions: Each ward participated in the trial for 6 consecutive 8-week periods. The wards were randomized to provide 1 of 3 treatments during each period: CMR, CMR plus postdischarge follow-up, and usual care without a clinical pharmacist.Main Outcomes and Measures: The primary outcome measure was the incidence of unplanned hospital visits (admissions plus emergency department visits) within 12 months. Secondary outcomes included medication-related admissions, visits with primary care clinicians, time to first unplanned hospital visit, mortality, and costs of hospital-based care.Results: Of the 2644 participants, 7 withdrew after inclusion, leaving 2637 for analysis (1357 female [51.5%]; median age, 81 [interquartile range, 74-87] years; median number of medications, 9 [interquartile range, 5-13]). In the modified intention-to-treat analysis, 922 patients received CMR, 823 received CMR plus postdischarge follow-up, and 892 received usual care. The crude incidence rate of unplanned hospital visits was 1.77 per patient-year in the total study population. The primary outcome did not differ between the intervention groups and usual care (adjusted rate ratio, 1.04 [95% CI, 0.89-1.22] for CMR and 1.15 [95% CI, 0.98-1.34] for CMR plus postdischarge follow-up). However, CMR plus postdischarge follow-up was associated with an increased incidence of emergency department visits within 12 months (adjusted rate ratio, 1.29; 95% CI, 1.05-1.59) compared with usual care. There were no differences between treatment groups regarding other secondary outcomes.Conclusions and Relevance: In this study of older hospitalized patients, CMR plus postdischarge follow-up did not decrease the incidence of unplanned hospital visits. The findings do not support the performance of hospital-based CMRs as conducted in this trial. Alternative forms of medication reviews that aim to improve older patients’ health outcomes should be considered and subjected to randomized clinical trials.
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| 11. |
- Kempen, Thomas G. H., 1988-
(författare)
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Medication reviews by clinical pharmacists in older hospitalised patients : Implementation, performance and effects
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Inappropriate use of medications is a leading cause of avoidable harm in health care. Medication reviews by clinical pharmacists improve medication use, but evidence on hard clinical outcomes in older hospitalised patients is scarce and implementation in practice is challenging. The aim of this thesis was to study the implementation, performance and effects of medication reviews by clinical pharmacists in older hospitalised patients.Methods A case study explored the factors involved in the implementation and sustainability of medication reviews by clinical pharmacists in Region Uppsala, Sweden. A pragmatic multicentre cluster-randomised crossover trial (MedBridge) was conducted to study the effects of hospital-based comprehensive medication reviews (CMRs) including post-discharge follow-ups on older patients’ healthcare utilisation, compared with only hospital-based reviews and usual care. The primary outcome measure was the incidence of unplanned hospital visits within 12 months. A process evaluation was conducted alongside the trial, for which different methods were applied: semi-structured interviews with patients and healthcare professionals, intervention fidelity assessment and process outcomes assessment. A practical tool to identify medication-related hospital admissions, one of the trial’s secondary outcomes, was developed and validated.Results Multiple factors involved in the implementation and sustainability of medication reviews by clinical pharmacists were identified. Examples of facilitating factors were a national focus on quality of care for the elderly and clinical pharmacy education. In total, 2637 participants (median age 81 years) were included in the MedBridge trial. The primary outcome measure did not differ between the treatment groups. Analysis of the interviews with patients and healthcare professionals resulted in seven and six themes, respectively, that were related to the performance of the trial’s interventions. A recurrent theme was the unclear role and responsibilities of the ward-based pharmacist. The intervention fidelity was high during hospital admission and lower surrounding discharge. In 77% of the intervention patients, at least one medication discrepancy or drug-related problem was solved. The developed tool, AT-HARM10, was deemed valid for use by pharmacy students to identify medication-related admissions in older patients.Conclusions This thesis suggests that, despite a high percentage of patients with medication discrepancies or drug-related problems being solved, hospital-based CMRs with and without post-discharge follow-ups, as conducted in the MedBridge trial, do not decrease the incidence of unplanned hospital visits in older patients. Future research and clinical initiatives may benefit from addressing the factors related to the implementation and performance of medication reviews that were identified in this thesis.
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| 12. |
- Kempen, Thomas, et al.
(författare)
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Intervention fidelity and process outcomes of medication reviews including post-discharge follow-up in older hospitalized patients : Process evaluation of the MedBridge trial.
- 2020
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Ingår i: Journal of Clinical Pharmacy and Therapeutics. - : Hindawi Limited. - 0269-4727 .- 1365-2710. ; 45:5, s. 1021-1029
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Tidskriftsartikel (refereegranskat)abstract
- WHAT IS KNOWN AND OBJECTIVE: Drug-related problems (DRPs) are a growing healthcare burden worldwide. In an ongoing cluster-randomized controlled trial in Sweden (MedBridge), comprehensive medication reviews (CMRs) including post-discharge follow-up have been conducted in older hospitalized patients to prevent and solve DRPs. As part of a process evaluation of the MedBridge trial, this study aimed to assess the intervention fidelity and process outcomes of the trial's interventions.METHODS: For intervention delivery, the percentage of patients that received intervention components was calculated per study group. Process outcomes, measured in about one-third of all intervention patients, included the following: the number of identified medication discrepancies, DRPs and recommendations to solve DRPs, correction rate of discrepancies, and implementation rate of recommendations.RESULTS AND DISCUSSION: The MedBridge trial included 2637 patients (mean age: 81 years). The percentage of intervention patients (n = 1745) that received the intended intervention components was 94%-98% during admission, and 40%-81% upon and after discharge. The percentage of control patients (n = 892) that received at least one unintended intervention component was 15%. On average, 1.1 discrepancies and 2.0 DRPs were identified in 652 intervention patients. The correction and implementation rates were 79% and 73%, respectively. Stop medication was the most frequently implemented recommendation (n = 293) and 77% of the patients had at least one corrected discrepancy or implemented recommendation.WHAT IS NEW AND CONCLUSION: The intervention fidelity within the MedBridge trial was high for CMRs during hospital stay and lower for intervention components upon and after discharge. The high prevalence of corrected discrepancies and implemented recommendations may explain potential effects of CMRs in the MedBridge trial.
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| 13. |
- Kempen, Thomas, et al.
(författare)
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Risk factors for and preventability of drug-related hospital revisits in older patients: A post-hoc analysis of a randomized clinical trial
- 2023
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Ingår i: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 89:5, s. 1575-1587
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aims of this study were (1) to identify older patients risk factors for drug-related readmissions and (2) to assess the preventability of older patients drug-related revisits. MethodsPost hoc analysis of a randomized clinical trial with patients aged >= 65 years at eight wards within four hospitals in Sweden. (1) The primary outcome was risk factors for drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. (2) Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results(1) Among 2637 patients (median age 81 years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio >1, P < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. (2) The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent related diseases were heart failure (n = 24, 28%) and chronic obstructive pulmonary disease (n = 13, 15%). The two most prevalent causes were inadequate treatment (n = 23, 27%) and insufficient or no follow-up (n = 22, 26%). Conclusion(1) Risk factors for drug-related readmissions in older hospitalized patients were age, previous hospital visits, medication use and multiple diseases. (2) Potentially preventable drug-related hospital revisits are common and might be prevented through adequate pharmacotherapy and continuity of care in older patients with cardiovascular or lung disease.
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| 14. |
- Kristoffersson, Anders N., 1985-, et al.
(författare)
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A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria
- 2020
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 75:2, s. 400-408
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own.OBJECTIVES: To develop a novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation.METHODS: Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time-kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations.RESULTS: The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an 'enhancer' effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam.CONCLUSIONS: A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.
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| 15. |
- Maarbjerg, Sabine F., et al.
(författare)
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Continuous infusion of piperacillin‐tazobactam significantly improves target attainment in children with cancer and fever
- 2021
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Ingår i: Cancer Reports. - : John Wiley & Sons. - 2573-8348. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildren with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.AimsThis study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.MethodsThis prospective PK study included children with cancer, aged 1–17 years, who were treated with piperacillin-tazobactam for suspected or verified infection. A piperacillin-tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high-performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC.ResultsWe included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1–54.0). A three-compartment model adequately described the concentration-time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses.ConclusionUnlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.
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| 16. |
- Nielsen, Søren, et al.
(författare)
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Effects of autism on 30-year outcome of anorexia nervosa
- 2022
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Ingår i: Journal of Eating Disorders. - : Springer Science and Business Media LLC. - 2050-2974. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term consequences of comorbid autism spectrum disorder (ASD) in individuals with anorexia nervosa (AN) are inadequately investigated. Methods: In the 1980s, 51 adolescent-onset AN cases (AN group) and 51 matched controls (COMP group) were recruited from the community. They have been examined on five occasions. The four last assessments included the Morgan-Russell Outcome Assessment Schedule (MROAS) to assess eating disorder outcomes (weight, dieting, menstruation), and related problems including psychiatric, psychosexual and socioeconomic state. In the present study, at age 44, when 30 years had elapsed, MROAS data were compared with previous results. At age 16, 21, 24 and 32 years, all individuals had been assessed regarding ASD. At the 30-year follow-up, the impact of the ASD on the MROAS data was analysed. Results: In the AN group, all core anorectic symptoms (weight, dieting, menstruation) were on a par with the COMP group at the 30-year follow-up, but the positive outcomes were limited to those who had never had an ASD diagnosis. Psychiatric state was significantly worse in the AN group, particularly in the subgroup who had an ASD diagnosis assigned. The AN group—again particularly those with ASD—had a more negative attitude to sexual matters than the COMP group. The AN group had worse outcomes than the COMP group for ‘personal contacts’, ‘social contacts,’ and ‘employment record’ at the 30-year follow-up and the outcomes were worse the more often an ASD diagnosis had been assigned. Limitations: Rare data collection points throughout 30 years (only 5 assessments). ASD was assessed in the first four studies but was not assessed again at the 30-year follow-up. Conclusions: Mental health, psychosexual, and socioeconomic status were compromised up to 30 years after AN onset. Coexisting ASD contributed to the poor outcome. Core anorectic symptoms had “normalised” three decades after AN onset. Plain English summary: Some individuals with anorexia nervosa (AN) also suffer from autism. In this study we have investigated outcome of AN 30 years after the onset of AN and whether the presence of autism affects the outcome. Since the 1980s we have followed 51 individuals with teenage-onset AN and 51 healthy controls. They have been examined on five occasions, and an instrument that measures symptoms of AN (weight, dieting, body image), psychiatric symptoms, ability to work, and relationships with partner, family, and friends has been used to assess outcome. Autism was assessed in the first four studies. Symptoms of AN had normalised at 30-year follow-up, but only among those without autism. Psychiatric symptoms, ability to work, and relationships were issues that persisted after 30 years in the AN group, and those who had both autism and a history of AN had even more pronounced problems in these areas. The AN group had a more negative attitude to sexual matters than the control group, the outcome was worse the more often an autism diagnosis had been assigned. Conclusions: Mental health, psychosexual, and socioeconomic status are affected up to 30 years after AN onset, particularly among those with autism.
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| 17. |
- Olsson, Anna, et al.
(författare)
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Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 64:6
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (<= 10(6) CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal beta-lactams, ciprofloxacin, and amikacin. Genes encoding beta-lactamases (e.g., bla(PAO) and bla(OXA-50)) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.
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| 18. |
- Olsson, Anna, et al.
(författare)
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Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time-kill experiments : agreement with in silico predictions.
- 2023
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Ingår i: Journal of Antimicrobial Chemotherapy. - 0305-7453 .- 1460-2091.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time-kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments.METHODS: Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time-kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations.RESULTS: The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions.CONCLUSIONS: Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time-kill data to predict the activity of antibiotic combinations at dynamic drug concentrations.
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| 19. |
- Senek, Marina, et al.
(författare)
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Population pharmacokinetics of levodopa gel infusion in Parkinson's disease : effects of entacapone infusion and genetic polymorphism
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.
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| 20. |
- Sulku, Johanna, et al.
(författare)
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Changes in critical inhaler technique errors in inhaled COPD treatment : A one-year follow-up study in Sweden
- 2022
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Ingår i: Respiratory Medicine. - : Elsevier. - 0954-6111 .- 1532-3064. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Background: Critical inhaler technique errors have been associated with lower treatment efficacy in chronic obstructive pulmonary disease (COPD). We aimed to assess and follow-up critical inhaler technique errors, and to investigate their association with COPD symptoms and exacerbations.Methods: COPD-diagnosed primary and secondary care outpatients (n = 310) demonstrated inhaler technique with inhaler devices they were currently using. Critical errors in opening, positioning and loading the inhaler device, and exhalation through dry-powder inhalers were assessed and corrected, and the assessment was repeated one year later. COPD Assessment Test, the modified Medical Research Council dyspnoea scale and history of exacerbations were collected at both visits.Results: The proportion of patients making >1 critical inhaler technique error was lower at follow-up in the total population (46% vs 37%, p = 0.01) and among patients with unchanged device models (46% vs 35%, p = 0.02), but not among patients with a new inhaler device model (46% vs 41%, p = 0.56). Not positioning the device correctly was the most common critical error at both visits (30% and 22%). Seventy-four percent of the patients had unchanged COPD treatment from baseline to follow-up. Treatment escalation, de-escalation, and switch was observed in 14%, 11%, and 1% of the patients, respectively. No association was found between critical errors and COPD symptoms or exacerbations.Conclusions: Assessment and correction of inhaler technique was associated with a decrease in critical inhaler technique errors. This effect was most pronounced in patients using the same device models throughout the follow-up period.
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| 21. |
- Sulku, Johanna, et al.
(författare)
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Critical inhaler technique errors in Swedish patients with COPD : a cross-sectional study analysing video-recorded demonstrations
- 2021
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Ingår i: npj Primary Care Respiratory Medicine. - : Springer Nature. - 2055-1010. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- A correct use of inhaler devices is essential in chronic obstructive pulmonary disease (COPD) treatment. Critical errors were studied by analysing 659 video-recorded demonstrations of inhaler technique from 364 COPD patients using six different inhaler device models. The majority of the included patients used two (55%) or more (20%) device models. Overall, 66% of the patients made ≥1 critical error with at least one device model. The corresponding numbers for patients using 1, 2 and ≥3 device models were 43%, 70% and 86%, respectively. The only factor associated with making ≥1 critical error was simultaneous use of two (adjusted odds ratios (aOR) 3.17, 95% confidence interval (95% CI) 1.81, 5.64) or three or more (aOR 8.97, 95% CI 3.93, 22.1) device models. In conclusion, the proportion of patients making critical errors in inhaler technique was substantial, particularly in those using several different device models. To obtain optimal COPD treatment, it is important to assess a patient's inhaler technique and to minimise the number of inhaler device models.
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| 22. |
- Sulku, Johanna
(författare)
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Inhaled pharmacological treatment and critical inhaler technique errors in patients with chronic obstructive pulmonary disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterised by persistent respiratory symptoms and a high risk of exacerbations. Preventive and maintenance pharmacological treatment is primarily administered through handheld inhalers, which are available in several different device-drug combinations. This thesis is about increasing the quality of drug treatment in COPD, where problems related to inhaled drugs are common. The overall aim was to assess and evaluate inhaled pharmacological treatment and critical inhaler technique errors in patients with COPD. The four studies included in this thesis derived from the Tools for Identifying Exacerbations study, which is an observational multicentre study in primary and secondary care in Sweden including 571 patients with COPD.The consequences of a change in the Global Initiative for Obstructive Lung Disease guidelines were investigated (Paper I). The refined COPD assessment of symptoms/risk of exacerbations lead to a high proportion of patients being reclassified to a lower risk group, which in turn had consequences for patients’ pharmacological treatment.The patients’ inhaled pharmacological treatments were assessed (Paper II). A high prevalence of inhaled corticosteroids (ICS) was identified, especially as a triple treatment, i.e., in combination with dual long-acting bronchodilators. Based on a previously developed tool, discontinuation of ICS could be tried in more than half of the patients.Proper inhaler technique is a prerequisite for adequate COPD treatment. Video-recorded demonstrations of inhaler technique were analysed (Paper III). Two-thirds of the patients made at least one critical inhaler technique error. The majority of the patients used a combination of different inhaler device models, which was the only factor associated with critical inhaler technique errors.The changes in inhaled pharmacological COPD treatment and inhaler technique were investigated one year after an initial evaluation and training (Paper IV). A reduction in the proportion of patients making critical inhaler technique errors was found but not in the subgroup of patients who had switched device models during the year. However, no association with COPD symptoms or exacerbations could be detected.The overall results contribute to increased knowledge and understanding of drug treatment in COPD. In order to optimise pharmacological treatment, it is essential to assess disease severity and inhaler technique, particularly in patients who switch device models. Further research is warranted to determine the most optimal educational intervention regarding inhaler technique, which has not yet been settled.
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| 23. |
- Swartling, Maria, et al.
(författare)
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Population pharmacokinetics of cefotaxime in intensive care patients
- 2022
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:2, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.METHODS: This 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.RESULTS: A 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%.CONCLUSION: A 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.
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| 24. |
- Swartling, Maria, et al.
(författare)
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Therapeutic drug monitoring of vancomycin and meropenem : Illustration of the impact of inaccurate information in dose administration time
- 2023
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 63:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.Methods: Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.Results: Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC24)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T>MIC, and 50% T>MIC, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.Conclusions: For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.
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| 25. |
- Thorsted, Anders, et al.
(författare)
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Extension of Pharmacokinetic/Pharmacodynamic Time-Kill Studies To Include Lipopolysaccharide/Endotoxin Release from Escherichia coli Exposed to Cefuroxime.
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - asm.aac.org. - 0066-4804 .- 1098-6596. ; 64:4
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Tidskriftsartikel (refereegranskat)abstract
- The release of inflammatory bacterial products, such as lipopolysaccharide (LPS)/endotoxin, may be increased upon the administration of antibiotics. An improved quantitative understanding of endotoxin release and its relation to antibiotic exposure and bacterial growth/killing may be gained by an integrated analysis of these processes. The aim of this work was to establish a mathematical model that relates Escherichia coli growth/killing dynamics at various cefuroxime concentrations to endotoxin release in vitro Fifty-two time-kill experiments informed bacterial and endotoxin time courses and included both static (0×, 0.5×, 1×, 2×, 10×, and 50× MIC) and dynamic (0×, 15×, and 30× MIC) cefuroxime concentrations. A model for the antibiotic-bacterium interaction was established, and antibiotic-induced bacterial killing followed a sigmoidal Emax relation to the cefuroxime concentration (MIC-specific 50% effective concentration [EC50], maximum antibiotic-induced killing rate [E max] = 3.26 h-1 and γ = 3.37). Endotoxin release was assessed in relation to the bacterial processes of growth, antibiotic-induced bacterial killing, and natural bacterial death and found to be quantitatively related to bacterial growth (0.000292 endotoxin units [EU]/CFU) and antibiotic-induced bacterial killing (0.00636 EU/CFU). Increased release following the administration of a second cefuroxime dose was described by the formation and subsequent antibiotic-induced killing of filaments (0.295 EU/CFU). Release due to growth was instantaneous, while release due to antibiotic-induced killing was delayed (mean transit time of 7.63 h). To conclude, the in vitro release of endotoxin is related to bacterial growth and antibiotic-induced killing, with higher rates of release upon the killing of formed filaments. Endotoxin release over 24 h is lowest when antibiotic exposure rapidly eradicates bacteria, while increased release is predicted to occur when growth and antibiotic-induced killing occur simultaneously.
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