Lisa Pont

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

ABSTRACT Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

ABSTRACT Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H2 antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

Drug Metabolism in Older People—A Key Consideration in Achieving Optimal Outcomes With Medicines

Hepatic clearance plays a key role in determining the systemic exposure of drugs and metabolites, which in turn has a major effect on variability in the beneficial and adverse effects of medicines. Aging results in a number of significant changes in the human liver including reductions in liver blood flow, size, drug-metabolizing enzyme content, and pseudocapillarization. Drug metabolism is also influenced by comorbid disease, frailty, concomitant medicines, and (epi)genetics. These changes have the potential to alter the hepatic clearance of drugs but need to be interpreted in the context of the pharmacokinetic (and pharmacodynamic) characteristics of the drug of interest. There is growing evidence that the age-related changes in the liver not only result in a decrease in the hepatic clearance of unbound drug but also influence variability in response to medicines in older people.

A systematic review of the prevalence and risk factors for adverse drug reactions in the elderly in the acute care setting

Adverse drug reactions (ADRs) are an important health issue. While prevalence and risk factors associated with ADRs in the general adult population have been well documented, much less is known about ADRs in the elderly population. The aim of this study was to review the published literature to estimate the prevalence of ADRs in the elderly in the acute care setting and identify factors associated with an increased risk of an ADR in the elderly. A systematic review of studies published between 2003 and 2013 was conducted in the Cochrane Database of Systematic Reviews, EMBASE, Google Scholar and MEDLINE. Key search terms included: “adverse drug reactions”, “adverse effects”, “elderly patients and hospital admission”, “drug therapy”, “drug adverse effects”, “drug related”, “aged”, “older patients”, “geriatric”, “hospitalization”, and “emergency admissions”. For inclusion in the review, studies had to focus on ADRs in the elderly and had to include an explicit definition of what was considered an ADR and/or an explicit assessment of causality, and a clear description of the method used for ADR identification, and had to describe factors associated with an increased risk of an ADR. Fourteen hospital-based observational studies exploring ADRs in the elderly in the acute care setting were eligible for inclusion in this review. The mean prevalence of ADRs in the elderly in the studies included in this review was 11.0% (95% confidence interval [CI]: 5.1%–16.8%). The median prevalence of ADRs leading to hospitalization was 10.0% (95% CI: 7.2%–12.8%), while the prevalence of ADRs occurring during hospitalization was 11.5% (95% CI: 0%–27.7%). There was wide variation in the overall ADR prevalence, from 5.8% to 46.3%. Female sex, increased comorbid complexity, and increased number of medications were all significantly associated with an increased risk of an ADR. Retrospective studies and those relying on identification by the usual treating team reported lower prevalence rates. From this review, we can conclude that ADRs constitute a significant health issue for the elderly in the acute care setting. While there was wide variation in the prevalence of ADRs in the elderly, based on the findings of this study, at least one in ten elderly patients will experience an ADR leading to or during their hospital stay. Older female patients and those with multiple comorbidities and medications appear to be at the highest risk of an ADR in the acute care setting.

Depression screening via a smartphone app: cross-country user characteristics and feasibility

BACKGROUND AND OBJECTIVE Smartphone applications (apps) have the potential to be valuable self-help interventions for depression screening. However, information about their feasibility and effectiveness and the characteristics of app users is limited. The aim of this study is to explore the uptake, utilization, and characteristics of voluntary users of an app for depression screening. METHODS This was a cross-sectional study of a free depression screening smartphone app that contains the demographics, patient health questionnaire (PHQ-9), brief anxiety test, personalized recommendation based on the participants results, and links to depression-relevant websites. The free app was released globally via Apples App Store. Participants aged 18 and older downloaded the study app and were recruited passively between September 2012 and January 2013. FINDINGS 8241 participants from 66 countries had downloaded the app, with a response rate of 73.9%. While one quarter of the participants had a previous diagnosis of depression, the prevalence of participants with a higher risk of depression was 82.5% and 66.8% at PHQ-9 cut-off 11 and cut-off 15, respectively. Many of the participants had one or more physical comorbid conditions and suicidal ideation. The cut-off 11 (OR: 1.4; 95% CI 1.2 to 1.6), previous depression diagnosis (OR: 1.3; 95% CI1.2 to 1.5), and postgraduate educational level (OR: 1.2; 95% CI 1.0 to 1.5) were associated with completing the PHQ-9 questionnaire more than once. CONCLUSIONS Smartphone apps can be used to deliver a screening tool for depression across a large number of countries. Apps have the potential to play a significant role in disease screening, self-management, monitoring, and health education, particularly among younger adults.

Validity of performance indicators for assessing prescribing quality: the case of asthma

ObjectivesThe aim of this study was to assess the concurrent validity between the identification of sub-optimal treatment based on clinical information and computer generated indicators. Indicators that are associated with sub-optimal treatment in one of the four steps of asthma management were assessed.DesignThe ability of each indicator to identify patients with sub-optimal asthma treatment from computerised general practitioner (GP) prescription records was assessed by comparing them with the results of an individual patient assessment using clinical data.SettingChronic asthma patients (n=146) registered with 16 Dutch GPs.Main measuresThe sensitivity and positive predictive value (PPV) of each performance indicator was determined.ResultsThe step-1 indicator, focusing on patients not prescribed a short-acting β-agonist, had an acceptable sensitivity (0.86), but a low PPV (0.52). The two step-2 indicators, targeting under-prescription of inhaled corticosteroids, had sensitivities of 0.74 and 0.37 and PPVs of 0.46 and 0.71, respectively. The step-3 indicator, which targeted under-dosing of inhaled corticosteroids, had a sensitivity of 0.07 and a PPV of 0.2. The fourth indicator, focusing on under-prescription of long-acting β-agonists, could not be validated due to inadequate numbers of patients with severe asthma in our study sample.DiscussionNone of the indicators investigated was considered valid for assessing prescriber performance, despite having good face and content validity. Performance indicators that have not been validated can only provide a broad-brush approach for assessing prescribing quality and should be used with extreme caution.

Nurse practitioner prescribing practice in Australia: Confidence in aspects of medication management

The findings of the 2010 national survey of nurse practitioner (NP) prescribing in Australia related to confidence in prescribing are reported. A significant correlation between years endorsed as a NP and prescribing confidence was found. NPs in Australia were significantly more confident in the prescribing aspects of commencing a new medication than adjusting or ceasing a medication prescribed by others. These findings are discussed in relation to promotion of the quality use of medicines and identification of potential strategies to promote the ongoing positive evolution of NP practice in Australia.

A systematic review of the outcomes reported in trials of medication review in older patients: the need for a core outcome set.

Aim Medication review has been advocated as one of the measures to tackle the challenge of polypharmacy in older patients, yet there is no consensus on how best to evaluate its efficacy. This study aimed to assess outcome reporting in trials of medication review in older patients. Methods Randomized controlled trials (RCTs), prospective studies and RCT protocols involving medication review performed in patients aged 65 years or older in any setting of care were identified from: (1) a recent systematic review; (2) RCT registries of ongoing studies; (3) the Cochrane library. The type, definition, and frequency of all outcomes reported were extracted independently by two researchers. Results Forty‐seven RCTs or prospective published studies and 32 RCT protocols were identified. A total of 327 distinct outcomes were identified in the 47 published studies. Only one fifth (21%) of the studies evaluated the impact of medication reviews on adverse events such as drug reactions or drug‐related hospital admissions. Most of the outcomes were related to medication use (n = 114, 35%) and healthcare use (n = 74, 23%). Very few outcomes were patient‐related (n = 24, 7%). A total of 248 distinct outcomes were identified in the 32 RCT protocols. Overall, the number of outcomes and the number and type of health domains covered by the outcomes varied largely. Conclusion Outcome reporting from RCTs concerning medication review in older patients is heterogeneous. This review highlights the need for a standardized core outcome set for medication review in older patients, to improve outcome reporting and evidence synthesis.

Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures

AIMS Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men. METHODS A cross-sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1696). Statistical agreement, expressed as Cohens kappa (κ), between these measurements was calculated. RESULTS Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI-ACH. While agreement was good between the ACB and ADS (κ = 0.628, 95% CI 0.593, 0.664), little agreement was found between remaining tools (κ = 0.091-0.264). CONCLUSIONS With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales.

Does a Mobile Phone Depression-Screening App Motivate Mobile Phone Users With High Depressive Symptoms to Seek a Health Care Professional’s Help?

Background The objective of disease screening is to encourage high-risk subjects to seek health care diagnosis and treatment. Mobile phone apps can effectively screen mental health conditions, including depression. However, it is not known how effective such screening methods are in motivating users to discuss the obtained results of such apps with health care professionals. Does a mobile phone depression-screening app motivate users with high depressive symptoms to seek health care professional advice? This study aimed to address this question. Method This was a single-cohort, prospective, observational study of a free mobile phone depression app developed in English and released on Apple’s App Store. Apple App Store users (aged 18 or above) in 5 countries, that is, Australia, Canada, New Zealand (NZ), the United Kingdom (UK), and the United States (US), were recruited directly via the app’s download page. The participants then completed the Patient Health Questionnaire (PHQ-9), and their depression screening score was displayed to them. If their score was 11 or above and they had never been diagnosed with depression before, they were advised to take their results to their health care professional. They were to follow up after 1 month. Results A group of 2538 participants from the 5 countries completed PHQ-9 depression screening with the app. Of them, 322 participants were found to have high depressive symptoms and had never been diagnosed with depression, and received advice to discuss their results with health care professionals. About 74% of those completed the follow-up; approximately 38% of these self-reported consulting their health care professionals about their depression score. Only positive attitude toward depression as a real disease was associated with increased follow-up response rate (odds ratio (OR) 3.2, CI 1.38-8.29). Conclusions A mobile phone depression-screening app motivated some users to seek a depression diagnosis. However, further study should investigate how other app users use the screening results provided by such apps.