[Risk management with regard to QT-prolonging drugs]. / Risicomanagement rond QT-verlengende geneesmiddelen.

Drug-induced QT prolongation increases the risk of Torsade de Pointes (TdP). Drug-induced QT prolongation is a complex and unpredictable system due to many uncertainties. Risk factors such as electrolyte disturbances, heart failure and genetics play an important role in estimating the effect on QT prolongation. Moreover, the degree of QT prolongation is not always directly related to the risk of TdP and the assessment of the QT-interval is variable depending on the type and timing of QT measurement. Therefore, the variation in QT measurement may be larger than the effect of certain drugs on the QT interval. Because of the potentially lethal risk, several measures are undertaken to reduce the risk of QT prolongation and TdP, while their effect and proportionality are unclear. We suggest we should be less stringent in certain settings when risk of TdP is extremely low given the limited availability of our resources.

External validity of an automated delirium prediction model (DEMO) and comparison to the manual VMS-questions: a retrospective cohort study.

BACKGROUND: It is estimated that one-third of delirium cases in hospitals could be prevented with appropriate interventions. In Dutch hospitals a manual instrument (VMS-questions) is used to identify patients at-risk for delirium. Delirium Model (DEMO) is an automated model which could support delirium prevention more efficiently. However, it has not been validated beyond the hospital it was developed in. AIM: To externally validate the DEMO and compare its performance to the VMS-questions. METHOD: A retrospective cohort study between July and December 2018 was conducted. Delirium cases were identified through a chart review, and the VMS-questions were extracted from the electronic health records. The DEMO was validated in patients ≥ 60 years, and a comparison with the VMS-questions was made in patients ≥ 70 years. RESULTS: In total 1,345 admissions were included. The DEMO predicted 59 out of 75 delirium cases (sensitivity 0.79, 95% CI = 0.68-0.87; specificity 0.75, 95% CI = 0.72-0.77). Compared to the VMS-questions, the DEMO showed a lower specificity (0.64 vs. 0.72; p < 0.001) and a comparable sensitivity (0.83 vs. 0.80; p = 0.56). The VMS-questions were missing in 20% of admissions, in which the DEMO correctly predicted 10 of 12 delirium cases. CONCLUSION: The DEMO showed acceptable performance for delirium prediction. Overall the DEMO predicted more delirium cases because the VMS-questions were missing in 20% of admissions. This study shows that automated instruments such as DEMO could play a key role in the efficient and timely deployment of measures to prevent delirium.

How to use quality indicators for antimicrobial stewardship in your hospital: a practical example on outpatient parenteral antimicrobial therapy.

BACKGROUND: Antimicrobial stewardship (AMS) teams are responsible for performing an AMS programme in their hospitals that aims to improve the quality of antibiotic use. Measuring the quality of antimicrobial use is a core task of a stewardship team. Measurement provides insight into the current quality of antibiotic use and allows for the establishment of goals for improvement. Yet, a practical description of how such a quality measurement using quality indicators (QIs) should be performed is lacking. OBJECTIVES: To provide practical guidance on how a stewardship team can use QIs to measure the quality of antibiotic use in their hospital and identify targets for improvement. SOURCES: General principles from implementation science, peer-reviewed publications, and experience from clinicians and researchers with AMS experience. CONTENT: We provide step-by-step guidance on how AMS teams can use QIs to measure the quality of antibiotic use. The principles behind each step are explained and illustrated with the description and results of an audit of patients receiving outpatient parenteral antimicrobial therapy in four Dutch hospitals. IMPLICATIONS: Improving the quality of antibiotic use is impossible without first gaining insight into that quality by performing a measurement with validated QIs. This step-by-step practice example of how to use quality indicators in a hospital will help AMS teams to identify targets for improvement. This enables them to perform their AMS programme more effectively and efficiently.

Co-trimoxazole induced hyperkalemia and potassium monitoring in hospitalized patients.

Background Co-trimoxazole is an antibiotic combination used for the treatment of Pneumocystis jirovecii pneumonia, amongst others. Co-trimoxazole is known to increase serum potassium. For this reason, Dutch guidelines advise serum potassium monitoring in high-risk patients. Objective This study aimed to determine average serum potassium rise after administration of intravenous co-trimoxazole in hospitalized patients, compared to intravenous ceftriaxone. This study also aimed to determine adherence to Dutch guidelines by measuring the incidence of serum potassium monitoring in these patients. Setting Data was collected retrospectively from patients in five departments of the Canisius Wilhelmina Hospital, a teaching hospital in Nijmegen, the Netherlands. Method Data was collected and compared from patients that received intravenous co-trimoxazole (n = 66) and intravenous ceftriaxone (n = 132) in the period of November 2008-November 2017. For each patient using co-trimoxazole, two patients using ceftriaxone were included in a paired fashion. Baseline and follow-up potassium were collected, if available. Additionally, it was tested if serum potassium was measured around the initiation of antibiotic therapy. Main outcome measure Changes in serum potassium where obtainable in 30 patients using cotrimoxazole and 40 patients using ceftriaxone. When compared to ceftriaxone, administration of intravenous co-trimoxazole was associated with a significant mean increase in serum potassium (+0.55 mmol/l, 95% CI 0.29-0.80, p < 0.001). After correction for confounders (baseline potassium, estimated glomerular filtration rate 30 ≤ 60, the presence of haematological malignancies and the usage of corticosteroids), this effect shrunk noticeably, but remained significant (+0.28 mmol/l, 95% CI 0.03-0.53, p = 0.031). Results The incidence of hyperkalemia at follow-up was 20% in the cotrimoxazole group, compared to 5% in the ceftriaxone group. Despite this, serum potassium was often not measured in patients using intravenous cotrimoxazole, being 76% at baseline and 55% in the period of 48-120 h after antibiotic therapy initiation, compared to 87% and 34% in the ceftriaxone group respectively. Conclusion Adherence to Dutch guidelines was poor as serum potassium monitoring was often not performed. As intravenous co-trimoxazole usage is associated with a significant increase in mean serum potassium, monitoring is strongly recommended.

Co-trimoxazole induced hyperkalemia and potassium monitoring in hospitalized patients.

Background Co-trimoxazole is an antibiotic combination used for the treatment of Pneumocystis jirovecii pneumonia, amongst others. Co-trimoxazole is known to increase serum potassium. For this reason, Dutch guidelines advise serum potassium monitoring in high-risk patients. Objective This study aimed to determine average serum potassium rise after administration of intravenous co-trimoxazole in hospitalized patients, compared to intravenous ceftriaxone. This study also aimed to determine adherence to Dutch guidelines by measuring the incidence of serum potassium monitoring in these patients. Setting Five departments of the Canisius Wilhelmina Hospital, a teaching hospital in Nijmegen, the Netherlands. Method Data was collected and compared from patients that received intravenous co-trimoxazole (n = 66) and intravenous ceftriaxone (n = 132) in the period of November 2008-November 2017. For each patient using co-trimoxazole, two patients using ceftriaxone were included in a paired fashion. Baseline and follow-up potassium were collected, if available. Additionally, it was tested if serum potassium was measured around the initiation of antibiotic therapy. Main outcome measure Changes in serum potassium where obtainable in 30 patients using cotrimoxazole and 40 patients using ceftriaxone. When compared to ceftriaxone, administration of intravenous co-trimoxazole was associated with a significant mean increase in serum potassium (+ 0.55 mmol/l, 95% CI 0.29-0.80, p < 0.001). After correction for confounders (baseline potassium, estimated glomerular filtration rate 30 to < 60, the presence of haematological malignancies and the usage of corticosteroids), this effect shrunk noticeably, but remained significant (+ 0.28 mmol/l, 95% CI 0.03-0.53, p = 0.031). Results The incidence of hyperkalemia at follow-up was 20% in the cotrimoxazole group, compared to 5% in the ceftriaxone group. Despite this, serum potassium was often not measured in patients using intravenous cotrimoxazole, being 76% at baseline and 55% in the period of 48-120 h after antibiotic therapy initiation, compared to 87% and 34% in the ceftriaxone group respectively. Conclusion Adherence to Dutch guidelines was poor as serum potassium monitoring was often not performed. As intravenous co-trimoxazole usage is associated with a significant increase in mean serum potassium, monitoring is strongly recommended.

Pharmacotherapy within a learning healthcare system: rationale for the Dutch Santeon Farmadatabase.

OBJECTIVES: The increasing number of available, often expensive, medicines asks for continuous assessment of rational prescribing. We aimed to develop a simple and robust data infrastructure in order to monitor hospital medicine utilisation in real time. METHODS: Within a collaboration (Santeon) of large teaching hospitals in the Netherlands, we set up a process for extraction, transformation, anonymisation and load of individual medicine prescription data and major clinical outcomes from different hospital information systems into a central database. Quarterly reports were constructed to monitor and validate the quality of the uploaded data. RESULTS: A central database has been developed that includes data from all patients from 2010 onwards and is refreshed on a weekly basis by an automated process. Beginning in 2017, the database holds data from almost 800 000 patients with prescriptions. All hospitals provide at least 18 mandatory data items per patient. Provided data include, among others, individual prescriptions, diagnosis data, and hospitalisation and survival data. The database is currently used to benchmark the level of biosimilar prescribing and to assess the impact of novel systemic treatments on survival rates in metastatic cancers. CONCLUSION: We showed that it is feasible for a group of hospitals to construct their own database that can serve as a tool to benchmark the positioning of medicines and to start with monitoring their impact on clinical outcomes.

Intravenous flucloxacillin treatment is associated with a high incidence of hypokalaemia.

Intravenous flucloxacillin is one of the most frequently used high-dose penicillin therapies in hospitalized patients, forming the cornerstone treatment of invasive Staphylococcus aureus infection. Being a nonreabsorbable anion, flucloxacillin has been suggested to cause hypokalaemia, although the frequency and magnitude of this unwanted effect is unknown. In a retrospective cohort, we investigated the incidence and extent of hypokalaemia after initiation of intravenous flucloxacillin or ceftriaxone therapy. In total, 77 patients receiving flucloxacillin (62% male, mean age 70.5 years) and 84 patients receiving ceftriaxone (46% male, mean age 70.8 years) were included. Hypokalaemia occurred significantly more often in patients receiving flucloxacillin than ceftriaxone (42% vs 14%, p < 10-4 ). Moreover, follow-up potassium levels were significantly lower during flucloxacillin therapy. In general, women were more prone to develop hypokalaemia than men. In conclusion, intravenous flucloxacillin use is associated with a striking incidence of hypokalaemia. Therefore, standardized potassium measurements are necessary.

Macrolide prescription in Dutch children: compliance with guidelines.

For reasons of antibiotic resistance and side effects, macrolides should be prescribed with care in the pediatric population. We evaluated the adherence to Dutch guidelines of macrolide prescription in children and estimated the risk of Mycoplasma pneumoniae-associated pneumonia based on Fischer's decision tree. In this retrospective study, we included children aged 0-18 years who were treated with azithromycin or clarithromycin for pulmonary disease in four settings from general practice to hospital ward for (1) the prescriptions not in accordance with the guideline of the Dutch Association of Pediatrics and (2) the risk of M. pneumoniae in patients with community-acquired pneumonia (CAP) according to Fischer's decision tree. The latter suggests that children older than three years with a fever lasting more than two days are at high risk for M. pneumoniae and that it is therefore justified to treat them with macrolides. In total, 189 macrolide prescriptions from 2015 until 2017 were analyzed: 139 children used macrolides for a pulmonary indication (75%); 18% (n = 25) of the prescriptions were not in accordance with Dutch guidelines. Only 9.1% of patients with CAP were classified as having a high risk of M. pneumoniae according to Fischer's decision tree. A significant proportion of macrolide prescriptions for Dutch children with a pulmonary disease appears not to be in accordance with the guidelines. Most patients with CAP treated with a macrolide actually had a low risk of having M. pneumoniae according to Fischer's decision tree. Both observations suggest overuse of macrolides in children.

An electronic trigger tool to optimise intravenous to oral antibiotic switch: a controlled, interrupted time series study.

BACKGROUND: Timely switch from intravenous (iv) antibiotics to oral therapy is a key component of antimicrobial stewardship programs in order to improve patient safety, promote early discharge and reduce costs. We have introduced a time-efficient and easily implementable intervention that relies on a computerized trigger tool, which identifies patients who are candidates for an iv to oral antibiotic switch. METHODS: The intervention was introduced on all internal medicine wards in a teaching hospital. Patients were automatically identified by an electronic trigger tool when parenteral antibiotics were used for >48 h and clinical or pharmacological data did not preclude switch therapy. A weekly educational session was introduced to alert the physicians on the intervention wards. The intervention wards were compared with control wards, which included all other hospital wards. An interrupted time-series analysis was performed to compare the pre-intervention period with the post-intervention period using '% of i.v. prescriptions >72 h' and 'median duration of iv therapy per prescription' as outcomes. We performed a detailed prospective evaluation on a subset of 244 prescriptions to evaluate the efficacy and appropriateness of the intervention. RESULTS: The number of intravenous prescriptions longer than 72 h was reduced by 19% in the intervention group (n = 1519) (p < 0.01) and the median duration of iv antibiotics was reduced with 0.8 days (p = <0.05). Compared to the control group (n = 4366) the intervention was responsible for an additional decrease of 13% (p < 0.05) in prolonged prescriptions. The detailed prospective evaluation of a subgroup of patients showed that adherence to the electronic reminder was 72%. CONCLUSIONS: An electronic trigger tool combined with a weekly educational session was effective in reducing the duration of intravenous antimicrobial therapy.

Lower Ribavirin Plasma Concentrations in HCV/HIV-Coinfected Patients Than in HCV-Monoinfected Patients Despite Similar Dosage.

BACKGROUND: Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV-coinfected patients. Our hypothesis is that HCV/HIV-coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. METHODS: A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated high-performance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. RESULTS: A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean ± SD RBV plasma concentrations were 1.82 ± 0.63 mg/L versus 2.25 ± 0.80 mg/L (P = 0.04) at week 4 and 2.14 ± 0.65 mg/L versus 2.62 ± 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. CONCLUSIONS: HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological response.

Treatment of osteoporosis in renal insufficiency.

Patients with osteoporosis often have chronic kidney disease (CKD). CKD is associated with bone and mineral disturbances, renal osteodystrophy, which like osteoporosis leads to a higher risk of fractures. Bisphosphonates are first-line therapy for osteoporosis; however, these are contra-indicated in patients with a GFR <30 ml/min. In this article, we have reviewed the diagnosis and treatment of osteoporosis in moderate to severe renal failure from data of clinical trials. Results have shown that osteoporosis patients and severe CKD with no signs of renal osteodystrophy, oral bisphosphonates (risedronate) seem to be a safe choice. Renal function and PTH should subsequently be monitored strictly. Denosumab, with regularly monitoring of calcium and adequate vitamin D levels or raloxifene are a possible second choice. In any case, one should be certain that there is no adynamic bone before treatment can be started. If there is any doubt, bone biopsies should be taken.

Ribavirin plasma concentration measurements in patients with hepatitis C: early ribavirin concentrations predict steady-state concentrations.

BACKGROUND: Ribavirin is an essential component in the treatment of chronic hepatitis C (HCV) infection. Although ribavirin dose is weight-based, data in the literature suggest large between-patient variability in plasma ribavirin concentrations. Recent studies indicate that higher ribavirin exposure results in higher sustained viral response rates. Monitoring ribavirin concentration is suggested in the literature, but it is unclear at what time point during treatment plasma ribavirin concentrations should be monitored. AIM: To investigate the association between early plasma ribavirin concentrations and ribavirin dosing with steady-state (Css) concentration and the between- and within-patient variability in plasma ribavirin concentration in clinical practice. METHODS: We performed a prospective observational cohort study in patients with HCV who received pegylated interferon in combination with oral weight-based ribavirin (12-15 mg/kg) twice daily. Trough plasma ribavirin concentrations at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 were studied using a validated high-performance liquid chromatography assay. RESULTS: In total, 53 patients (37 male, 16 female) with a mean age of 51 years (range, 26-68 years) were included and 209 samples were collected. There was a significant correlation between Week 2 as well as Week 4 and plasma ribavirin Css (r = 0.589 and r = 0.714, P < 0.05, respectively). Ribavirin Css was reached at Week 8 of HCV treatment. There was no correlation between dose in mg/kg and Css (r = 0.181, P = 0.263). The between- and within-patient coefficients of variation of plasma ribavirin concentrations at Week 8 and beyond were 43% and 13%, respectively. CONCLUSION: In HCV-infected patients, ribavirin steady-state concentrations can be predicted by measurement of concentrations made early after the start of therapy.

The influence of acetylsalicylic acid intake by healthy volunteers on duplicate PFA-100 measurements.

The PFA-100 device is increasingly used for assessing platelet function. Its use to monitor anti-platelet therapy, like acetylsalicylic acid (ASA), has been described. In most studies single PFA-100 measurements were used. In this study, we evaluate the influence of ASA on duplicate measurements using collagen/epinephrine cartridges. Twelve healthy volunteers received a single dose of 160 mg ASA and 12 other healthy volunteers received 30 mg ASA during 10 days followed by 80 mg ASA during 10 days. PFA-100 measurements were performed in duplicate 1 and 24 h after the final intake of medication. The mean coefficient of variation of duplicate measurements before medication was 8.4% and at least two times higher after the intake of a single dose of 160 mg ASA or 30 mg ASA during 10 days. Per individual, huge differences between duplicate measurements were observed after ASA ingestion. Differences were less pronounced after ingestion of 80 mg ASA during 10 days, because six of 12 volunteers had a maximum PFA-100 value>300 s in both measurements. As a consequence, one should be cautious to use the PFA-100 to monitor ASA therapy in individual patients.