Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.

Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has challenged healthcare globally. An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post-COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge. METHODS: This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs. RESULTS: Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16-17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34-21.5) as independent risk factors for PEs. CONCLUSIONS: PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.

TRough versus AUC Monitoring of cyclosporine: A randomized comparison of adverse drug reactions in adult allogeneic stem cell recipients (TRAM study).

OBJECTIVE: To investigate the incidence and severity of adverse drug reactions of cyclosporine using AUC-targeted therapeutic drug monitoring (TDM) compared to trough level (Ctrough )-targeted TDM in adult allogeneic stem cell recipients. METHODS: Blind, monocenter, intervention study. Subjects were 1:1 randomized into either an AUC group or a Ctrough group. Adverse drug reactions were accessed two and four weeks after start of treatment. RESULTS: Forty patients were included, resulting in 15 evaluable subjects (AUC group) and 13 evaluable subjects (Ctrough group). Grade two/three toxicity was observed in 46% (Ctrough group) versus 60% of subjects (AUC group) (P = .463). There was no significant difference between two and four weeks after start of cyclosporine for nausea (P = .142 resp. P = .122), renal dysfunction (P = .464 resp. P = 1.000), and hypomagnesemia (P = 1.000 resp. P = .411). Subjects in the AUC group reached the therapeutic goal earlier (72,7% versus 43,0% at third sampling point, P = .332) and were within the target range more consistently. CONCLUSION: This study showed no reduction in incidence and severity of cyclosporine-induced toxicity with AUC- versus trough level-targeted TDM. Although modeled dosing based on AUC led to faster optimal target attainment, this did not result in less toxicity in the early days after transplantation.

The pharmacotherapy team: A novel strategy to improve appropriate in-hospital prescribing using a participatory intervention action method.

AIMS: Prescribing medication is a complex process that, when done inappropriately, can lead to adverse drug events, resulting in patient harm and hospital admissions. Worldwide cost is estimated at 42 billion USD each year. Despite several efforts in the past years, medication-related harm has not declined. The aim was to determine whether a prescriber-focussed participatory action intervention, initiated by a multidisciplinary pharmacotherapy team, is able to reduce the number of in-hospital prescriptions containing ≥1 prescribing error (PE), by identifying and reducing challenges in appropriate prescribing. METHODS: A prospective single-centre before- and after study was conducted in an academic hospital in the Netherlands. Twelve clinical wards (medical, surgical, mixed and paediatric) were recruited. RESULTS: Overall, 321 patients with a total of 2978 prescriptions at baseline were compared with 201 patients with 2438 prescriptions postintervention. Of these, m456 prescriptions contained ≥1 PE (15.3%) at baseline and 357 prescriptions contained ≥1 PEs (14.6%) postintervention. PEs were determined in multidisciplinary consensus. On some study wards, a trend toward a decreasing number of PEs was observed. The intervention was associated with a nonsignificant difference in PEs (incidence rate ratio 0.96, 95% confidence interval 0.83-1.10), which was unaltered after correction. The most important identified challenges were insufficient knowledge beyond own expertise, unawareness of guidelines and a heavy workload. CONCLUSION: The tailored interventions developed with and implemented by stakeholders led to a statistically nonsignificant reduction in inappropriate in-hospital prescribing after a 6-month intervention period. Our prescriber-focussed participatory action intervention identified challenges in appropriate in-hospital prescribing on prescriber- and organizational level.

Evaluation of the concurrent use of potassium-influencing drugs as risk factors for the development of hyperkalemia.

BACKGROUND: Hyperkalemia is a potentially dangerous electrolyte abnormality with a reported incidence of 1-10 % in hospitals. Patients are especially at risk of developing this complication if they use a combination of potassium supplements and potassium sparing diuretics or renin-angiotensin-aldosterone-system (RAAS) inhibitors. Previous studies on the occurrence of hyperkalemia in patients who use multiple potassium influencing drugs simultaneously were either small in sample size or did not investigate the full range of drugs involved. OBJECTIVE: To assess the prevalence of hyperkalemia and to identify risk factors for its development in hospitalised patients using potassium supplements, potassium-sparing diuretics and/or RAAS-inhibitors concurrently. SETTING: The study was conducted at the Onze Lieve Vrouwe Hospital in Amsterdam, The Netherlands from January 2009 to May 2010. METHOD: A retrospective, nested case-control study included hospitalised patients who used a combination of potassium-influencing drugs. Cases were patients with serum potassium ≥ 5.5 mmol/l, controls were patients with normal serum potassium levels. Cases and controls were included in a ratio of 1:2. The following known risk factors associated with hyperkalemia were recorded and statistically analyzed: diabetes mellitus, congestive heart failure, decreased renal function, advanced age, gender and use of heparin, digoxin, non-steroidal anti-inflammatory drugs, beta-blockers, calcineurin antagonists and trimethoprim. MAIN OUTCOME MEASURE: Identify risk factors for the development of hyperkalemia as a result of the concurrent use of potassium supplements, RAAS inhibitors and/or potassium-sparing diuretics. RESULTS: Of 774 patients included in this study, 52 patients developed hyperkalemia; a prevalence of 6.7 %. The only risk factor found to be significantly associated with hyperkalemia was lowered renal function, expressed as estimated glomerular filtration rate (eGFR) <50 ml/min (adjusted OR 5.08; 95 % CI 2.46-10.48). None of the other tested risk factors was identified as significant. CONCLUSION: This study showed that decreased renal function (eGFR <50 ml/min) was associated with a fivefold increased risk for hyperkalemia in patients using potassium-influencing drugs. While previous studies showed that hyperkalemia substantially increases below a threshold of eGFR <30 or 40 ml/min, we observed a lower threshold of eGFR <50 ml/min. It is therefore recommended that physicians should be particularly alert while monitoring the use of potassium-influencing drugs in patients with decreased renal function.