Compulsory Indications in Hospital Prescribing Software Tested with Antibacterial Prescriptions.

The aim was to assess how making the indication field compulsory in our electronic prescribing system influenced free text documentation and to visualise prescriber behaviour. The indication field was made compulsory for seven antibacterial medicines. Text recorded in the indication field was manually classified as 'indication present', 'other text', 'rubbish text', or 'blank'. The proportion of prescriptions with an indication was compared for four weeks before and after the intervention. Indication provision increased from 10.6% to 72.4% (p<0.01) post-intervention. 'Other text' increased from 7.6% to 25.1% (p<0.01), and 'rubbish text' from 0.0% to 0.6% (p<0.01). Introducing the compulsory indication field increased indication documentation substantially with only a small increase in 'rubbish text'. An interactive report was developed using a live data extract to illustrate indication provision for all medicines prescribed at our tertiary hospital. The interactive report was validated and locally published to support audit and quality improvement projects.

Optimising interruptive clinical decision support alerts for antithrombotic duplicate prescribing in hospital.

INTRODUCTION: Duplicate prescribing clinical decision support alerts can prevent important prescribing errors but are frequently the cause of much alert fatigue. Stat dose prescriptions are a known reason for overriding these alerts. This study aimed to evaluate the effect of excluding stat dose prescriptions from duplicate prescribing alerts for antithrombotic medicines on alert burden, prescriber adherence, and prescribing. MATERIALS AND METHODS: A before (January 1st, 2017 to August 31st, 2022) and after (October 5th, 2022 to September 30th, 2023) study was undertaken of antithrombotic duplicate prescribing alerts and prescribing following a change in alert settings. Alert and prescribing data for antithrombotic medicines were joined, processed, and analysed to compare alert rates, adherence, and prescribing. Alert burden was assessed as alerts per 100 prescriptions. Adherence was measured at the point of the alert as whether the prescriber accepted the alert and following the alert as whether a relevant prescription was ceased within an hour. Co-prescribing of antithrombotic stat dose prescriptions was assessed pre- and post-alert reconfiguration. RESULTS: Reconfiguration of the alerts reduced the alert rate by 29 % (p < 0.001). The proportion of alerts associated with cessation of antithrombotic duplication significantly increased (32.8 % to 44.5 %, p < 0.001). Adherence at the point of the alert increased 1.2 % (4.8 % to 6.0 %, p = 0.012) and 11.5 % (29.4 % to 40.9 %, p < 0.001) within one hour of the alert. When ceased after the alert over 80 % of duplicate prescriptions were ceased within 2 min of overriding. Antithrombotic stat dose co-prescribing was unchanged for 4 out of 5 antithrombotic duplication alert rules. CONCLUSION: By reconfiguring our antithrombotic duplicate prescribing alerts, we reduced alert burden and increased alert adherence. Many prescribers ceased duplicate prescribing within 2 min of alert override highlighting the importance of incorporating post-alert measures in accurately determining prescriber alert adherence.

Artefactually low creatinine by Beckman Coulter enzymatic method due to immunoglobulin M paraprotein interference.

An 81-year-old man was admitted to hospital with symptomatic coronavirus disease (COVID-19) infection. He had a background of progressive chronic inflammatory demyelinating polyneuropathy associated with Waldenstrom's macroglobulinaemia. His plasma creatinine on four separate samples was inconceivably low (all ≤13 µmol/L), as measured by a Beckman Coulter enzymatic assay) after being 72 µmol/L 3 months earlier. On further investigation, his serum immunoglobulin M (IgM) was 15.4 g/L and his plasma creatinine measured by Roche enzymatic and Roche Jaffe methods was 62 µmol/L and 64 µmol/L, respectively. This was consistent with results post dilution studies and polyethylene glycol (PEG) precipitation on the Beckman Coulter assay. There was no evidence of similar interference when reviewing creatinine results from 10 other patients with IgM paraproteinaemia who had been tested in our laboratory. Clinicians and laboratorians are reminded that enzymatic creatinine is not free from interferences. IgM paraprotein negative interference of enzymatic creatinine is rare and specific to a patient's IgM and assay combination, but should be considered in patients with an unexplained low enzymatic creatinine result. Useful investigations to identify an interference include dilution studies, PEG precipitation and measuring creatinine on an alternative method such as Jaffe, mass spectrometry or an enzymatic method from a different platform.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Changes in inpatient medicine prescribing during COVID-19 lockdown.

BACKGROUND: New Zealand went into lockdown March 2020 successfully eliminating the circulation of the coronavirus disease 2019 (COVID-19) virus. During lockdown there were reduced rates of respiratory infections and hospital admission numbers were low. At the time, rumours of benefit and harm of medicines for COVID-19 were widespread in the lay and medical media. AIM: To describe changes in inpatient prescribing in an acute general medicine service during the New Zealand COVID-19 lockdown in 2020. METHODS: Rates of prescribing of medicines during the 33 days of lockdown were compared with a 33-day control period before lockdown. Prescriptions, patients and bed days were calculated from the hospital patient administration and electronic prescribing and administration systems. RESULTS: In the general medicine service, acute admissions were 20% lower during lockdown (from 1216 pre-lockdown to 974). There was a small decrease in the rate of prescriptions per patient (10.1 vs 10.4, P = 0.01) during lockdown, and the average length of stay was shorter (3.2 vs 3.6 days). Nebulised administration decreased by 75% (1.3% vs 5.3% of admissions) but unexpectedly there was no change in the prescribing rates of antibacterial medicines, e.g. amoxicillin (26% vs 26%). There were no changes in rates of prescribing of medicines being rumoured to potentially improve (e.g. hydroxychloroquine) or worsen (e.g. angiotensin-converting enzyme inhibitors) COVID-19 outcomes. CONCLUSIONS: Acute medical admissions decreased 20% during lockdown for COVID-19, with a proportional decrease in prescriptions. Reduced rates of respiratory tract infections did not lead to decreased prescribing of antibacterial medicines. Rumour-based prescribing did not eventuate.

Paracentesis for cancer-related ascites in palliative care: An international, prospective cohort study.

BACKGROUND: Paracentesis is commonly undertaken in patients with cancer-related ascites. AIM: To systematically investigate the symptomatic benefits and harms experienced by patients with cancer undergoing paracentesis using real-world data in the palliative care setting. DESIGN: Prospective, multisite, observational, consecutive cohort study. Benefits and harms of paracentesis were assessed between 01/07/2018 and 31/02/2021 as part of routine clinical assessments by treating clinicians at four timepoints: (T0) before paracentesis; (T1) once drainage ceased; (T2) 24 h after T1 and (T3) 28 days after T1 or next paracentesis, if sooner. SETTING/PARTICIPANTS: Data were collected from 11 participating sites across five countries (Australia, England, Hong Kong, Malaysia and New Zealand) on 111 patients undergoing paracentesis via a temporary (73%) or indwelling (21%) catheter: 51% male, median age 69 years, Australia-modified Karnofsky Performance Score 50. RESULTS: At T1 (n = 100), symptoms had improved for most patients (81%), specifically abdominal distension (61%), abdominal pain (49%) and nausea (27%), with two-thirds experiencing improvement in ⩾2 symptoms. In the remaining patients, symptoms were unchanged (7%) or worse (12%). At least one harm occurred in 32% of patients, the most common being an ascitic leak (n = 14). By T3, 89% of patients had experienced some benefit and 36% some harm, including four patients who experienced serious harm, one of which was a fatal bowel perforation. CONCLUSION: Most patients obtained rapid benefits from paracentesis. Harms were less frequent and generally mild, but occasionally serious and fatal. Our findings help inform clinician-patient discussions about the potential outcomes of paracentesis in this frail population.

Preanalytical Stability of Flucloxacillin, Piperacillin, Tazobactam, Meropenem, Cefalexin, Cefazolin, and Ceftazidime in Therapeutic Drug Monitoring: A Structured Review.

BACKGROUND: Therapeutic drug monitoring is increasingly being used to optimize beta-lactam antibiotic dosing. Because beta-lactams are inherently unstable, confirming preanalytical sample stability is critical for reporting reliable results. This review aimed to summarize the published literature on the preanalytical stability of selected widely prescribed beta-lactams used in therapeutic drug monitoring. METHODS: The published literature (2010-2020) on the preanalytical stability of flucloxacillin, piperacillin, tazobactam, meropenem, cefalexin, cefazolin, and ceftazidime in human plasma, serum, and whole blood was reviewed. Articles examining preanalytical stability at room temperature, refrigerated, or frozen (-20°C) using liquid chromatography with mass spectrometry or ultraviolet detection were included. RESULTS: Summarizing the available data allowed for general observations to be made, although data were conflicting in some cases (piperacillin, tazobactam, ceftazidime, and meropenem at room temperature, refrigerated, or -20°C) or limited (cefalexin, cefazolin, and flucloxacillin at -20°C). Overall, with the exception of the more stable cefazolin, preanalytical instability was observed after 6-12 hours at room temperature, 2-3 days when refrigerated, and 1-3 weeks when frozen at -20°C. In all cases, excellent stability was detected at -70°C. Studies focusing on preanalytical stability reported poorer stability than studies investigating stability as part of method validation. CONCLUSIONS: Based on this review, as general guidance, clinical samples for beta-lactam analysis should be refrigerated and analyzed within 2 days or frozen at -20°C and analyzed within 1 week. For longer storage times, freezing at -70°C was required to ensure sample stability. This review highlights the importance of conducting well-designed preanalytical stability studies on beta-lactams and other potentially unstable drugs under clinically relevant conditions.

Unbound vitamin D concentrations are not decreased in critically ill patients.

BACKGROUND: Free concentrations of highly protein bound hormones, such as cortisol and thyroxine, are unchanged in critical illness despite substantial decreases in total concentration. Total 25-hydroxyvitamin D (25(OH)D) concentration is decreased in critical illness, but the free concentration of 25(OH)D has had less attention. AIM: To compare total and calculated free 25(OH)D concentrations in critically ill patients with healthy controls. METHODS: In this case-control study, 38 patients with critical illness were compared with 68 healthy controls; 25(OH)D was measured by liquid chromatography tandem mass spectrometry (LCMS/MS) and vitamin D binding protein (VDBP) by direct sandwich enzyme-linked immunosorbent assay. Total and calculated free 25(OH)D concentrations were compared using unpaired t-tests. RESULTS: Total 25(OH)D concentrations were significantly lower in critically ill patients than controls (37 (95% confidence interval 31-43) vs 57 (53-60) nmol/L). Calculated free concentrations of 25(OH)D were not lower in critically ill patients than healthy controls (26 (22-29) vs 19 (18-20) pmol/L). CONCLUSIONS: Calculated free 25(OH)D concentrations are not decreased in critical illness. Measuring total 25(OH)D concentrations in patients with critical illness potentially underestimates vitamin D and overestimates the number of patients who are deficient in vitamin D.

Oral amoxicillin challenge for low-risk penicillin allergic patients.

BACKGROUND: Penicillin allergy is the most reported adverse drug reaction (ADR). Being labelled with 'penicillin allergy' is associated with suboptimal antibiotic therapy and poor patient outcomes. Most labelled with 'penicillin allergy' are at low risk of harm from penicillins and guidelines recommend testing for accurate diagnosis. Although skin testing is recommended to exclude immunoglobulin E (IgE)-mediated reactions, there is limited access in most settings. AIMS: To evaluate oral amoxicillin challenge without prior skin testing for patients labelled with 'penicillin allergy' assessed as low risk during hospital admission. METHODS: General Medical inpatients with a 'penicillin allergy' label were assessed. For those who had tolerated a penicillin since the index event, the ADR label was removed. Those assessed as 'low risk' were administered 250 mg amoxicillin orally without prior skin testing. The durability of de-labelling was subsequently assessed by review of clinical records. RESULTS: Of 224 patients with a history of a penicillin ADR, 162 (72%) were low risk. A further 12 were excluded and of the remaining 150, 56 (37%) had tolerated penicillins since their index reaction and were de-labelled without challenge, 15 (10%) with a non-allergic history were de-labelled. The remaining 79 were offered an oral amoxicillin challenge; 38 declined and 41 tolerated amoxicillin. Overall, 112 of the 224 (50%) patients had their ADR label removed. CONCLUSIONS: A careful ADR history enables de-labelling of many patients. An oral amoxicillin challenge without prior skin testing is safe and feasible for low-risk penicillin allergic patients while in hospital.

Drug metabolism in severe chronic obstructive pulmonary disease: A phenotyping cocktail study.

AIMS: To evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with healthy volunteers and using the modified Inje drug cocktail. METHODS: This was a single-centre pharmacokinetic study with 12 healthy participants and 7 participants with GOLD D COPD. Midazolam 1 mg, dextromethorphan 30 mg, losartan 25 mg, omeprazole 20 mg, caffeine 130 mg and paracetamol 1000 mg were simultaneously administered and intensive pharmacokinetic sampling was conducted over 8 hours. Drug metabolism by CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, UGT1A6 and UGT1A9 in participants with COPD were compared with phenotypes in healthy controls. RESULTS: The oral clearance (95% confidence interval) in participants with COPD relative to controls was: midazolam 63% (60-67%); dextromethorphan 72% (40-103%); losartan 53% (52-55%); omeprazole 35% (31-39%); caffeine 52% (50-53%); and paracetamol 73% (72-74%). There was a 5-fold increase in AUC for omeprazole and approximately 2-fold increases for caffeine, losartan, dextromethorphan, and midazolam. The AUC of paracetamol, which is mostly glucuronidated, was increased by about 60%. CONCLUSION: Severe COPD is associated with a clinically significant reduction in oral drug clearance. This may be greater for cytochrome P450 substrates than for glucuronidated drugs. This supports reduced starting doses when prescribing for patients with severe COPD.

Influence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study.

Individual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Therefore, better understanding of these biological relationships is required. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Clinical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). ACTRN12620000832976, 21 Aug 2020, https://www.anzctr.org.au/ACTRN12620000832976.aspx .

A persuasive approach to antimicrobial stewardship in Christchurch hospitals produced a sustained decrease in intravenous clarithromycin dosing and expenditure via a switch to azithromycin orally.

AIMS: To assess a persuasive multimodel approach to decreasing unnecessary intravenous (IV) clarithromycin use for community-acquired pneumonia (CAP) in Canterbury District Health Board (CDHB) hospitals. METHODS: In December 2013, CDHB guidelines for empiric treatment of CAP changed to prioritise oral azithromycin over IV clarithromycin. The multimodel approach we used to implement this change included obtaining stakeholder agreement, improved guidelines access, education and pharmacist support. The impact of the intervention was evaluated by comparing macrolide usage and expenditure for the four years pre- and post-intervention. RESULTS: Mean annual clarithromycin IV use decreased by 72% from 6.4 to 1.8 defined daily doses (DDDs) per 1,000 occupied bed days (OBDs) post-intervention, while oral azithromycin increased by 833% (4.2 to 39.2 DDDs per 1,000 OBDs). Concurrently, oral clarithromycin use decreased by 91% (32.9 to 2.9 DDDs per 1,000 OBDs), and roxithromycin by 71% (17.0 to 5.0 DDDs per 1,000 OBDs). Mean annual total macrolide use decreased by 21% (68.2 to 53.9 DDDs per 1,000 OBDs), while expenditure decreased by 69% mainly through avoided IV administration. CONCLUSIONS: A persuasive multimodel approach to support adoption of CAP guidelines produced a sustained decrease in IV clarithromycin use, which may have clinical benefits such as reduced occurrence of catheter-related complications.

The pharmacokinetics of metformin in patients receiving intermittent haemodialysis.

The aims of this study were to characterise the population pharmacokinetics of metformin in patients receiving haemodialysis, and to determine the doses that will maintain median metformin plasma concentrations below 5 mg L-1 for a typical individual. Metformin plasma concentrations from 5 patients receiving thrice weekly intermittent haemodialysis followed by metformin 500 mg postdialysis were fitted to a published pharmacokinetic model. Additional models to describe the dialytic pharmacokinetics of metformin were explored. Doses of 250 and 500 postdialysis were simulated from the model for a typical haemodialysis patient. The published 2-compartment pharmacokinetic model with an additional parameter to describe haemodialysis clearance provided a reasonable fit to the data. Deterministic simulations from the model for a typical individual suggest that metformin doses of 250-500 mg postdialysis and 250 mg given once daily should maintain median metformin plasma concentrations below 5 mg L-1 .

Clinical decision support in a hospital electronic prescribing system informed by local data: experience at a tertiary New Zealand centre.

BACKGROUND: An electronic prescribing and administration (ePA) system has been progressively rolled out to Canterbury District Health Board (CDHB, Christchurch, New Zealand) public hospitals since 2014, and is currently used for around 1300 tertiary beds. ePA data can be used to monitor user behaviour, and to evaluate and inform the local customisation of clinical decision support (CDS) tools within the ePA system. AIMS: To describe retrospectively illustrative vignettes of CDHB ePA analyses that have been used for CDS. METHODS: Alerts were developed according to a set of common principles agreed upon by the CDHB CDS Working Group. Alerts were informed and evaluated by extracting and parsing data for various time periods during 2016 to 2018 from the CDHB ePA database. RESULTS: There was a median of 74 000 prescriptions a month. After examining 525 spironolactone prescriptions, the high dose alert threshold was set at 100 mg with an expected alert burden of 3%. The presence of a ceftriaxone shortage prescribing alert for 1 week was associated with a prescribing rate that was lower than 95% of the preceding 52 weeks. Following review of 367 fentanyl patch alerts, revision of the alert led to false positives falling from 43% to 3% (P < 0.0001). At the point of firing, 6% of antithrombotic drug interactions alerts led to immediate changes in prescriptions (94% overridden), and a further 22% were changed within 30 min after the alert. CONCLUSIONS: Local data extracts from ePA systems can inform iterative configuration of the software and monitor user behaviour.

Routine Therapeutic Drug Monitoring of Dabigatran: Experience at a Tertiary Center.

BACKGROUND: A liquid chromatography-mass spectrometry assay to determine plasma dabigatran concentrations has been available for routine clinical use at our tertiary institutions since 2017. The aim of the study was to describe (1) the use of the assay over time; (2) the indications for testing; and (3) subsequent dabigatran prescribing decisions. METHODS: Patients for whom dabigatran concentrations were measured were identified using the laboratory database, and clinical data were extracted from the associated electronic health records. RESULTS: There were 233 samples in 24 months. The use of dabigatran increased over time, with a mean (95% confidence interval) increase of +0.5 (0.3-0.7) samples per month. Dabigatran concentrations ranged from <1 to 1060 mcg/L. The main reasons for testing were uncertainty about impact on renal function and drug interactions (39%), to inform prescribing decisions after thromboembolic or bleeding events (21%), and for investigation following dose-adjustment (16%). Dabigatran dose was changed after 30% (68/233) of assay results. CONCLUSIONS: The clinical use of the dabigatran assay has increased, with almost one-third of results associated with a subsequent change in dabigatran prescribing.

Preanalytical Stability of Piperacillin, Tazobactam, Meropenem, and Ceftazidime in Plasma and Whole Blood Using Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Therapeutic drug monitoring (TDM) is increasingly used to optimize the dosing of beta-lactam antibiotics in critically ill patients. However, beta-lactams are inherently unstable and degrade over time. Hence, patient samples need to be appropriately handled and stored before analysis to generate valid results for TDM. The appropriate handling and storage conditions are not established, with few and conflicting studies on the stability of beta-lactam antibiotics in clinical samples. The aim of this study was to assess the preanalytical stability of piperacillin, tazobactam, meropenem, and ceftazidime in human plasma and whole blood using a liquid chromatography-tandem mass spectrometry method for simultaneous quantification. METHODS: A reverse phase liquid chromatography-tandem mass spectrometry method for the quantification of piperacillin, tazobactam, meropenem, and ceftazidime in plasma after protein precipitation was developed and validated. The preanalytical stability of these beta-lactams was assessed in EDTA- and citrate-anticoagulated plasma at 24, 4, and -20°C. The whole blood stability of the analytes in EDTA-anticoagulated tubes was assessed at 24°C. Stability was determined by nonlinear regression analysis defined by the lower limit of the 95th confidence interval of the time to 15% of degradation. RESULTS: Based on the lower limit of the 95th confidence interval of the time to 15% of degradation, piperacillin, tazobactam, meropenem, and ceftazidime were stable in EDTA-anticoagulated plasma for at least 6 hours at 24°C, 3 days at 4°C, and 4 days at -20°C. Stability in EDTA- and citrate-anticoagulated plasma was similar. Stability in whole blood was similar to plasma at 24°C. CONCLUSIONS: Plasma samples for the TDM of piperacillin, tazobactam, meropenem, and ceftazidime should be processed within 6 hours if kept at room temperature and within 3 days if kept at 4°C. All long-term storage of samples should be at -80°C.

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (Css ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and Css and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere-Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on Css . At 3 months post-transplant modelling revealed an association between tacrolimus Css and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% Css variance. Jonckheere-Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, Css decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus Css , further validation in larger cohorts is required.