Context:
Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality.
Objective:
We examined whether critical illness is more strongly associated with relative or ...absolute hyperglycemia.
Design:
The study was an observational cohort study.
Patients and Setting:
A total of 2290 patients acutely admitted to a tertiary hospital.
Main Outcome Measure:
The relative hyperglycemia (stress hyperglycemia ratio SHR) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined.
Results:
In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment 95% confidence interval, 1.18–1.28; P < .001) and glucose (odds ratio, 1.18 per mmol/L 1.13–1.23; P < .001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment 1.13–1.28; P < .001), but not glucose (odds ratio, 1.03 per mmol/L 0.97–1.11; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose ≤10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 1.4–4.2; P = .001) and fifth (3.9 2.3–6.8; P < .001) SHR quintiles than in the lowest SHR quintile.
Conclusions:
SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients.
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 .
Corynebacterium species are increasingly recognized as important pathogens in granulomatous mastitis. Currently, there are no published treatment protocols for Corynebacterium breast infections. This ...study describes antimicrobial treatment options in the context of other management strategies used for granulomatous mastitis. Corynebacterium spp. isolated from breast tissue and aspirate samples stored from 2002 to 2013 were identified and determined to the species level using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), 16S RNA sequencing, and rpoB gene targets. The MICs for 12 antimicrobials were performed using Etest for each isolate. Correlations of these with antimicrobial characteristics, choice of antimicrobial, and disease outcome were evaluated. Corynebacterium spp. from breast tissue and aspirate samples were confirmed in 17 isolates from 16 patients. Based on EUCAST breakpoints, Corynebacterium kroppenstedtii isolates (n = 11) were susceptible to seven antibiotic classes but resistant to β-lactam antibiotics. Corynebacterium tuberculostearicum isolates (n = 4) were multidrug resistant. Two nonlipophilic species were isolated, Corynebacterium glucuronolyticum and Corynebacterium freneyi, both of which have various susceptibilities to antimicrobial agents. Short-course antimicrobial therapy was common (median, 6 courses per subject; range, 1 to 9 courses). Patients with C. kroppenstedtii presented with a hot painful breast mass and underwent multiple surgical procedures (median, 4 procedures; range, 2 to 6 procedures). The management of Corynebacterium breast infections requires a multidisciplinary approach and includes culture and appropriate sensitivity testing to guide antimicrobial therapy. Established infections have a poor outcome, possibly because adequate concentrations of some drugs will be difficult to achieve in lipophilic granulomata. Lipophilic antimicrobial therapy may offer a therapeutic advantage. The role of immunotherapy has not been defined.
Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is ...a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism SNP rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter MATE1 (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.
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.
Summary
The publication of the Australasian Creatinine Consensus Working Group's position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) ...with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010.
The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m2.
Age‐related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m2 is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing.
If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing.
The CKD‐EPI formula has been validated as a tool to estimate GFR in some populations of non‐European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples.
The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.
The measurement of vitamin D-binding protein (VDBP) by immunoassay has been confounded by variable antibody recognition of the Gc1s, Gc1F and Gc2 phenotypes. This has led to spurious conclusions ...regarding vitamin D status in different ethnic groups. In order to overcome these problems there is a requirement for VDBP antibodies that are unaffected by phenotype status. Here we report the generation and testing of three monoclonal antibodies to VDBP which recognise linear epitopes and are unaffected by vast molar excesses of synthetic peptides spanning these phenotypic domains. These IgG1 kappa antibodies were purified and biotinylated to allow suitable pairings to develop a sandwich ELISA for circulating VDBP. The VDBP ELISA is unaffected by actin and confirms that VDBP levels are significantly reduced in sepsis patients and non-sepsis intensive care patients compared to normal healthy subjects. Levels of VDBP along with total 25OH vitamin D3 can be used to calculate free 25OH vitamin D3 levels and these compare well with consensus values determined independently. The VDBP ELISA meets acceptable performance criteria and as such can be used in conjunction with total 25OH vitamin D3 to determine the free 25OH vitamin D3 status in various cohorts.
•A monoclonal antibody 2-sites ELISA for vitamin D-binding protein is described.•The ELISA is unaffected by common phenotype peptides and actin.•Lower levels are shown in sepsis and ICU patients.•Calculated free vitamin D correlate with levels measured directly.
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.
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.
Patients for whom dabigatran concentrations were measured were identified using the laboratory database, and clinical data were extracted from the associated electronic health records.
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.
The clinical use of the dabigatran assay has increased, with almost one-third of results associated with a subsequent change in dabigatran prescribing.
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