The Influence of a Therapeutic Drug Monitoring Service on Vancomycin-Associated Nephrotoxicity.

Vancomycin's widespread use as the mainstay antibiotic against methicillin-resistant Staphylococcus aureus infections is complicated by its narrow therapeutic index. Therapeutic drug monitoring using area under the concentration-time curve (AUC)-guided dosing is recommended to optimize therapy and prevent vancomycin-associated nephrotoxicity (VAN). In 2018, a consultative therapeutic drug monitoring Advisory Service (the Service) was piloted at an Australian hospital to enable AUC-guided vancomycin dosing. This study sought to compare the incidence of VAN pre- and post-Service implementation. A 4-year retrospective observational study of intravenous vancomycin therapy (greater than 48 hours) in adults (aged 18 years or older), spanning 3 years before and 1-year after implementation of the Service was undertaken. Nephrotoxicity was defined as an increase in serum creatinine concentrations of 26.5 µmol/L or greater or 50% or more from baseline, on 2 or more consecutive days. Univariate analysis was performed to compare patients before and after implementation, and with and without VAN. Independent factors associated with VAN were identified using a multivariate model. In total, 971 courses of vancomycin therapy, administered to 781 patients, were included: 764 courses (603 patients) before implementation and 207 courses (163 patients) after implementation. The incidence of VAN decreased by 5% after Service implementation (15% before implementation vs 10% after implementation; P = .075). Independent factors associated with VAN were sepsis, heart failure, solid-organ transplant, concomitant piperacillin-tazobactam, and average vancomycin AUC during therapy. In conclusion, there was a nonsignificant trend toward a reduced incidence of VAN after the Service. Larger prospective studies are needed to confirm the efficacy of the Service.

Obstetric cholestasis: A case report on rapid bile acid elevation.

Obstetric cholestasis is a pregnancy-specific liver disorder which most commonly develops in the second or third trimester. It typically presents with generalised pruritus, often worst on the hands and feet, and no rash. Diagnosis is made on the basis of clinical presentation and elevated bile acid levels. Whilst obstetric cholestasis usually has no significant maternal adverse outcomes, aside from decreased quality of life from pruritus, it can lead to significant foetal complications, including stillbirth. There are no treatments for obstetric cholestasis, which resolves only following delivery. Thus, depending on the severity of obstetric cholestasis, early induction of labour may be recommended. As symptoms may precede bile acid elevation, repeat testing after a week is usually recommended when initial levels are normal. This report describes a case where a 35-year-old pregnant woman presented with pruritus but a normal bile acid level of 3 µmol/L. On repeat testing the following day the level had risen to 62, diagnosing obstetric cholestasis, and resulting in an urgent induction of labour at 38 weeks and 2 days of gestation. The patient gave birth to a healthy girl. This highlights the importance of close monitoring and consideration of early repeated blood tests where clinical suspicion is high, and/or a diagnosis of obstetric cholestasis would have significant management implications, to prevent adverse foetal outcomes.

Delirium as a Risk Factor for Mortality in Critically Ill Patients With Cancer.

PURPOSE: Although delirium is known to negatively affect critically ill patients, little data exist on delirium in critically ill patients with cancer. METHODS: We analyzed 915 critically ill patients with cancer between January and December 2018. Delirium screening was performed using the Confusion Assessment Method for the intensive care unit (ICU), performed twice daily. Confusion Assessment Method-ICU incorporates four features of delirium: acute fluctuations in mental status, inattention, disorganized thinking, and altered levels of consciousness. Multivariable analysis controlling for admitting service, pre-ICU hospital length of stay (LOS), metastatic disease, CNS involvement, Mortality Probability Model II score on ICU admission, mechanical ventilation, and others was performed to determine precipitating factors for delirium, ICU, and hospital mortality and LOS. RESULTS: Delirium occurred in 40.5% (n = 317) of patients; 43.8% (n = 401) were female; the median age was 64.9 (interquartile range, 54.6-73.2) years; 70.8% (n = 647) were White, 9.3% (n = 85) were Black, and 8.9% (n = 81) were Asian. The most common cancer types were hematologic (25.7%, n = 244) and gastrointestinal (20.9%, n = 191). Delirium was independently associated with age (OR, 1.01; 95% CI, 1.00 to 1.02; P = .038), longer pre-ICU hospital LOS (OR, 1.04; 95% CI, 1.02 to 1.06; P < .001), not resuscitating on admission (OR, 2.18; 95% CI, 1.07 to 4.44; P = .032), CNS involvement (OR, 2.25; 95% CI, 1.20 to 4.20; P = .011), higher Mortality Probability Model II score (OR, 1.02; 95% CI, 1.01 to 1.02; P < .001), mechanical ventilation (OR, 2.67; 95% CI, 1.84 to 3.87; P < .001), and sepsis diagnosis (OR, 0.65; 95% CI, 0.43 to 0.99; P = .046). Delirium was also independently associated with higher ICU mortality (OR, 10.75; 95% CI, 5.91 to 19.55; P < .001), hospital mortality (OR, 5.84; 95% CI, 4.03 to 8.46; P < .001), and ICU LOS (estimate, 1.67; 95% CI, 1.54 to 1.81; P < .001). CONCLUSION: Delirium significantly worsens outcome in critically ill patients with cancer. Delirium screening and management should be integrated into the care of this patient subgroup.

The diagnostic indicators of gestational diabetes mellitus from second trimester to birth: a systematic review.

BACKGROUND: Gestational diabetes mellitus (GDM) is glucose intolerance first recognised during pregnancy. Both modalities and thresholds of the GDM diagnostic test, the Oral Glucose Tolerance Test (OGTT), have varied widely over time and among countries. Additionally, OGTT limitations include inconsistency, poor patient tolerability, and questionable diagnostic reliability. Many biological parameters have been reported to be modified by GDM and could potentially be used as diagnostic indicators. This study aimed to 1) systematically explore biomarkers reported in the literature as differentiating GDM from healthy pregnancies 2) screen those indicators assessed against OGTT to propose OGTT alternatives. MAIN BODY: A systematic review of GDM diagnostic indicators was performed according to PRISMA guidelines (PROSPERO registration CRD42020145499). Inclusion criteria were full-text, comprehensible English-language articles published January 2009-January 2021, where a biomarker (from blood, ultrasound, amniotic fluid, placenta) was compared between GDM and normal glucose tolerance (NGT) women from the second trimester onward to immediately postpartum. GDM diagnostic method had to be clearly specified, and the number of patients per study higher than 30 in total or 15 per group. Results were synthesised by biomarkers. RESULTS: Of 13,133 studies identified in initial screening, 174 studies (135,801 participants) were included. One hundred and twenty-nine studies described blood analytes, one amniotic fluid analytes, 27 ultrasound features, 17 post-natal features. Among the biomarkers evaluated in exploratory studies, Adiponectin, AFABP, Betatrophin, CRP, Cystatin-C, Delta-Neutrophil Index, GGT, TNF-A were those demonstrating statistically and clinically significant differences in substantial cohorts of patients (> 500). Regarding biomarkers assessed versus OGTT (i.e. potential OGTT alternatives) most promising were Leptin > 48.5 ng/ml, Ficolin3/adiponectin ratio ≥ 1.06, Chemerin/FABP > 0.71, and Ultrasound Gestational Diabetes Score > 4. These all demonstrated sensitivity and specificity > 80% in adequate sample sizes (> / = 100). CONCLUSIONS: Numerous biomarkers may differentiate GDM from normoglycaemic pregnancy. Given the limitations of the OGTT and the lack of a gold standard for GDM diagnosis, advanced phase studies are needed to triangulate the most promising biomarkers. Further studies are also recommended to assess the sensitivity and specificity of promising biomarkers not yet assessed against OGTT. TRIAL REGISTRATION: PROSPERO registration number CRD42020145499.

Evaluation of a Pilot Vancomycin Precision Dosing Advisory Service on Target Exposure Attainment Using an Interrupted Time Series Analysis.

This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real-world clinical setting. The Service provided area under the concentration-time curve (AUC)-guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy (> 48 hours) in adults (≥ 18 years old) was undertaken over a 54-month period to evaluate attainment of established vancomycin pharmacokinetic/pharmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400-600) before (36-month period) and after (18-month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients); 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3-46.0%); this increased by 10.4% (95% CI, 1.2-19.6%, P = 0.03) after the Service, and was sustained throughout the post-Service evaluation period. Post-Service target attainment at 48-72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3-14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets; however, optimization of the Service may further improve the use of vancomycin.