Antimicrobial stewardship, procalcitonin testing, and rapid blood-culture identification to optimize sepsis care in critically ill adult patients: A quality improvement initiative.

We examined the effect of an antimicrobial stewardship program (ASP), procalcitonin testing and rapid blood-culture identification on hospital mortality in a prospective quality improvement project in critically ill septic adults. Secondarily, we have reported antimicrobial guideline concordance, acceptance of ASP interventions, and antimicrobial and health-resource utilization.

An in vitro comparison of four different immunoassays for the monitoring of Infliximab biosimilars drug levels.

BACKGROUND: SB2 (Renflexis®, Merck) and CT-P13 (Inflectra®, Pfizer) are biosimilars of the reference Infliximab (Remicade®, Janssen) and are approved in Canada for use in indications for which Infliximab is approved, including inflammatory bowel disease. These biosimilars are structurally different but exhibit comparable physicochemical characteristics, pharmaceutical effectiveness and immunogenicity compared to Infliximab. Optimal Infliximab therapy currently relies on therapeutic drug monitoring offered by several reference laboratories. OBJECTIVE: Because the appropriate dosing depends on accurate determination of drug levels and anti-drug antibodies, the ability of current Infliximab assays to measure the biosimilars and corresponding antibodies needs to be demonstrated. METHODS: The correlation between Infliximab and the biosimilars measured with four different enzyme-linked immunosorbent assays for Infliximab detection was evaluated. Spiked serum samples were assayed with kits from (A) Immunodiagnostik/ALPCO Diagnostics, (B) R-Biopharm, (C) Theradiag and (D) Progenika Biopharma. The impact of various concentrations of antibodies to Infliximab on the quantification of biosimilars was also tested. RESULTS: A good correlation of SB2, CT-P13 and reference Infliximab spiked serum samples was observed with the four assays. The observed bias between the original drug and biosimilars is clinically insignificant and less than the usual analytical variability observed with these methods. The quantification of the biosimilars and Infliximab was equally impacted in serums containing antibodies to Infliximab. The recovery of the drugs was inversely correlated with the concentration of anti-Infliximab antibodies, suggesting common immunodominant epitopes for SB2, CT-P13 and Infliximab. CONCLUSION: The ability of these assays to properly quantify the biosimilars Renflexis® and Inflectra® has been demonstrated. The therapeutic drug monitoring required for Infliximab therapy can be adequately performed with the biosimilars using the kits currently in use or available in clinical laboratories.

Bone Mineral Density and Fat-Soluble Vitamin Status in Adults with Cystic Fibrosis Undergoing Lung Transplantation: A Pilot Study.

PURPOSE: Patients with cystic fibrosis (CF) often experience low bone mineral density (BMD) pre- and post-lung transplantation (LTX). The study purpose was to describe BMD and micronutrient status in adults with CF pre- and post-LTX. METHODS: Twelve patients with CF (29 ± 8 years) were recruited from the CF clinic at the University of Alberta Lung Transplant Program. BMD and vitamins A, D, E, K status, and parathyroid hormone were measured pre- and post-LTX. RESULTS: No significant differences pre- and post-LTX were observed at the different bone sites measured (lumber-spine, femoral-neck (FN), hip, and femoral-trochlea) (P > 0.05). BMD T-scores (<-2) was present in lumbar-spine, FN, hip, and femoral-trochlea in 33%, 17%, 17%, and 25% of individuals pre-LTX and 58%, 33%, 58%, and 33% of individuals post-LTX, respectively. More than 50% of patients had suboptimal vitamin K levels (PIVKA-II values >3 ng/mL) pre- and post-LTX. CONCLUSION: Adults with CF pre- and post-LTX had reduced BMD and suboptimal vitamin K status.

A Canadian Study toward Changing Local Practice in the Diagnosis of Pediatric Celiac Disease.

Background. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition endorses serological diagnosis (SD) for pediatric celiac disease (CD). The objective of this study was to pilot SD and to prospectively evaluate gastrointestinal permeability and mucosal inflammation at diagnosis and after one year on the gluten-free diet (GFD). We hypothesized that SD would be associated with similar short term outcomes as ED. Method. Children, 3-17 years of age, referred for possible CD were eligible for SD given aTTG level ≥200 U/mL, confirmed by repeat aTTG and HLA haplotypes. Gastrointestinal permeability, assessed using sugar probes, and inflammation, assessed using fecal calprotectin (FC), at baseline and after one year on a GFD were compared to patients who had ED. Results. Enrolled SD (n = 40) and ED (n = 48) patients had similar demographics. ED and SD groups were not different in baseline lactulose: mannitol ratio (L : M) (0.049 versus 0.034; p = 0.07), fractional excretion of sucrose (%FES; 0.086 versus 0.092; p = 0.44), or fecal calprotectin (FC; 89.6 versus 51.4; p = 0.05). At follow-up, urine permeability improved and was similar between groups, L : M (0.022 versus 0.025; p = 0.55) and %FES (0.040 versus 0.047; p = 0.87) (p > 0.05). FC improved but remained higher in the SD group (37.1 versus 15.9; p = 0.04). Conclusion. Patients on the GFD showed improved intestinal permeability and mucosal inflammation regardless of diagnostic strategy. This prospective study supports that children diagnosed by SD have resolving mucosal disease early after commencing a GFD.

Knowledge of Fecal Calprotectin and Infliximab Trough Levels Alters Clinical Decision-making for IBD Outpatients on Maintenance Infliximab Therapy.

BACKGROUND: Infliximab is an effective therapy for inflammatory bowel disease (IBD). However, more than 50% of patients lose response. Empiric dose intensification is not effective for all patients because not all patients have objective disease activity or subtherapeutic drug level. The aim was to determine how an objective marker of disease activity or therapeutic drug monitoring affects clinical decisions regarding maintenance infliximab therapy in outpatients with IBD. METHODS: Consecutive patients with IBD on maintenance infliximab therapy were invited to participate by providing preinfusion stool and blood samples. Fecal calprotectin (FCP) and infliximab trough levels (ITLs) were measured by enzyme linked immunosorbent assay. Three decisions were compared: (1) actual clinical decision, (2) algorithmic FCP or ITL decisions, and (3) expert panel decision based on (a) clinical data, (b) clinical data plus FCP, and (c) clinical data plus FCP plus ITL. In secondary analysis, Receiver-operating curves were used to assess the ability of FCP and ITL in predicting clinical disease activity or remission. RESULTS: A total of 36 sets of blood and stool were available for analysis; median FCP 191.5 µg/g, median ITLs 7.3 µg/mL. The actual clinical decision differed from the hypothetical decision in 47.2% (FCP algorithm); 69.4% (ITL algorithm); 25.0% (expert panel clinical decision); 44.4% (expert panel clinical plus FCP); 58.3% (expert panel clinical plus FCP plus ITL) cases. FCP predicted clinical relapse (area under the curve [AUC] = 0.417; 95% confidence interval [CI], 0.197-0.641) and subtherapeutic ITL (AUC = 0.774; 95% CI, 0.536-1.000). ITL predicted clinical remission (AUC = 0.498; 95% CI, 0.254-0.742) and objective remission (AUC = 0.773; 95% CI, 0.622-0.924). CONCLUSIONS: Using FCP and ITLs in addition to clinical data results in an increased number of decisions to optimize management in outpatients with IBD on stable maintenance infliximab therapy.

A study investigating the association of dermatological and infusion reactions to infliximab and infliximab trough levels.

BACKGROUND: Although infliximab is an effective therapy for inflammatory bowel disease (IBD), it is associated with dermatological events and infusion reactions. It is not known whether a relationship between these adverse events (AEs) and infliximab trough levels (ITLs) exists. OBJECTIVES: To report the prevalence of infliximab-associated AEs in IBD patients receiving stable maintenance infliximab therapy, and to correlate ITLs with dermatological and infusion reactions to infliximab. METHODS: Adult IBD patients receiving stable maintenance infliximab therapy were recruited from the University of Alberta Infusion Clinic (Edmonton, Alberta). ITLs were measured in blood samples collected before infusion, and the patients' records were reviewed for dermatological and infusion reactions to infliximab. RESULTS: One-quarter (18 of 71 [25.4%]) of patients experienced dermatological or infusion reactions to infliximab: nine (12.7%) dermatological events and nine (12.7%) infusion reactions. The median ITL was similar among patients with and without these AEs (7.2 µg/mL [interquartile range (IQR) 2.0 µg/mL to 13.3 µg/mL] versus 6.6 µg/mL [IQR 3.2 µg/mL to 12.7 µg/mL]; P=0.648). The median ITL of patients who experienced infusion reactions (2.0 µg/mL [IQR 0.1 µg/mL to 5.7 µg/mL]) was lower than that of patients who experienced no such AEs (6.6 µg/mL [IQR 3.2 µg/mL to 12.7 µg/mL]; P=0.008]) and lower than that of patients who experienced dermatological AEs (13.3 µg/mL [IQR 8.8 µg/mL to 17.4 µg/mL]; P<0.001). CONCLUSION: One-quarter of IBD outpatients receiving stable maintenance infliximab therapy experienced dermatological and infusion reactions. Low ITLs were correlated with infusion reactions, and normal or high ITLs with dermatological events.

The sensitivity and specificity of guaiac and immunochemical fecal occult blood tests for the detection of advanced colonic adenomas and cancer.

PURPOSE: Fecal immunochemical tests (FITs) have been developed to address analytical problems inherent in the older guaiac-based fecal occult blood tests (g-FOBTs). Our aim was to compare the performance characteristics of one g-FOBT (Hemoccult II) and two FITs (the Hemoccult ICT and MagStream HemSp) relative to colonoscopy for the detection of colorectal cancer and significant precursor lesions. We also examined whether a 1-day collection strategy would negatively impact test diagnostic performance. METHODS: We used a prospective observational cohort design in a Canadian population eligible for screening. All participants received colonoscopy after performing the occult blood tests. RESULTS: One thousand seventy-five individuals were enrolled (mean age 56.3 years, 53.8 % females). Using colonoscopy as the gold standard, the sensitivity for screen-relevant neoplasm was determined for Hemoccult II (7.2, 95 % CI: 1.1-13.4), Hemoccult ICT (23.2 %: 13.2-33.1), and MagStream HemSp using 67 µg/gram stool as the cut-off (23.2 %: 13.2-33.1). The Magstream HemSp, using a cut-off threshold of 30 µg/gram stool, had the lowest specificity at 87.6 % (85.4-89.6), while the Hemoccult II had the highest at 98.8 % (98.1-99.5). Single-day stool testing reduced the false-positive rates of all tests without significantly reducing the sensitivity. CONCLUSION: We found that FITs have a significantly increased sensitivity but reduced specificity for screen-relevant neoplasm compared to g-FOBT using colonoscopy as the gold standard. Optimal threshold levels for hemoglobin detection depend on the desired trade off between sensitivity and false-positive rate. Single-day testing with an FIT may be an option to enhance population compliance with screening.

Trace elements and vitamins at diagnosis in pediatric-onset inflammatory bowel disease.

AIM: To compare serum vitamin and mineral levels at diagnosis in children with inflammatory bowel disease (IBD) versus a control group without. METHODS: In a retrospective cohort study, serum levels of iron, zinc, folate, selenium, vitamin B( 12), vitamin A, and vitamin E in children with IBD at diagnosis were compared with gender- and age-matched controls. RESULTS: A total of 154 patients with IBD (mean age 11.27 ± 3.74 years, 83 boys, 80 with Crohn's disease) were recruited. The mean duration of symptoms prior to diagnosis was 5.4 ± 3.2 months for patients with Crohn's disease and 4.6 ± 2.9 months for patients with ulcerative colitis. A control group of 64 children was recruited. The mean serum zinc levels were 11.33 ± 4.16 µmol/L for ulcerative colitis, 8.74 ± 2.08 µmol/L for Crohn's disease and 11.49 ± 1.63 µmol/L for controls (P < .001). CONCLUSIONS: In newly diagnosed children with IBD, serum zinc levels are significantly lower compared with children without IBD.

Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood.

To investigate associations of 2 vitamin D receptor (VDR) gene polymorphisms and acute lower respiratory tract infection (ALRI), we compared 56 young children hospitalized with ALRI and 64 children without a history of ALRI. The FokI ff genotype was associated with an adjusted relative odds of ALRI that was approximately 7 times that of FokI FF. A weaker association with the TaqI polymorphism was also found. These data provide preliminary evidence of associations of VDR polymorphisms with the risk of ALRI (predominantly viral bronchiolitis) in young children, consistent with a potential role of vitamin D in the immune response to respiratory tract infection.

Are national vitamin D guidelines sufficient to maintain adequate blood levels in children?

BACKGROUND: Vitamin D insufficiency (defined as 25-hydroxyvitamin D [25(OH)D] concentrations <40 nmol/L) may be associated with subclinical adverse effects on bone mineralization. The current vitamin D status of children and adolescents in Canada has not been described. The purpose of this study was to describe the association between 25(OH)D serum concentration and dietary vitamin D intake, and other potential determinants of vitamin D status, among a sample of children and adolescents aged 2-16 years presenting to a pediatric emergency department in Edmonton, Alberta (latitude 52 degrees N) at the end of winter. METHODS: In early April 2003, 90 patients between the ages of 2 and 16 years who presented to the pediatric emergency department in Edmonton volunteered to participate. All participants and/or parents or guardians completed questionnaires regarding potential risk factors for vitamin D insufficiency, detailed dietary assessments, and anthropometric measurements. Serum 25(OH)D concentrations were measured in 68 of 90 participants. RESULTS: The mean serum 25(OH)D concentration was 47.2 nmol/L (95% CI 43.8-50.8 nmol/L). 34% of participants had vitamin D insufficiency (<40 nmol/L) and 6% were deficient (<25 nmol/L). Boys and girls aged 9-16 years had a prevalence of insufficiency of 69% and 35% respectively, while boys and girls 2-8 years old had a prevalence of insufficiency of 22% and 8% respectively. Dietary vitamin D intake per kilogram body weight was the most important independent determinant of 25(OH)D concentration (r = 0.446, p<0.001). Vitamin D intake, age and male sex best predicted insufficiency. No subject was insufficient if they had an intake >0.45 mcg/kg/day. INTERPRETATION: Vitamin D insufficiency may be common among children and adolescents at the beginning of spring. The risk may be highest among older children because vitamin D intake does not adequately rise in proportion with increases in body mass. Further studies are needed to assess whether Canadian dietary vitamin D recommendations should be changed.

Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events.

BACKGROUND: Azathioprine (AZA), used to treat inflammatory bowel disease (IBD), is metabolized by thiopurine methyltransferase (TPMT). The accumulation of individual metabolites varies because humans display genetic polymorphism for TPMT expression. Deficiencies in TPMT result in accumulation of toxic metabolites, followed by neutropenia and hepatic inflammation. Concern over acute toxicity frequently leads to under dosing and frequent monitoring tests and visits. OBJECTIVE: To determine whether assessment of TPMT activity before the administration of AZA would predict acute toxicity and, thus, allow for reductions in health care costs related to biochemical screening for, and management of, AZA-induced adverse events. METHODS: Before AZA treatment, 29 patients with IBD were prospectively randomized to one of two groups: group 1, in which no TPMT assay was performed, was started on AZA at 1 mg/kg/day and then titrated every two weeks to a target dose of 2.5 mg/kg/day; and group 2, in which TPMT assays were performed, was started on AZA at the target dose of 2.5 mg/kg/day. For both groups, complete blood count and liver enzymes were monitored weekly for six weeks and at monthly intervals thereafter. Additional tests and health care interventions were undertaken at the discretion of the attending physicians. RESULTS: Of the 29 patients in the study, 15 were randomly assigned to group 1 and 14 to group 2. Demographics and disease activity were similar for both groups. Mean follow-up time was 7.1 months (range 3.5 to 10.7 months). Eight patients from group 1 and six patients from group 2 withdrew as a result of AZA-induced adverse events. There was no correlation between the TPMT activity and the development of AZA-induced adverse events. The direct health care costs for group 1 (300.11 dollars per patient) were lower than in group 2 (348.87 dollars per patient). CONCLUSION: The prospective assessment of TPMT enzyme activity before initiating AZA therapy in IBD patients incurred additional cost and did not predict AZA-induced toxicity.

Do cardiac troponins provide prognostic insight in hemodialysis patients?

BACKGROUND: The diagnosis of myocardial necrosis in patients with chronic renal failure is often difficult because biochemical markers of cardiac damage such as creatine kinase MB (CKMB) and cardiac troponin T (cTnT) may be spuriously elevated. Recent small studies also report unexplained elevations in cardiac troponin I (cTnI) in chronic renal failure patients undergoing hemodialysis. The relative incidence of elevated cardiac troponins in this population and their relationship to clinical events remain unknown. OBJECTIVE: To determine the incidence and prognostic significance of asymptomatic elevations of cTnT and cTnI in patients undergoing hemodialysis for chronic renal failure. DESIGN: Prospective cohort study. SETTING: University tertiary care teaching hospital. PATIENTS: One hundred thirteen patients over 21 years of age undergoing onsite hemodialysis were enrolled between December 1997 and February 1998. MEASUREMENTS: All-cause and cardiovascular mortality, hospitalization for acute myocardial infarction, unstable angina or congestive heart failure, new onset sustained arrhythmia or need for unscheduled emergency hemodialysis due to volume overload at 30 days and six months. RESULTS: The incidence of abnormal results for cTnT, cTnI and CKMB were 42%, 15% and 4%, respectively. Independent predictors of mortality at six months were median age greater than 63 years (odds ratio 14.3, 95% CI 1.5 to 130.3, P=0.019) and positive cTnT (odds ratio 13.6, 95% CI 2.5 to 73.2, P=0.002). Diabetics were more likely to have positive cTnI and cTnT results than nondiabetics (P<0.001 and P=0.023, respectively). CONCLUSIONS: cTnT is commonly elevated in patients with chronic renal failure even in the absence of acute coronary syndromes. cTnT may be an important independent prognostic marker in patients on hemodialysis for chronic renal failure. While less common, elevations of cTnI are more frequent than CKMB elevations. The basis of these cardiac troponin elevations is unclear. These findings may represent, in part, a subclinical myocardial injury, an inflammatory response to chronic renal failure or a chronically volume overloaded state.

Does chronic Chlamydia pneumoniae infection increase the risk of myocardial injury? Insights from patients with non-ST-elevation acute coronary syndromes.

BACKGROUND: Cumulative evidence suggests a positive association between Chlamydia pneumoniae (Cpn) infection and risk of future coronary events among patients with stable coronary artery disease. However, its prognostic role in unstable coronary syndromes is less well defined. Because Cpn immunoglobulin A (IgA) may be a more reliable indicator of chronic infection than immunoglobulin G (IgG), we speculated that in patients with non-ST-elevation acute coronary syndromes (ACS), this marker might serve as a more useful prognostic tool. Accordingly, we evaluated plasma samples acquired at presentation in 178 patients with ACS for a possible association between Cpn IgA titer and biochemical evidence of myocardial injury. METHODS: Cpn IgG (positive if > or =1:32), and IgA titers (positive if > or =1:16) were measured by use of the microimmunofluorescence technique in 70 patients with ACS in whom myocardial injury developed associated with their presenting events (elevated CK-MB and/or troponin I); and in 108 patients with ACS without such injury. The odds ratios (ORs) for myocardial injury associated with consecutive antibody titers were determined for each of Cpn IgG and IgA. Multiple logistic regression was applied to adjust for key baseline characteristics. RESULTS: Median age of subjects was 64 years; 63% were male and 33% were smokers. The median antibody titers among those with and without myocardial injury respectively were as follows: IgG (1:128 vs 1:128), IgA (1:32 vs <1:16, P =.2). The adjusted ORs for myocardial injury associated with consecutive IgA titers were as follows: IgA > or =1:16, adjusted OR 1.49 (P =.22); > or =1:32, OR 1.95 (P =.04); > or =1:64, OR 1.37 (P =.38); > or =1:128, OR 0.77 (P =.55). No significant trend was found for any IgG titer. CONCLUSIONS: Among patients with non-ST-elevation ACS, a Cpn IgA > or =1:32 at presentation was associated with a significantly higher risk of myocardial injury complicating the presenting event.