Children may need higher vancomycin doses to achieve therapeutic levels.

AIM: Vancomycin is frequently used in paediatric hospitals. Data suggest trough levels of 10-20 mg/L are needed to achieve bacterial killing. This study aimed to evaluate if commonly used dosing regimens are efficient in reaching these levels and if therapeutic drug monitoring (TDM) was appropriately used. METHODS: All children receiving intravenous vancomycin at the Children´s Hospital Iceland between 2012 and 2016 were included. Vancomycin trough levels were registered. Student t test, Wilcoxon test and regression models were used for statistical analysis. RESULTS: A total of 105 children received 163 vancomycin treatments (55/105 neonates). Average daily dose in neonates was 23.4 mg/kg/day and 38.4 mg/kg/day for older children. No TDM was done in 58 treatments (35.6%). First trough levels were <10mg/L in 52.4% and <15mg/L in 92% of cases. Therapeutic levels were less likely achieved in children with malignancy (11.8%) compared with others (36.8%, p = 0.09). CONCLUSIONS: In more than half of the cases, trough drug levels were <10 mg/L and malignancy was associated with the lowest probability of reaching therapeutic levels. This study suggests that starting doses of vancomycin in children should be higher, especially in relation to malignant diseases and supports the importance of antibiotic stewardship to ensure optimal antibiotic use.

The majority of patients with psoriatic arthritis are not eligible for randomised clinical trials.

OBJECTIVES: To identify the proportion of patients with psoriatic arthritis (PsA) who would meet inclusion criteria of the randomised clinical trials that were performed leading up to registration of the tumour necrosis factor inhibitors (TNFi). METHODS: Data from 329 patients with PsA were obtained from an Icelandic database, ICEBIO, medical records at the University Hospital of Iceland, and the private out-patient clinic Laeknasetrid Ltd. The patients were classified according to whether they met the inclusion criteria of the clinical trials that were performed ahead of the registration of each respective TNFi. The reasons for exclusion were also explored. RESULTS: 34% of the patients with complete data available met the inclusion criteria. Clinical data in respect to exclusion and inclusion criteria were incomplete for 13% of the cases. The proportion of patients who met the inclusion criteria was highest among those who received adalimumab and etanercept (53%). Patients who received in iximab had the lowest inclusion rate (23%). The main reason why patients did not meet the inclusion criteria was too few swollen and/or tender joints, or in 45% of excluded cases. CONCLUSIONS: Our results demonstrate that two thirds of patients with PsA in Iceland who are treated with TNFi would not have qualified for the randomised clinical trials performed leading up to the registration of the medications. Further studies with regards to whether outcomes are different between those who met the inclusion criteria and those who did not remain to be performed.

Outpatient Use of Antimicrobials in Patients With Rheumatoid Arthritis Before and After Treatment With Tumor Necrosis Factor Inhibitors: A Nationwide Retrospective Cohort Study.

OBJECTIVE: The objective of this study was to investigate the effect of tumor necrosis factor α inhibitor (TNFi) initiation on the use of antimicrobials among biologic-naïve patients with rheumatoid arthritis (RA). METHODS: Information on all biologic-naïve patients with RA was extracted from ICEBIO, a nationwide registry. Each patient was matched on age, sex, and calendar time to five randomly selected individuals from the general population. All filled antimicrobial and glucocorticoid prescriptions in the 2 years before and after initiation of the first TNFi were extracted from the Prescription Medicines Register. Prescriptions were quantified by using the number of filled prescriptions (NP) and defined daily doses. RESULTS: We extracted information on 359 patients with RA and 1795 comparators. During the 24 months before initiating treatment with TNFi, patients with RA received more prescriptions for antimicrobials than their matched general population comparators (mean ± SD: 2.8 ± 3.4 vs 1.6 ± 2.7; P < 0.001). The 24-month mean NP for patients with RA increased to 3.5 ± 3.9 (P < 0.001) after initiating TNFi: antibiotics, 2.6 ± 3.2 to 3.2 ± 3.5 (P < 0.001); antivirals, 0.06 ± 0.5 to 0.16 ± 0.7 (P = 0.004); and antimycotics, 0.14 ± 0.5 to 0.22 ± 0.9 (P = 0.06). The 12-month mean NP was highest in the second year after TNFi initiation (1.9 ± 2.4). No association was found between NP and glucocorticoids, age, body mass index, or pre-TNFi Disease Activity Score 28-joint count and C-reactive protein. CONCLUSION: Patients with RA on TNFi are more commonly treated for infections in the outpatient settings than previously reported. Patients are prescribed more antimicrobials in the 2 years preceding TNFi initiation than the general population, and this use further increases after initiation of TNFi. In contrast to what is reported for infections requiring hospitalization, outpatient antimicrobial use remained elevated for at least 2 years.

Patients with psoriatic arthritis who are not eligible for randomised controlled trials for TNF inhibitors have treatment response and drug survival similar to those who are eligible.

Objectives: To determine in a retrospective cohort whether patients with psoriatic arthritis (PsA) who would not have fulfilled the inclusion criteria for randomised controlled trials (RCTs) for the TNF inhibitor (TNFi) chosen for their treatment (excl) have similar benefits and drug survival as those patients who would have (incl). Methods: All patients with rheumatic disorders who are treated with biological disease-modifying antirheumatic drugs in Iceland are registered in ICEBIO. On 1 February 2016, 329 individuals with PsA were registered in ICEBIO, of whom 231 had data available for their first start of TNFi and could be evaluated according to the inclusion criteria of the respective RCTs. Disease activity was collected at baseline using Visual Analogue Scale (pain, fatigue and global (patient and physician) assessments), swollen joint count (SJC) and tender joint count (TJC), Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) and Health Assessment Questionnaire (HAQ). Treatment response was measured at 6 and 18 months according to American College of Rheumatology response criteria, DAS28-CRP and Disease Activity Score in Psoriatic Arthritis for 28 joints. Drug survival rate was also analysed. Results: The demographics of these two groups were similar at baseline, although the incl group had higher SJC (5.5 vs 3.8) and subsequently higher DAS28-CRP (4.6 vs 4.2). While a larger change in disease activity was observed in the incl group with respect to HAQ and SJC, both groups had similar disease activity at follow-up. Drug survival was similar in both groups. Conclusions: Patients with PsA who would not have fulfilled the inclusion criteria in RCTs reach similar disease activity scores at follow-up of 6 and 18 months and have similar drug survival as those patients who would have been included in RCTs.

Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial.

BACKGROUND: Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well. METHODS: The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239. FINDINGS: Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1-1·9). During days 1-720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25-1·13; pnon-inferiority<0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45-1·61; pnon-inferiority=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring. INTERPRETATION: Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR. FUNDING: Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.