Critically-Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network (DILIN) criteria.

Purpose: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, the effect of weight-based fluconazole dosing on liver injury has not been assessed. This study evaluated how often patients met Drug Induced Liver Injury Network (DILIN) criteria when receiving fluconazole daily doses of <6mg/kg versus ≥6mg/kg. Methods: This multi-center, retrospective cohort study was performed in critically-ill fluconazole recipients hospitalized from January 2009 to December 2012. It included patients who received ≥3 fluconazole doses with ≥1 dose administered in the intensive care unit. Patients were excluded if they were pregnant, presented with acetaminophen toxicity, received fluconazole within 1 week of liver transplantation, or missed >1 fluconazole dose during therapy. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after fluconazole discontinuation using DILIN criteria. The Fisher’s exact test was used to detect differences in the primary outcome of patients meeting DILIN criteria by weight-based dosing as well as in subgroups of patients with kidney dysfunction, liver disease, septic shock, and those receiving a loading dose. Results: Two-hundred and forty-eight of 767 patients met inclusion criteria; 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. Of the 199 patients receiving <6 mg/kg of fluconazole, 55% met DILIN criteria versus 46.9% of the 49 patients in the ≥6 mg/kg cohort (p=0.20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. In analysis of subgroups, 77.3% of patients with cirrhosis and 76.3% with septic shock met DILIN criteria (p<0.001 for both compared to those without these conditions). Conclusions: Weight-based fluconazole dosing did not affect the number of critically-ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically-ill patients

Critically-Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network (DILIN) criteria.

Purpose: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, the effect of weight-based fluconazole dosing on liver injury has not been assessed. This study evaluated how often patients met Drug Induced Liver Injury Network (DILIN) criteria when receiving fluconazole daily doses of <6mg/kg versus ≥6mg/kg. Methods: This multi-center, retrospective cohort study was performed in critically-ill fluconazole recipients hospitalized from January 2009 to December 2012. It included patients who received ≥3 fluconazole doses with ≥1 dose administered in the intensive care unit. Patients were excluded if they were pregnant, presented with acetaminophen toxicity, received fluconazole within 1 week of liver transplantation, or missed >1 fluconazole dose during therapy. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after fluconazole discontinuation using DILIN criteria. The Fisher’s exact test was used to detect differences in the primary outcome of patients meeting DILIN criteria by weight-based dosing as well as in subgroups of patients with kidney dysfunction, liver disease, septic shock, and those receiving a loading dose. Results: Two-hundred and forty-eight of 767 patients met inclusion criteria; 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. Of the 199 patients receiving <6 mg/kg of fluconazole, 55% met DILIN criteria versus 46.9% of the 49 patients in the ≥6 mg/kg cohort (p=0.20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. In analysis of subgroups, 77.3% of patients with cirrhosis and 76.3% with septic shock met DILIN criteria (p<0.001 for both compared to those without these conditions). Conclusions: Weight-based fluconazole dosing did not affect the number of critically-ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically-ill patients

Detection of porcine circovirus type 1 in commercial porcine vaccines by loop-mediated isothermal amplification

A loop-mediated isothermal amplification (LAMP) method with a real-time monitoring system was developed for the detection of porcine circovirus type 1 (PCV1) in commercial swine vaccines. This method was highly specific for PCV1. No cross-reaction to porcine circovirus type 2, porcine parvovirus, pseudorabies virus, classical swine fever virus, and porcine reproductive and respiratory syndrome virus was observed. The analytical sensitivity of the LAMP for PCV1 DNA was 10 copies/μl in the case of positive recombinant plasmid comparable to that obtained from the nested polymerase chain reaction (nested PCR). Furthermore, 25 commercial swine vaccines were tested by both the LAMP and the nested PCR, and three of them were tested positive for PCV1 DNA. These results indicate that PCV1 DNA can be real-time detected by the LAMP; the method was highly specific, sensitive, and rapid for the detection of PCV1 DNA, particularly in commercial swine vaccines

Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality

<p>Abstract</p> <p>Objective</p> <p>Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting. Therefore, we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large randomized controlled trial with clinical endpoints.</p> <p>Study Design</p> <p>The pilot study was a randomized double blinded placebo controlled trial. Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton, Alberta, Canada (population ~1 million). Major exclusion criteria included the current use of insulin or high dose metformin, decreased renal function, or a glycosylated hemoglobin <7%. Patients were to be randomized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes, as well as clinical events.</p> <p>Results</p> <p>Fifty-eight patients were screened over a six month period and all were excluded. Because of futility with respect to enrollment, the pilot study was abandoned. The mean age of screened patients was 77 (SD 9) years and 57% were male. The main reasons for exclusion were: use of insulin therapy (n = 23; 40%), glycosylated hemoglobin <7% (n = 17; 29%) and current use of high dose metformin (n = 12; 21%). Overall, contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent (n = 27; 51%). On average, patients were receiving 1,706 mg (SD 488 mg) of metformin daily and 12 (44%) used only metformin.</p> <p>Conclusion</p> <p>Despite uncertainty in the scientific literature, there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive randomized trial virtually impossible.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00325910</p

One dose of a porcine circovirus 2 subunit vaccine induces humoral and cell-mediated immunity and protects against porcine circovirus-associated disease under field conditions

International audienceThis study investigated the efficacy of a one-dose porcine circovirus 2 (PCV2) subunit vaccine based on the PCV2 Cap protein expressed in a baculovirus system on two different farms at which a history of porcine circovirus-associated disease (PCVD) was present. Morbidity, mortality, average daily weight gain, carcass weight, PCV2 load in serum and vaccine immunogenicity were assessed. Serology to porcine reproductive and respiratory syndrome virus (PRRSV) and was performed. A double-blind, randomised, and controlled field trial was performed distributing 818 piglets between two treatment groups. At inclusion (weaning at 21±3 days of age), 408 animals (group B) received a 2-mL intramuscular dose of Porcilis PCV (vaccinated group). Controls (group A, 410 pigs) received 2mL of the adjuvant Diluvac Forte intramuscularly. Weights were recorded at inclusion and at 12 and 26 weeks of age, and the average daily weight gain (ADWG) was calculated. The carcass weights of the pigs from farm 2 were recorded at slaughter (274 days old). All dead animals (died or culled) underwent autopsy to classify them as PMWS-affected or not. At each farm, blood samples were taken from 22 pigs/group for serologic studies. A beneficial effect was found after vaccination with a single dose of a PCV2 Cap vaccine against PCVD. The vaccination reduced the mortality rate and morbidity, reduced PCV2 viremia and viral load, improved productive performances (e.g. ADWG: +70g/day between 12 and 26 weeks of age when viremia and the specific disease occurred) as well as carcass weight at slaughter age (+4.5kg). These effects were associated with virologic and clinical protection from the immunogenicity of the vaccine measured as activation of both a humoral and a cellular immune response

Porcine circovirus type 2 (PCV2)-infection and re-inoculation with homologous or heterologous strains: virological, serological, pathological and clinical effects in growing pigs.

Long-term PCV2 infection and/or concurrent infection with genotypes PCV2a and PCV2b may play a role in the development of clinical porcine circovirus-associated disease (PCVAD). To evaluate this premise, 24 11-week-old specific pathogen-free (SPF) pigs were randomly assigned to 1 of 4 treatments: negative controls, a single inoculation with PCV2a, single inoculation followed by re-inoculation with a homologous PCV2a strain, or repeated inoculations with heterologous strains (PCV2a, PCV2b). Pigs were evaluated for clinical signs daily through 140 days post inoculation (dpi). Serum samples were collected every other day from dpi 0 through 14 and weekly thereafter. PCV2-inoculated pigs were viremic by dpi 2 and 13 of 18 pigs remained viremic at 140 dpi. No statistical differences in the onset, level, or duration of PCV2 viremia were detected among treatment groups. Anti-PCV2 antibodies were detected between 14 and 28 dpi and were present through 140 dpi without statistical differences in antibody response among treatment groups. In the current study, pigs had extended viremia combined with detectable tissue PCV2 antigen levels despite the presence of high levels of anti-PCV2 antibody; however, no clinical disease was observed