A randomized, controlled, single-blinded, multicenter evaluation of the efficacy and safety of a once weekly two dose otic gel containing florfenicol, terbinafine and betamethasone administered for the treatment of canine otitis externa.

BACKGROUND: Otitis externa is a common problem in small animal practice. Compliance with daily treatment is a major cause of treatment failure. The hypothesis tested is that a novel otic gel applied to the ear canal twice with a one-week interval is as efficacious as a daily otic suspension in the treatment of canine otitis externa. The study included 286 privately owned dogs with otitis externa. In this single blinded randomized study, enrolled dogs received either an otic gel containing 1% florfenicol, 1% terbinafine and 0.1% betamethasone acetate twice with a one-week interval or a suspension containing hydrocortisone aceponate, miconazole and gentamicin daily for 5 days. Ears were cleaned with saline prior to administration of the first dose of medication. Dogs were evaluated at day (D) 0, 7, 28 and 56 with an otitis index score (OTIS-3), otic culture and cytology, pain and pruritus, and overall response to treatment (owner and investigator evaluation). Outcome measures were improvement of the OTIS-3 and number of dogs in clinical remission at each time point. RESULTS: OTIS-3 decreased significantly (p < 0.0001) by 63 and 64% for the otic gel and by 63 and 61% for the suspension on D28 and D56 respectively. There was no significant difference between groups at any time point with regard to clinical success, pain, pruritus, overall assessments or otic cytology and culture. The treatment response was considered excellent or good by approximately three quarters of both the clinicians and Owners. Otitis recurrence at D56 was seen in 11% of both groups. Adverse events attributable to the ear medications were not noted. CONCLUSIONS: Administering an otic gel twice at a one-week interval is an effective, safe and convenient way to treat canine otitis externa.

A randomized placebo-controlled trial of the efficacy and safety of a terbinafine, florfenicol and betamethasone topical ear formulation in dogs for the treatment of bacterial and/or fungal otitis externa.

BACKGROUND: Treatment of infected otitis externa (OE) relies on the topical application of specific formulations that most often contain an antibiotic, an antifungal and a glucocorticoid. This study is to report the results of a randomized, placebo-controlled field trial evaluating the efficacy and safety of OSURNIA™ (Elanco Animal Health, a division of Eli Lilly and Company, Greenfield, IN), a novel topical ear medication containing florfenicol, terbinafine and betamethasone acetate in an adaptable gel. The study includes 284 dogs with bacterial and/or fungal OE who were randomly assigned to receive two doses of Osurnia or its vehicle, one week apart. Dogs were evaluated at various time points through Day 45, and a total clinical score (TCS) was calculated based on pain, erythema, exudate, swelling, odor and ulceration. The primary outcome measure was the rate of treatment success (RTS), defined as a TCS of 0, 1 or 2 on Day 45. Before and after treatment, a "clap test" was performed to subjectively assess hearing, and blood and urine were collected for routine clinical pathology. RESULTS: The RTS was significantly higher in ears treated with Osurnia (64.78%) than with placebo (43.42%). There was no significant interaction between efficacy and duration of history, recurrence of otitis or body weight. Adverse events were similar between groups. All dogs treated with Osurnia maintained their hearing, and there were no relevant clinical pathology changes. CONCLUSIONS: The application of two doses of Osurnia, one week apart, is effective and safe to treat microbial otitis externa in dogs.

Hepatitis C virus-infected kidney waitlist patients: Treat now or treat later?

Currently many but not all centers transplant hepatitis C virus (HCV) viremic positive (+) donor kidneys into HCV+ recipients. Directed donation of HCV+ organs reduces the wait time to transplantation for HCV+ patients. Direct-acting antiviral (DAA) therapy can cure HCV in virtually all who are infected. Some have suggested that treatment of HCV+ waitlisted patients be deferred with the hope that earlier transplantation will provide better outcomes than early DAA therapy. However, there are not enough organs to guarantee prompt transplantation for the current waitlist of infected candidates. A Markov medical decision analysis model was created to compare the overall outcomes of delayed DAA therapy (Option 1) to immediate DAA therapy (Option 2) in waitlisted HCV+ patients. Option 1 patients were modeled to be transplanted 1 year earlier, with a higher cumulative transplant incidence (54% at 5 years post-listing vs 45% for Option 2). Despite this, Option 2 provided 0.43 (95% confidence interval [CI] 0.38-0.49) more life years than Option 1. However, Option 1 was preferred for regions with much greater access to HCV+ organs or in patients with very low HCV+-associated mortality. The best option from an individual patient's perspective will differ by region and candidate.

Hepatitis B and C serologic profiles of Canadian organ donors and recipients: retrospective 10-year review at a single center.

BACKGROUND: Hepatitis C virus (HBV) and hepatitis C virus (HCV) are important causes of hepatitis and can be transmitted from organ donor to recipient. This study aimed to determine HBV and HCV serologic profiles of a population of Canadian solid organ transplant (SOT) donors and recipients, including prevalence of recipient HBV immunity. METHODS: Data on age, gender, organ transplanted, and pre-transplant HBV and HCV serology for SOT donors and recipients at a Canadian hospital from 2001 to 2011 were obtained from a transplant database. RESULTS: There were 2455 recipients (2205 adults, 250 children), and 1559 donors. Over 50% of adult and 44% of pediatric recipients were HBV non-immune pre-transplant. Pediatric recipients were more likely to have HBV vaccine immunity than were adult recipients (48.8% vs. 28.9%, P < 0.001). Prevalence of HBV vaccine immunity was highest in renal recipients (48.3% in adult, 63.2% in pediatric recipients). Recipient HBV vaccine immunity increased from 5.8% in 2001 to 44.5% in 2011 (P < 0.001). Of 134 adult recipients with prior HBV infection, 59 (44%) were co-infected with HCV. Only 0.6% of adult non-liver recipients had acute or chronic HBV infection and 3.2% were anti-HCV positive. Only 2 donors had acute or chronic HBV infection, 29 had prior HBV infection, 9 were isolated hepatitis B core antibody positive, and 15 were anti-HCV positive. CONCLUSIONS: The prevalence of HBV vaccine immunity in SOT candidates is low, but increased from 2001 to 2011. Opportunities for quality improvement in pre-transplant HBV immunization exist. HCV co-infection is common in recipients with prior HBV infection. Prevalence of HCV infection in non-liver transplant recipients is low.

Evaluation of cyclosporine-sparing effects of polyunsaturated fatty acids in the treatment of canine atopic dermatitis.

A randomised, double-blinded, placebo-controlled multicentre trial was conducted in 36 dogs with atopic dermatitis to evaluate the cyclosporine-sparing effect of polyunsaturated fatty acids. Dogs were stable on their individual cyclosporine dosage and received either a mainly omega-3 fatty acid product with a minor omega-6 fatty acid fraction or placebo, orally for 12 weeks. Dogs were examined every 4 weeks and the Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) was determined by a clinician. Pruritus, quality of life, global condition and coat quality were scored by the owner. If the dog's CADESI-03 and/or pruritus score improved by at least 25% compared with the previous visit, the cyclosporine dosage was decreased by approximately 25%. If the scores deteriorated by at least 25%, the cyclosporine dosage was increased by the same percentage. The median daily cyclosporine dosage/kg bodyweight decreased in the active group from 4.1 mg to 2.6 mg and in the placebo group from 3.5 mg to 3.3 mg over the study period. The difference between the two groups was significant (P = 0.009). The improvement in median pruritus score from inclusion to completion was significantly greater in the active group than in the placebo group (P = 0.04). There was no significant difference in CADESI-03 changes between groups (P = 0.38). The results of this study indicate a cyclosporine-sparing effect of a mainly omega-3 fatty acid supplement in dogs with atopic dermatitis.

Outcomes of Lung Transplantation in Recipients With Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infection negatively impacts patient and graft survival following nonhepatic solid organ transplantation. Most data, however, are in kidney transplant, where despite modest impact on outcomes, transplantation is recommended for those with mild to moderate hepatic fibrosis given overall benefit compared to remaining on dialysis. In lung transplantation (LuTx), there is little data on outcomes and international guidelines are vague on the criteria under which transplant should be considered. The University of Alberta Lung Transplant Program routinely considers patients with HCV for lung transplant based on criteria extrapolated from the kidney transplant literature. Here we describe the outcomes of 27 HCV-positive, compared to 443 HCV-negative LuTx recipients. Prior to transplant, five patients were treated for HCV and cured. At the time of transplant, 14 patients remained HCV RNA positive. The 1-, 3-, and 5-year survival were similar in HCV RNA-positive versus -negative recipients at 93%, 77%, and 77% versus 86%, 75%, and 66% (p = 0.93), respectively. Long-term follow-up in eight patients demonstrated no significant progression of fibrosis. In our cohort, HCV did not impact LuTx outcomes and in the era of interferon-free HCV therapies this should not be a barrier to LuTx.

Epidemiology and risk factors for nosocomial bloodstream infections in solid organ transplants over a 10-year period.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of morbidity and mortality in solid organ transplantation (SOT). We sought to determine the types of nosocomial BSIs and risk factors for them in SOT. METHODS: Prospectively collected databases of all SOT and nosocomial BSIs occurring at our institution for a 10-year period were reviewed. RESULTS: From 2003-2012, we observed 157 nosocomial BSI episodes in 2257 SOTs, the majority of which were caused by staphylococci and enterococci (67.5%). The most common sources of BSI were central line, organ space, respiratory, and gastrointestinal. Kidney transplant patients had the lowest risk of acquiring a BSI compared with other SOT types. Lung transplant patients were at increased risk of methicillin-resistant Staphylococcus aureus BSI and heart transplant patients were at increased risk of a Candida albicans BSI, when compared to other organ transplant types. When coagulase-negative Staphylococcus (CoNS) or C. albicans was isolated, the central line was most often the source. The implementation of central-line bundles during the study period correlated temporally with a decreased rate of CoNS BSI. Over the 10-year period, vancomycin-resistant enterococci became the most common enterococcal BSI. Donor-positive cytomegalovirus status was associated with an increased risk of BSI, when compared to donor-negative patients. CONCLUSIONS: This study demonstrates the common sources, risk factors, and causative organisms of BSI, which can guide empiric antibiotic choices, and highlights areas where preventative interventions could be targeted to prevent nosocomial BSI in SOT.

Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Long-term outcome of lung transplantation in previous intravenous drug users with talc lung granulomatosis.

Talc lung granulomatosis results from the intravenous use of medication intended for oral use. Talc (magnesium silicate) acts as filler in some oral medications; when injected intravenously, it deposits in the lungs leading to airflow obstruction and impaired gas exchange. Allocation of donor lungs to previous intravenous drug users is controversial. After a careful selection process, 19 patients with talc lung granulomatosis have received lung allografts in our program. Long-term survival for these patients is excellent and our results suggest the previous use of intravenous drugs should not necessarily preclude lung transplantation.

Donor-derived bacteremia in liver transplant recipients despite antibiotic prophylaxis.

As the disparity between the number of candidates listed for transplant and the number of donors continues to grow, marginal organ donors are increasingly utilized. This includes bacteremic donors which may carry an increased risk of transmission of infection. It is recommended that recipients of organs from bacteremic donors receive antibiotic prophylaxis based on the susceptibilities of the donor isolate to prevent transmission. Here, we present four cases of donor-derived bacteremia, despite appropriate antimicrobial prophylaxis, in four liver transplant recipients. Transmitted pathogens included Staphylococcus aureus in two cases, and Escherichia coli and Group B Streptococcus each in one case. Interestingly, none of the nonhepatic organs (n=10) utilized from these bacteremic donors resulted in transmissions. These cases highlight the fact that risk of transmission from bacteremic donors is not eliminated with antimicrobial therapy in the donor and recipient. As no transmissions occurred in recipients of nonhepatic organs from these donors, these cases also suggest that liver recipients may be at higher risk of donor transmitted bacteremia.

Granulocyte colony-stimulating factor for hepatitis C therapy-associated neutropenia: systematic review and economic evaluation.

Hepatitis C virus (HCV) treatment requires maximal adherence to pegylated interferon (Peg-IFN) and ribavirin to achieve a sustained virologic response (SVR). Neutropenia is the most common cause for Peg-IFN dose reduction. Our objectives were to evaluate the effectiveness, safety and cost-effectiveness of granulocyte colony-stimulating factor (G-CSF) versus Peg-IFN dose reduction for HCV therapy-associated neutropenia in treatment naïve adults. We conducted a systematic review to identify controlled trials and observational studies. Study selection, quality assessment and data extraction were completed independently by two investigators. Cost-effectiveness and cost-utility analyses compared G-CSF with dose reduction. Nineteen studies were included. In one trial, the SVR for those receiving G-CSF was 54.5% (95% CI: 34.7-73.1) compared with 26.3% (95% CI: 11.8-48.8) for dose reduction. The remaining studies were case series or retrospective cohorts and provided weak evidence for the relationship between SVR and G-CSF. The risk of adverse events, including infection, associated with G-CSF was low (13.1%; 95% CI: 8.0-20.8) and clinically insignificant. G-CSF had an incremental cost-effectiveness ratio of $41,701 per SVR achieved in genotype 1, and $16,115 per SVR achieved in genotype 2 or 3. Estimates were robust under a variety of resource and intervention scenarios. While administration of G-CSF may enable patients to remain on or resume optimal HCV therapy, there was weak evidence that this improves the likelihood of SVR compared with dose reduction. Adverse effects of G-CSF are mild. The economic evaluation was inconclusive.

Recommended curriculum for subspecialty training in transplant infectious disease on behalf of the American Society of Transplantation Infectious Diseases Community of Practice Educational Initiatives Working Group.

The American Society of Transplantation Infectious Diseases (ID) Community of Practice has established an education workgroup to identify core components of a curriculum for training specialists in transplant ID. Clinical, laboratory, and research training form the triad of components on which an additional year of ID training, dedicated to the care of solid organ and hematopoietic stem cell transplant recipients, should be based. The recommended training environment would have access to adequate numbers of transplant patients, along with qualified faculty committed to teaching specialized fellows in this area. The learning objectives for both inpatient and outpatient clinical training are presented. The laboratory component requires trainees to attain expertize in utilizing and interpreting cutting-edge diagnostics used in transplant medicine. The research component may involve basic science, and translational or clinical research individualized to the trainee. Finally, suggestions for evaluation of both the fellows and the training program are provided.

Improving access to care by allowing self-referral to a hepatitis C clinic.

BACKGROUND: Estimates suggest that more than 250,000 Canadians are infected with hepatitis C virus (HCV), but less than 10% have been treated. Access to specialists in Canada is usually via health care professional (HCP) referral and, therefore, may be a barrier to HCV care. However, clinics that operate in conjunction with the Hepatitis Support Program, Edmonton, Alberta, allow self-referral. It is hypothesized that this improves access to care without increasing inappropriate referrals. OBJECTIVE: To compare the baseline characteristics and outcomes of HCV patients who self-referred with those who were HCP-referred. METHODS: Data were collected from the Hepatitis Support Program HCV database and chart reviews. RESULTS: Between December 17, 2002, and December 31, 2007, 1563 patients were referred including 336 self- (21.5%) and 1227 HCP-referrals (78.5%). Self- and HCP-referred patients were similar in terms of age (mean [+/- SD] 43.0+/-10.3 years versus 43.9+/-10.0 years, respectively; P=0.18), sex (56.8% versus 62.0% [men], respectively; P=0.08) and risk factors for HCV (P=0.3), with 49.7% and 52.6%, respectively, identifying injection drug use as the primary risk factor. The two groups had similar HCV genotype distributions and liver biopsy fibrosis scores with similar treatment rates (31.3% versus 33.2%; P=0.6). Treatment outcomes were excellent (sustained virological response 40.2% for genotype 1, 67% for genotypes 2 and 3) in patients completing therapy and were similar between the two groups. CONCLUSION: Self-referred patients comprised 21.5% of patients accessing care in the clinic. Self- and HCP-referred patients had similar characteristics, treatment rates and outcomes. Facilitating self referral to an HCV clinic can improve access to care, including risk reduction education and HCV treatment.

Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation.

Screening for latent tuberculosis infection (LTBI) is recommended prior to organ transplantation. The Quantiferon-TB Gold assay (QFT-G) may be more accurate than the tuberculin skin test (TST) in the detection of LTBI. We prospectively compared the results of QFT-G to TST in patients with chronic liver disease awaiting transplantation. Patients were screened for LTBI with both the QFT-G test and a TST. Concordance between test results and predictors of a discordant result were determined. Of the 153 evaluable patients, 37 (24.2%) had a positive TST and 34 (22.2%) had a positive QFT-G. Overall agreement between tests was 85.1% (kappa= 0.60, p < 0.0001). Discordant test results were seen in 12 TST positive/QFT-G negative patients and in 9 TST negative/QFT-G positive patients. Prior BCG vaccination was not associated with discordant test results. Twelve patients (7.8%), all with a negative TST, had an indeterminate result of the QFT-G and this was more likely in patients with a low lymphocyte count (p = 0.01) and a high MELD score (p = 0.001). In patients awaiting liver transplantation, both the TST and QFT-G were comparable for the diagnosis of LTBI with reasonable concordance between tests. Indeterminate QFT-G result was more likely in those with more advanced liver disease.

Staphylococcus aureus bacteremia in patients receiving pegylated interferon-alpha and ribavirin for chronic hepatitis C virus infection.

Bacteremia has rarely been reported in patients receiving treatment for hepatitis C virus (HCV) infection. We describe the features and investigation of four cases of Staphylococcus aureus bacteremia occurring between 3 November 2004 and 10 January 2005 in patients on therapy for chronic HCV infection. The unusual occurrence of S. aureus bacteremia in a series of patients led to an epidemiologic investigation and molecular typing methods were employed to assess the relatedness of cases. The mean time of bacteremia onset was week 10 of HCV treatment. No patient had neutropenia previously. The average duration of bacteremia was 2.6 days and complications included acute renal failure (2/4), disseminated intravascular coagulopathy (DIC) with sepsis syndrome (1/4), septic arthritis (1/4), spinal epidural abscess (1/4) and endocarditis (1/4). Two patients were in the same weight class for dosing, but no other epidemiologic links were found. One patient admitted to intravenous drug use (IVDU) and a second was suspected of IVDU. The two other patients were cirrhotic, but had no further identifiable risk factors. All bacterial isolates were methicillin-susceptible. By pulsed-field gel electrophoresis, two cases were found to have identical bacterial strains. However, fluorescent-based amplified fragment-length polymorphism analysis demonstrated distinct band patterns in all four cases. The epidemiologic data and molecular analysis of this cluster of S. aureus bacteremia cases among patients receiving combination therapy for treatment of chronic HCV infection suggest that these cases were not related. Additionally, IVDU and cirrhosis, but not neutropenia, are identified as potential risk factors for this uncommon complication of HCV therapy.

Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection.

Recently, we documented that immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. The aim of the present study was to determine whether there is any association between serum immunoglobulin levels and hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. Charts from 116 patients with biochemical, serologic, virologic and histologic evidence of chronic hepatitis C infection and serum immunoglobulin levels (IgA, IgG, IgM and total) were reviewed. The mean (+/-SD) age of the study population was 46 +/- 11 years and 67 (58%) were male. There were significant correlations between serum IgA (r = 0.39, P = 0.00001), IgG (r = 0.49, P = 0.000002) and total (r = 0.51, P = 0.000003) immunoglobulin levels and the stage of hepatic fibrosis. When serum immunoglobulin levels were included into logistic regression analysis with variables known to be associated with advanced disease (male gender, age >40 years at onset of infection, duration of infection beyond 20 years and concurrent alcohol abuse) only IgA, IgG and total immunoglobulin levels (P < 0.05, <0.05 and <0.005, respectively) emerged as independent predictors of hepatic fibrosis. Our data indicate a strong association between serum immunoglobulin levels (IgA, IgG and total) and hepatic fibrosis in patients with HCV infection. This finding supports the need to further investigate whether immunoglobulins independently promote disease progression in patients with chronic HCV infection.