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      Treatment of Disseminated Aspergillosis with Posaconazole in 10 Dogs

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          Abstract

          Background

          Few effective treatments for disseminated Aspergillus infections in dogs are available. Posaconazole has potent and broad‐spectrum activity against Aspergillus spp., but its use has not yet been sufficiently evaluated in dogs.

          Hypothesis/Objectives

          The aim of this study was to determine the safety and efficacy of posaconazole for the treatment of naturally occurring disseminated Aspergillus infections in dogs.

          Animals

          Ten client‐owned dogs with disseminated aspergillosis.

          Methods

          Prospective, nonrandomized, noncontrolled study with posaconazole administered to dogs at dosage of 5 mg/kg PO q12h. The primary veterinarian or the veterinary specialist caring for the dogs provided patient data.

          Results

          The treatment response for dogs with disseminated disease while receiving posaconazole was defined as clinical remission (n = 4) and clinical improvement (n = 6). There was a high rate of relapse during treatment or after cessation of treatment in both groups, and most dogs died or were euthanized due to progressive disease. Excluding 1 dog concurrently treated with terbinafine that remains alive 5 years after diagnosis, the mean survival time for dogs was 241 days (range 44–516 days). Three other dogs lived >1 year after starting treatment. No clinically relevant adverse events or increases in serum liver enzyme activity occurred during treatment with posaconazole.

          Conclusions and Clinical Importance

          Posaconazole appears to be safe and well‐tolerated for treatment of disseminated Aspergillus infections in dogs. Long‐term survival >1 year is possible with prolonged treatment, but relapse is common.

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          Most cited references45

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          Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America.

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            Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.

            Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.
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              Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.

              Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02). This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors. 2008 Massachusetts Medical Society
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                Author and article information

                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0891-6640
                1939-1676
                Jan-Feb 2016
                14 November 2015
                : 30
                : 1 ( doiID: 10.1111/jvim.2016.30.issue-1 )
                : 167-173
                Affiliations
                [ 1 ] Department of Small Animal Clinical SciencesVirginia‐Maryland College of Veterinary Medicine Blacksburg VA
                [ 2 ] Department of Small Animal Clinical SciencesCollege of Veterinary Medicine, University of Tennessee Knoxville TN
                [ 3 ]MiraVista Diagnostics Indianapolis IN
                [ 4 ]Diagnostic Services Knoxville TN
                Author notes
                [*] [* ]Corresponding author: V.K. Corrigan, Department of Small Animal Clinical Sciences, Virginia‐Maryland College of Veterinary Medicine, 245 Duck Pond Drive, Blacksburg VA 24061, Mail Code 0442; e‐mail: vavet10@ 123456vt.edu .
                Article
                JVIM13795
                10.1111/jvim.13795
                4913654
                26566711
                7fd2ba83-f8a3-4289-89c3-f533393a9395
                Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 24 February 2015
                : 04 October 2015
                : 15 October 2015
                Page count
                Pages: 7
                Categories
                Standard Article
                SMALL ANIMAL
                Standard Articles
                Infectious Disease
                Custom metadata
                2.0
                jvim13795
                January/February 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:17.06.2016

                Veterinary medicine
                aspergillus,diskospondylitis,fungal,pyelonephritis
                Veterinary medicine
                aspergillus, diskospondylitis, fungal, pyelonephritis

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