Antimicrobial stewardship programs in solid-organ transplant recipients in Switzerland.

INTRODUCTION: Antimicrobial stewardship programs (ASPs) are essential for minimizing the emergence of antimicrobial resistance, while improving patient outcomes. The current status of ASP in the field of organ transplantation in Switzerland has not been well characterized. METHODS: We describe in this article the current status of ASP and discuss challenges and opportunities of implementing ASP dedicated to solid-organ transplant (SOT) recipients in Switzerland. RESULTS: ASP have been implemented in the Swiss healthcare system over the last years, although specific strategies for SOT recipients are mostly based on transplant infectious diseases (TID) consultations rather than structured institutional interventions. Even so, there is a unique opportunity for developing a successful ASP in Switzerland that also specifically addresses areas of practice relevant to SOT recipients. This is due to the existent network of TID specialists in close collaboration with transplant physicians, the small number of centers involved in the care of transplant recipients, and the development of the Swiss Transplant Cohort Study (STCS), a prospective nationwide cohort of SOT recipients in Switzerland. The STCS can identify actual challenges through the updated reports on the epidemiology on transplant infections, accurately monitor the impact of potential antimicrobial stewardship interventions, and represent an opportunity for nesting of pragmatic randomized controlled trials to address key questions about optimized antibiotic use for SOT recipients. CONCLUSIONS: Although ASP in SOT recipients rely more on specific TID consultations than in general antimicrobial stewardship teams, we identified several opportunities for the implementation of a successful ASP in Switzerland

Donor-derived fulminant herpes simplex virus hepatitis after liver transplantation: Two cases and review of literature

BACKGROUND Fulminant herpetic hepatitis due to herpes simplex virus (HSV), serotype 1 or 2, is a rare but often fatal complication after solid organ transplantation (SOT). HSV hepatitis in SOT recipients can occur either due to primary infection acquired post transplantation, viral reactivation in a seropositive patient, or as donor-derived infection. Cases of fatal hepatitis have been reported in the liver as well as in other SOT recipients. The fatal outcome is mostly due to delayed diagnosis and treatment, which is explained by the lack of clinical specificity of HSV hepatitis. METHODS We report two cases of fatal donor-derived HSV hepatitis in liver-transplanted recipients. We reviewed all published cases of donor-derived HSV infections after SOT with an evaluation of the presence of prophylaxis and outcome. RESULTS In both liver recipients, the retrospective determination of HSV serostatus was negative, and both cases occurred in the absence of cytomegalovirus or HSV prophylaxis. A review of the literature showed a significant series of cases of severe hepatitis, mostly fatal, as well as the absence of specific preventive therapy guidelines in cases of HSV serology mismatch. CONCLUSIONS The occurrence of two fatal donor-derived hepatitis made the Swiss Transplant Infectious Diseases working group modify its national recommendations regarding pretransplant serostatus determination and HSV prophylaxis after liver transplantation. Further studies are needed to assess this approach

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study.

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis

Preventive strategies against cytomegalovirus and incidence of α-herpesvirus infections in olid-organ transplant recipients: A nationwide cohort study.

We assessed the impact of antiviral preventive strategies on the incidence of herpes-simplex virus (HSV) and varicella-zoster virus (VZV) infections in a nationwide cohort of transplant recipients. Risk factors for the development of HSV/VZV infection were assessed by Cox PH regression. We included 2781 patients (56% kidney, 20% liver, 10% lung, 7.3% heart, 6.7% others). Overall, 1264 (45%) patients received antiviral prophylaxis [(val)ganciclovir (n=1126) or (val)acyclovir (n=138)]. Incidences for HSV and VZV infections were 28.9 and 12.1 cases per 1000 person-years, respectively. Incidence of HSV/VZV infections at 1-year post-transplant was 4.6% (95% CI 3.5-5.8) in patients receiving antiviral prophylaxis vs. 12.3% (95% CI 10.7-14) in patients without prophylaxis; this was particularly observed for HSV infections: 3% (95% CI 2.2-4) vs. 9.8% (95% CI 8.4-11.4), respectively. A lower rate of HSV/VZV infections was also seen in donor or recipient CMV-positive patients receiving (val)ganciclovir prophylaxis as compared to a preemptive approach. Female gender (HR 1.663, p=0.001), HSV seropositivity (HR 5.198, p<0.001), previous episodes of rejection (HR 1.95, p=0.004), and use of a preemptive approach (HR 2.841, p=0.017) were significantly associated with a higher risk for HSV infection. While HSV/VZV infections were common after transplantation, antiviral prophylaxis significantly reduced symptomatic HSV infections. This article is protected by copyright. All rights reserved

Immunosuppression management in renal transplant recipients with normal-immunological risk: 10-year results from the Swiss Transplant Cohort Study.

Primary maintenance immunosuppressive therapies for renal transplant recipients underwent significant changes in recent years. We aimed to assess time trends and the impact of immunosuppressive regimens in first renal transplant recipients without immunological risk (blood group incompatibility, pre-existing donor-specific antibodies, positive B/T cell cross-match) in a prospective national multicentre cohort. The Swiss Transplant Cohort Study (STCS) prospectively enrols all patients receiving solid organ transplants in Switzerland since 2008 and systematically collects high quality clinical and laboratory data using standardised definitions. The current STCS nested study enrolled all adult transplant-na&amp;iuml;ve normal-immunological risk renal transplant recipients up to the end of 2017 and investigated different immunosuppressive strategies across a variety of transplantation relevant outcomes. Of 1191 recipients enrolled at six transplant centres, 115 (10%) died with a functioning allograft and 92 (8%) lost their allograft during a median follow-up time of 5.8 years. The predominant immunosuppressive therapy comprised tacrolimus, mycophenolate mofetil and prednisone (73.7%), whereas 24.3% were treated with ciclosporin instead of tacrolimus. Primary immunosuppression with an mTOR inhibitor (1.1%) or other immunosuppressive combinations (0.8%) was rare. In the years following 2011, ciclosporin-based immunosuppression decreased significantly. The incidence of graft loss was significantly higher in patients with ciclosporin-based than with tacrolimus-based immunosuppression (adjusted hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.29&amp;ndash;2.14; p &amp;lt;0.01), but the occurrence of acute transplant rejections did not differ significantly (adjusted HR 1.48, 95% CI 0.82&amp;ndash;2.65; p = 0.19). The longitudinal course of the renal allograft function was significantly better (p = 0.013) in recipients of tacrolimus-based immunosuppressive therapy. Graft failure-free survival was higher (HR 1.25, 95% CI 0.97&amp;ndash; 1.6; p = 0.08) with tacrolimus-based than with ciclosporin-based immunosuppression. Cytomegalovirus infections occurred more frequently with ciclosporin-based immunosuppression (9.7% vs 6.4% after 1 year), whereas the incidence of BK virus infections was similar in both groups. The median time to prednisone discontinuation was 1.9 years and did not differ between the two groups. Eleven cases of post-transplantation lymphoproliferative disorder were observed during the follow-up period (1 with ciclosporin-based and 10 with tacrolimus-based immunosuppression). The available data show that primary maintenance immunosuppression with tacrolimus has displaced ciclosporin-based therapies. The tacrolimus-based immunosuppression therapy showed consistently better results across almost all assessed clinically relevant outcomes. (ClinicalTrials.gov Number: NCT01204944)

Association of Antiviral Prophylaxis and Rituximab Use with Post-transplant Lymphoproliferative Disorders (PTLD): A Nationwide Cohort Study.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein-Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation and outcome of histologically-proven PTLD. We included 4'765 patients with a follow-up duration of 23`807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV-positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years post-transplant were 3.51; 2.24; 1.75/1'000 py and 0.44; 0.25; 0.29/1'000 py for EBV- PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199-1.436], p=0.264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751-6.521], p=0.150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but (57/4'574) patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077-0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD

An analytical model for quantification of geosynthetic benefits in roadway base stabilization

Stabilization of base aggregate using geosynthetics may provide improved performance in flexible pavements. Through the aggregate-geosynthetic interaction, the induced shear stress in the base aggregates is transferred to the geosynthetic resulting in the development of tensile stresses. The tensioned geosynthetic applies in turn additional lateral confinement to the aggregates to restrain their movement under repeated traffic loading. The use of geosynthetics in base stabilization has been reported to result in reduced rutting depths in roadways. Design guidelines, either empirical or mechanistic-empirical, have been established for the design of non-stabilized roadways. These guidelines, however, do not take the geosynthetic effect into account. Accordingly, the geosynthetic benefits in base stabilization need to be quantified in a way that can easily be incorporated into the existing design procedures. This study proposed an analytical model to achieve this goal. In this study, the additional lateral confinement provided by the geosynthetic was modeled as a uniform additional confining stress within the geosynthetic influence zone. The pavement section was considered as an infinitely long elastic solid under plane strain conditions, which allowed the model framework to be established using the theory of elasticity. The aggregate-geosynthetic interaction, on the other hand, was modeled using the soil-geosynthetic composite (SGC) model. As a result, an additional confining stress could be defined from the stress-displacement relationships in the elastic model framework. An increased elastic modulus could then be predicted from the additional confining stress with a specific criterion for equivalency of the original base course with additional confinement and an alternative base course with enhanced elastic modulus but without additional confinement. The increased modulus can be used as an updated property for the geosynthetic-stabilized base aggregate in mechanistic-empirical pavement design procedures. The predicted equivalent increased moduli were validated using the results from repeated loading triaxial tests of two published studies. Overall, reasonably good agreement was found between model predictions and the test results. Predictions from this model were also compared against those of another analytical model, and close results were observed. A sensitivity analysis conducted using the proposed model indicated that model predictions are particularly sensitive to the original base modulus, geosynthetic properties (including confined geosynthetic stiffness and the stiffness of the soil-geosynthetic composite) and the thickness of the geosynthetic influence zone.Civil, Architectural, and Environmental Engineerin

HIV-Positive-to-HIV-Positive Liver Transplantation.

Most countries exclude human immunodeficiency virus (HIV)-positive patients from organ donation because of concerns regarding donor-derived HIV transmission. The Swiss Federal Act on Transplantation has allowed organ transplantation between HIV-positive donors and recipients since 2007. We report the successful liver transplantation from an HIV-positive donor to an HIV-positive recipient. Both donor and recipient had been treated for many years with antiretroviral therapy and harbored multidrug-resistant viruses. Five months after transplantation, HIV viremia remains undetectable. This observation supports the inclusion of appropriate HIV-positive donors for transplants specifically allocated to HIV-positive recipients