Postoperative antimicrobials after lung transplantation and the development of multidrug-resistant bacterial and Clostridium difficile infections: an analysis of 500 non-cystic fibrosis lung transplant patients.

BACKGROUND: Broad-spectrum antimicrobials are given prophylactically post-transplant, although these agents are a risk factor for multidrug-resistant (MDR) infections and Clostridium difficile infection (CDI). This study aimed to determine whether an association exists between the duration of antimicrobials given early post-transplant and the development of MDR infections or CDI. METHODS: A single-center retrospective analysis was performed on lung transplants from September 2009 to August 2014. Patients were excluded for cystic fibrosis (CF) or postoperative survival less than 30 d. Qualifying infections were defined as any new positive MDR bacterial culture or C. difficile assay from postoperative day 7-90 d after a broad-spectrum antimicrobial. RESULTS: A total of 500 patients, 61% male, were identified, median age of 62 yr. MDR infections occurred in 169 (34%) and CDI in 31 (6%). Non-ICU days were associated with a decreased risk of MDR/CDI (OR 0.891, p = 0.0002), and duration of Gram-positive antimicrobials (OR 1.073, p = 0.0219) was associated with an increased risk. CONCLUSIONS: One-third (34%) of non-CF lung transplants develop MDR infections and 6% develop CDI within 90 d of postoperative antimicrobials. The duration of Gram-positive antimicrobials may increase the risk of MDR/CDI, while early transfer from the ICU may have a protective effect.

Patients with cirrhosis show a relative increase in thrombin generation that is correlated with lower antithrombin levels.

Predicting the risk of bleeding or thrombosis in cirrhotic patients is difficult due to reduced levels and dysregulation of both procoagulant and anticoagulant factors. We utilized thrombin generation and microvesicle analysis to better understand the regulation of haemostasis in cirrhotic patients. We studied 24 patients with cirrhosis vs. 21 healthy controls. Cirrhotic patients had reduced prothrombin activity (40 ±â€Š9 vs. 112 ±â€Š15), protein C activity (36 ±â€Š10 vs. 114 ±â€Š19) and antithrombin activity (43 ±â€Š14 vs. 109 ±â€Š10). Peak thrombin generation was reduced in cirrhotic patients (165 ±â€Š47 vs. 232 ±â€Š101), but the ratio of peak thrombin generation to prothrombin activity was increased in cirrhotic patients (4.2 ±â€Š1.0 vs. 2.1 ±â€Š0.9) indicating a relative increase in thrombin generation in cirrhosis. The termination time ratio was increased in cirrhotic patients (7.2 ±â€Š1.9 vs. 3.1 ±â€Š0.7) and correlated with reduced antithrombin levels, indicating that cirrhotic patients took longer to stop thrombin generation than controls. Cirrhotic patients showed reduced procoagulant microvesicles from platelets (39 500 ±â€Š24 800 vs. 107 700 ±â€Š74 200) and other cells, but levels overlapped with controls. Cirrhotic patients showed a wide range of procoagulant and anticoagulant levels leading to variability in the regulation of thrombin generation. In conclusion, compared with healthy controls, patients with cirrhosis have lower antithrombin levels that lead to slower downregulation of thrombin generation and more overall thrombin being produced for a given procoagulant level in blood, but also low normal levels of procoagulant microvesicles that would slow initiation of thrombin generation. Whether an individual cirrhosis patient is at a greater risk of bleeding vs. thrombosis may depend on their specific imbalance in procoagulants vs. anticoagulants.

A new epoprostenol formulation for the treatment of pulmonary arterial hypertension.

PURPOSE: The pharmacology and pharmacokinetics of a novel formulation of epoprostenol for the treatment of pulmonary arterial hypertension (PAH) are reviewed, with guidance on addressing a number of important safety considerations. SUMMARY: Epoprostenol is a direct vasodilator of the pulmonary and systemic vasculature indicated for improving exercise capacity in patients with PAH. Veletri, a recently approved formulation of epoprostenol for continuous i.v. infusion, offers increased stability relative to other available epoprostenol products. Therefore, the use of Veletri can lessen the therapy burden associated with the other available formulation of the drug by allowing for the advance preparation of infusion pump cassettes (at certain concentrations) and administration at room temperature without the need for cooling with ice packs. Sterility, however, is of concern with outpatient preparation of epoprostenol-containing cassettes stored for the maximum duration according to stability guidelines. All epoprostenol infusions are classified as high-risk therapies due to complex dosing, the drug's short half-life, and the potential for life-threatening rebound PAH with abrupt discontinuation. Adverse effects reported in ≥10% of participants in clinical trials of Veletri included flushing (58%), headache (49%), nausea or vomiting (32%), hypotension (16%), chest pain (11%), and anxiety, nervousness, or agitation (11%). As with other epoprostenol formulations, the use of Veletri requires an evaluation of health-system medication-use practices to ensure patient safety. CONCLUSION: Veletri provides an epoprostenol therapy option that reduces some of the inconveniences of the other formulation. Drug stability is dependent on cassette concentrations, which may be limited by sterility concerns with outpatient preparation. Use of this new agent within the health system requires an evaluation of practices to ensure patient safety.

Effect of immunosuppression for first kidney or kidney/pancreas transplant on sensitization at the time of second transplant.

BACKGROUND: Previously transplanted patients are more likely to be sensitized, leading to prolonged waitlist times and decreased graft survival. This analysis of the United Network for Organ Sharing kidney/pancreas transplant database investigates factors at the time of first transplant associated with increased sensitization in patients undergoing second transplantation. METHODS: Records of nonsensitized patients (panel reactive antibodies [PRA] <20%) receiving a primary transplant in 1999 or later were analyzed to determine whether immunosuppressive agents at the time of first transplant were associated with a change in PRA from first to second transplant. Variables included gender, race, human leukocyte antigen (HLA) mismatch, rabbit antithymocyte globulin (RATG), interleukin-2 receptor antagonists, tacrolimus (FK), cyclosporine A (CSA), and mycophenolate mofetil/sodium (MMF). RESULTS: For the primary endpoint of increase in PRA greater than or equal to 20%, African Americans (AA) versus non-AA (OR 2.63, P<0.0001) and HLA nonzero mismatch versus zero mismatch (OR 2.90, P<0.0001) were associated with increased sensitization. The effect of immunosuppressive regimen depended on race and HLA status. In non-AAs/HLA mismatch (1-6), interleukin-2 receptor antagonists versus RATG (OR 1.40, P=0.001), CSA versus FK (OR 1.69, P<0.001) and no MMF versus MMF (OR 1.39, P<0.001) were also associated with increased sensitization. In AAs/HLA mismatch (1-6), no induction versus RATG (OR 1.59, P=0.031) and CSA versus FK (OR 1.68, P=0.006) were associated with increased sensitization. CONCLUSIONS: These data suggest a reduced risk of sensitization at the time of second transplant when using more potent immunosuppression with RATG, FK, and MMF for nonsensitized primary kidney or kidney/pancreas transplant patients. These effects seem to be related to race and HLA mismatch.

Cardioprotective medication use after renal transplantation.

Cardiovascular disease is the leading cause of death in renal transplant patients. This study compares the use of cardioprotective medications in adult kidney transplant recipients at a single center with recommendations, which have been validated in the general population. Cardioprotective medication use was retrospectively collected post-renal transplant. Patients were defined as high risk if they had pre-transplant coronary heart disease or equivalent risk. "Optimal" treatment was defined as a patient receiving aspirin, statin, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker, and a beta-blocker according to cardiovascular risk. The percentage of high-risk patients optimally treated at one, three, six, and 12 months was 7.7%, 11.5%, 17.6%, and 18.8%, respectively. Although the use of cardioprotective medications was evident in transplant recipients, opportunities exist to increase the use of optimal cardioprotective regimens after renal transplantation.