Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

INTRODUCTION: Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. METHODS: This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. RESULTS: Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2% vs. 9.5%, p = .03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3% vs 7.7%, p = .56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. CONCLUSION: This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.

Safety of Valganciclovir 450 mg 3 Times Weekly for Cytomegalovirus Prophylaxis in Solid Organ Transplant Recipients Requiring Hemodialysis.

BACKGROUND: Valganciclovir is the most commonly used antiviral for cytomegalovirus (CMV) prophylaxis in solid organ transplant recipients. However, there are limited clinical outcomes-supported data available to guide valganciclovir dosing in patients on hemodialysis (HD). This study aimed to assess the safety of our institution's current dosing strategy of valganciclovir 450 mg 3 times weekly post-HD. METHODS: This was a single-center retrospective review of all adult nonkidney transplant recipients between May 2016 and June 2018. Patients with end-stage renal disease requiring HD for >28 days posttransplant receiving valganciclovir 450 mg 3 times weekly post-HD were matched with non-HD patients receiving valganciclovir prophylaxis dosed per renal function. The primary endpoints were incidence of leukopenia, neutropenia, and thrombocytopenia while on valganciclovir prophylaxis. RESULTS: A total of 465 nonkidney transplants were performed during the study period, with 37 patients included in the HD group who were matched to 111 control patients in the non-HD group. Liver transplant recipients comprised 84% and 72% of each group, with none being CMV D+/R-. The rates of leukopenia (51.4% vs 51.4%, P = 1.00), severe neutropenia (absolute neutrophil count <500 cells/µL, 15.8% vs 14.0%, P = .85), and thrombocytopenia (24.3% vs 20.7%, P = .64) were similar in both HD and non-HD groups. There were no cases of CMV infection while on valganciclovir prophylaxis in either group. CONCLUSIONS: Valganciclovir 450 mg 3 times weekly was found to have similar rates of leukopenia, neutropenia, thrombocytopenia, and CMV infection in comparison to valganciclovir dosed per renal function in non-HD transplant recipients.

Assessment of Carfilzomib Treatment Response in Lung Transplant Recipients With Antibody-mediated Rejection.

Data supporting the use of carfilzomib (CFZ) for treatment of antibody-mediated rejection (AMR) in lung transplantation in combination with plasmapheresis and intravenous immunoglobulin suggest positive outcomes through donor-specific antibody (DSA) depletion or conversion to noncomplement-activating antibodies. Herein, we describe our center's experience treating AMR with CFZ. METHODS: All patients treated with CFZ for AMR from 2014 to 2019 were included. The primary outcome was a positive response to CFZ was defined as: (1) loss of DSA C1q-fixing ability after last CFZ dose; (2) clearance of de novo DSA; or (3) decrease in de novo DSA mean fluorescence intensity of >3000. RESULTS: Twenty-eight patients with 31 AMR episodes were treated with CFZ. A positive response was observed in 74.4% of AMR episodes and 82.1% of patients. This response was driven by loss of complement 1q fixation (70.6%), elimination of class I DSAs (78.6%), and reduction in both classes I (median 2815, 79.5% reduction from baseline) and II DSA mean fluorescence intensity (3171, 37.1%). CONCLUSIONS: CFZ shows potential for ameliorating AMR; however, additional studies are needed to define optimal time of administration.

A metabolomics-guided approach to discover Fusarium graminearum metabolites after removal of a repressive histone modification.

Many secondary metabolites are produced by biosynthetic gene clusters (BGCs) that are repressed during standard growth conditions, which complicates the discovery of novel bioactive compounds. In the genus Fusarium, many BGCs reside in chromatin enriched for trimethylated histone 3 lysine 27 (H3K27me3), a modification correlated with transcriptional gene silencing. Here we report on our progress in assigning metabolites to genes by using a strain lacking the H3K27 methyltransferase, Kmt6. To guide isolation efforts, we coupled genetics to multivariate analysis of liquid chromatography-mass spectrometry (LCMS) data from both wild type and kmt6, which allowed identification of compounds previously unknown from F. graminearum. We found low molecular weight, amino acid-derived metabolites (N-ethyl anthranilic acid, N-phenethylacetamide, N-acetyltryptamine). We identified one new compound, protofusarin, as derived from fusarin biosynthesis. Similarly, we isolated large amounts of fusaristatin A, gibepyrone A, and fusarpyrones A and B, simply by using the kmt6 mutant, instead of having to optimize growth media. To increase the abundance of metabolites underrepresented in wild type, we generated kmt6 fus1 double mutants and discovered tricinolone and tricinolonoic acid, two new sesquiterpenes belonging to the tricindiol class. Our approach allows rapid visualization and analyses of the genetically induced changes in metabolite production, and discovery of new molecules by a combination of chemical and genetic dereplication. Of 22 fungal metabolites identified here, 10 compounds had not been reported from F. graminearum before. We show that activating silent metabolic pathways by mutation of a repressive chromatin modification enzyme can result in the discovery of new chemistry even in a well-studied organism, and helps to connect new or known small molecules to the BGCs responsible for their production.

Assessing treatment and monitoring of musculoskeletal conditions using opioid versus nonopioid therapy: A cross-sectional study.

The purpose of this study is to examine the treatment of noncancer musculoskeletal pain in different clinical settings by assessing patient demographics, pain diagnoses, opioid analgesic monitoring, and alternative treatments.Data was collected in a retrospective chart review involving 300 randomly selected charts with an active musculoskeletal diagnosis based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes. The population consisted of primary care outpatient clinic and emergency department encounters during the timeframe of January 1, 2016 to March 31, 2016 in a predominantly rural community in Michigan. Variables included prescription medications, musculoskeletal conditions, and prescription drug monitoring modalities. Statistical analysis was accomplished using means, standard deviations, proportions, 2-sample proportional tests, multivariable logistic regression, and multinomial regression models.Opioid prescribing was observed in 64% of outpatient and 68.9% of emergency department encounters. Back pain was the most common problem with 61.9% patients prescribed opioids having at least 1 diagnosis of back pain. Patients on opioids were older (mean age 58) than patients taking nonopioids (mean age 50). For every year of increasing age, there is a 3.1% increase in the odds of an opioid being prescribed (odds ratio 1.03, confidence interval 1.012-1.049, P = .001). Documentation was extremely low with only 15.2%, 1.5%, and 1.5% of patient charts prescribed opioids demonstrating documentation of urine drug screens, pain agreements, and review of a state prescription drug monitoring program, respectively.Despite drug monitoring recommendations, low rates of monitoring were observed. Back pain was the largest contributing pain location and had higher opioid use compared to other sites. Many patients had additional pain medications being concurrently prescribed with opioids suggesting that musculoskeletal pain is not often controlled by a single medication type. Reported alcohol abuse, active tobacco use, and illicit substance use can serve as predictors when assessing patients for pain management options. The use of alternative measures and integrative treatment modalities (which saw low utilization in this study) should be implemented as either primary or supplementary therapy as a way to reduce the pharmacologic burden on the patient.

Phosphine-mediated partial reduction of alkynes to form both (E)- and (Z)-alkenes.

A mild, phosphine-mediated partial reduction of alkynyl carbonyls to the corresponding alkenes was developed. Tuning of the reaction conditions led to either the (E)- or (Z)-diastereomer with high selectivity. A range of alkynyl esters, amides, and ketones were reduced to form alkenes in good to high yields and with excellent functional group tolerance.

Safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infections: A single-center study.

BACKGROUND: Infection with cytomegalovirus (CMV) is an important cause of morbidity and mortality following solid organ transplantation. Resistance to ganciclovir can rarely develop via mutations in UL97 or UL54. There are limited published studies assessing the safety and efficacy of foscarnet for the management of ganciclovir-resistant or refractory cytomegalovirus infection and many centers are reluctant to utilize this important therapy because of concerns about toxicity. METHODS: Solid organ recipients transplanted between January 1, 2006 and December 31, 2014 who received at least 1 dose of foscarnet were retrospectively reviewed to assess treatment outcomes, tolerability, and safety of foscarnet. RESULTS: Ten of 31 (32.3%) patients who received foscarnet during the study period died during treatment with foscarnet, whereas all 21 surviving recipients successfully cleared infection. Of these surviving patients, 3 (14.3%) developed significant renal dysfunction, defined as >25% decline in estimated glomerular filtration rate during treatment; one-third had definitive renal biopsy results consistent with foscarnet-induced toxicity. CONCLUSION: Although mortality was high in this population, foscarnet use, with proper precautions, was generally safe and significant renal dysfunction was lower than previously reported in other sources, even with extended use.