Clyde D. Ford

Recurrent Clostridium difficile infection (CDI) is a consequence of intestinal dysbiosis and is particularly common following hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) is an effective method of treating CDI by correcting intestinal dysbiosis by passive transfer of healthy donor microflora. FMT has not been widely used in immunocompromised patients, including HSCT recipients, owing to concern for donor-derived infection. Here, we describe initial results of an FMT program for CDI at a US HSCT center. Seven HSCT recipients underwent FMT between February 2015 and February 2016. Mean time post HSCT was 635 days (25-75 interquartile range [IQR] 38-791). Five of the patients (71.4%) were on immunosuppressive therapy at FMT; 4 had required long-term suppressive oral vancomycin therapy because of immediate recurrence after antibiotic cessation. Stool donors underwent comprehensive health and behavioral screening and laboratory testing of serum and stool for 32 potential pathogens. FMT was administered via the naso-jejunal route in 6 of the 7 patients. Mean follow-up was 265 days (IQR 51-288). Minor post-FMT adverse effects included self-limited bloating and urgency. One patient was suspected of having post-FMT small intestinal bacterial overgrowth. No serious adverse events were noted and all-cause mortality was 0%. Six of 7 (85.7%) patients had no recurrence; 1 patient recurred at day 156 post FMT after taking an oral antibiotic and required repeat FMT, after which no recurrence has occurred. Diarrhea was improved in all patients and 1 patient with gastrointestinal graft-versus-host disease was able to taper off systemic immunosuppression after FMT. With careful donor selection and laboratory screening, FMT appears to be a safe and effective therapy for CDI in HSCT patients and may confer additional benefits. Larger studies are necessary to confirm safety and efficacy and explore other possible effects.

Inhibitors of histone deacetylase activity are emerging as a potentially important new class of anticancer agents. In the current studies, exposing A2780 ovarian cancer cells to the histone deacetylase inhibitor trichostatin A (TSA) produced a marked change in cellular morphology, proliferation, and differentiation. Within 24 h of TSA treatment, there was a morphological transformation of the cells, with increased cytoplasm, a more epithelial-like columnar appearance, and the emergence of distinct cellular boundaries. Commensurate with the morphological transformation, TSA also inhibited cell proliferation; cells treated with TSA for 72 h increased to 110% of the initial cell numbers versus control cell numbers of 622%, with a corresponding reduction in mitotic activity and a flow cytometry S-phase fraction of 3.9% in TSA-treated cells versus 28.8% for control. TSA also induced epithelial-like differentiation with increased cytokeratin expression from 2% of controls to 22-25% of TSA-treated cells and the reappearance of intercellular plasma membrane junctions and primitive microvilli. Immunocytochemical analyses indicate the molecular mechanism underlying the actions of TSA on A2780 cell cycle progression and differentiation involves reexpression of the CDK inhibitor p21. Elevated levels of p21, in TSA-treated cells, were associated with a reduction in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). TSA also caused a decrease in the helix-loop-helix inhibitor of differentiation/DNA binding protein Id1, with no change in Id2 levels. In conclusion, the observed TSA-induced changes in p21, Rb, and Id1 are consistent with cell cycle senescence and differentiation of A2780 ovarian cancer cells.

OBJECTIVE To determine the frequency, risk factors, and outcomes for vancomycin-resistant Enterococcus (VRE) colonization and infection in patients with newly diagnosed acute leukemia. DESIGN Retrospective clinical study with VRE molecular strain typing. SETTING A regional referral center for acute leukemia. PATIENTS Two hundred fourteen consecutive patients with newly diagnosed acute leukemia between 2006 and 2012. METHODS All patients had a culture of first stool and weekly surveillance for VRE. Clinical data were abstracted from the Intermountain Healthcare electronic data warehouse. VRE molecular typing was performed utilizing the semi-automated DiversiLab System. RESULTS The rate of VRE colonization was directly proportional to length of stay and was higher in patients with acute lymphoblastic leukemia. Risk factors associated with colonization include administration of corticosteroids (P=0.004) and carbapenems (P=0.009). Neither a colonized prior room occupant nor an increased unit colonization pressure affected colonization risk. Colonized patients with acute myelogenous leukemia had an increased risk of VRE bloodstream infection (BSI, P=0.002). Other risk factors for VRE BSI include severe neutropenia (P=0.04) and diarrhea (P=0.008). Fifty-eight percent of BSI isolates were identical or related by molecular typing. Eighty-nine percent of bloodstream isolates were identical or related to stool isolates identified by surveillance cultures. VRE BSI was associated with increased costs (P=0.0003) and possibly mortality. CONCLUSIONS VRE colonization has important consequences for patients with acute myelogenous leukemia undergoing induction therapy. For febrile neutropenic patients with acute myelogenous leukemia, use of empirical antibiotic regimens that avoid carbapenems and include VRE coverage may be helpful in decreasing the risks associated with VRE BSI.