Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.

IMPORTANCE: Clostridium difficile infection (CDI) is a major burden in health care and community settings. CDI recurrence is of particular concern because of limited treatment options and associated clinical and infection control issues. Fecal microbiota transplantation (FMT) is a promising, but not readily available, intervention. OBJECTIVE: To determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada. INTERVENTIONS: Patients were randomly allocated to receive frozen (n = 114) or fresh (n = 118) FMT via enema. MAIN OUTCOMES AND MEASURES: The primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events. Noninferiority margin was set at 15%. RESULTS: A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population. In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, -1.6% [95% CI, -10.5% to ∞]; P = .01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, -5.2% to ∞]; P < .001 for noninferiority). There were no differences in the proportion of adverse or serious adverse events between the treatment groups. CONCLUSIONS AND RELEVANCE: Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea. Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01398969.

Structure-Activity Relationship Studies of a Series of Semisynthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridium difficile-Associated Diarrhea.

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 µg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

Infectious diarrhea: an overview.

Diarrheal disease, which is most often caused by infectious pathogens, is a significant cause of morbidity and mortality worldwide, especially in children. This is particularly true in developing countries. Recent outbreaks of infectious diarrhea in developed countries, including the USA, are often attributed to food handling and distribution practices and highlight the need for continued vigilance in this area. Another common cause of infectious diarrhea, Clostridium difficile infection (CDI), has historically been associated with the use of antibiotics and exposure to a health-care setting but is now increasingly common in the community in persons who lack the typical risk factors. Recent scientific advances have also led to new and proposed new therapies for infectious diarrhea, including fecal microbiota transplant (FMT) for recurrent C. difficile infection (RCDI), probiotics for prevention of antibiotic-associated diarrhea (AAD) and CDI, and the use of zinc supplementation in the treatment of acute diarrhea in children. Other therapies that have been in use for decades, such as the oral rehydration solution (ORS), continue to be the targets of scientific advancement in an effort to improve delivery and efficacy. Finally, post-infectious irritable bowel syndrome (PI-IBS) is an increasingly recognized occurrence. Attempts to understand the mechanism behind this phenomenon are underway and may provide insight into potential treatment options.

Colonic decompression and direct intraluminal medical therapy for Clostridium difficile-associated megacolon using a tube placed endoscopically in the proximal colon.

AIM: Urgent colectomy for severe Clostridium difficile infection can be associated with increased morbidity and mortality. We aimed to use endoscopic methods for treatment. METHOD: We describe a technique of placing an intracolonic tube facilitating decompression and direct delivery of vancomycin to the proximal colon along with enemas on a regular and frequent basis that may not be possible with vancomycin enemas alone. RESULTS: Successful resolution of the C. difficile infection and avoidance of surgery. CONCLUSION: While further long-term evaluation is required, our initial results have shown it to be effective in treating select patients with recalcitrant Clostridium difficile-associated megacolon.

A severe case of rat lungworm disease in Hawa'i.

A 23-year-old man living on the island of Hawa'i developed a life threatening case of eosinophilic meningitis caused by infection with Angiostrongylus cantonensis (rat lungworm disease: RLWD). He was comatose for 3 months, incurring brain and nerve damage sufficiently extensive that he was not expected to recover. The case was complicated by secondary infections of methicillin-resistant Staphylococcus aureus, Clostridium difficile, and pneumonia, which resulted in an empyema requiring a thoracoscopy and decortication. He was treated with prednisone, mebendozal, and pain medication for RLWD, and antibiotics and antifungal medications for the secondary infections. The administration of herbal supplements was requested by the family and approved, and these were administered through a gastric tube. Less than a month after being declared in a persistent vegetative state the man was able to talk, eat, and had regained some muscle functions. After release from the hospital he continued the use of supplements and received treatments of intravenous vitamin therapy. Four years after onset of the illness he is able to ride a bicycle, is a part time student, plays guitar, and is fluent in two foreign languages. RLWD is an emerging tropical disease of growing importance in Hawa'i.

Intracolonic use of vancomycin for treatment of clostridium difficile colitis in a patient with a diverted colon: report of a case.

Clostridium difficile-associated pseudomembranous colitis (PMC) is a common affliction of postoperative patients. Risk factors include antibiotic therapy, recent surgery, and hospitalization (1,2,3). We present a case of PMC in a diverted colon and its treatment using vancomycin enemas.

Pseudomembranous colitis without diarrhea presenting clinically as acute intestinal pseudo-obstruction.

Pseudomembranous colitis usually presents with diarrhea in a clinical setting of recent antibiotic use. It is uncommon to see it as a cause of obstipation and colonic pseudo-obstruction. We report an unusual case of an elderly woman with hypertension, congestive heart failure, chronic obstructive pulmonary disease, chronic renal insufficiency, and diabetes mellitus, who was admitted with fever, abdominal pain, and distension without diarrhea. She presented with decreased stool frequency and obstipation. She did not respond to conservative management. Colonoscopy revealed a picture of pseudomembranous colitis, and Clostridium difficile toxin was positive. She responded well to metronidazole therapy.

Tiflitis aguda: a propósito de un caso / Acute typhlitis: a case report

Se presenta un caso clínico de un paciente varón de 51 años que ingresó en nuestro hospital por presentar rectorragia. En el enema opaco se apreció una imagen de defecto de repleción en el ciego y en la colonoscopia una masa cecal necrosada que posteriormente expulsó con la defecación, siendo el resultado histopatológico de necrosis. Se decidió realizar una laparotomía exploradora encontrando como hallazgos significativos la inflamación de todo el ciego y del apéndice, así como la escara de implantación del pólipo expulsado y una masa submucosa paraapendicular, por lo cual se continuó la intervención con una hemicolectomía derecha. El diagnóstico de anatomía patológica fue de tiflitis aguda, una rara enfermedad cecal de la cual comentaremos algunos aspectos (AU)

Rickets of premature infants induced by calcium deficiency. A case report.

Rickets of prematurity is not uncommon in neonatal intensive care units. Nutritional rickets in childhood is usually caused by vitamin D deficiency, but the rickets of prematurity is mainly attributable to calcium and phosphorus deficiencies. We present a premature infant with sequelae of necrotizing enterocolitis who needed prolonged administration of total parenteral nutrition (TPN), and who sustained ricketic fracture. After high calcium-fortified TPN supplementation the fracture healed well, and serum alkaline phosphatase dropped. This finding shows (1) serum calcium and phosphorus levels are of predictive value regarding rickets, (2) regular follow-ups of alkaline phosphatase levels combined with radiography in high-risk groups of premature infants are good tools for monitoring rickets, and (3) prolonged TPN administration needs to contain higher calcium and phosphorus concentrations in prematurity than in childhood.

[Intestinal stenosis during ulceronecrotizing enterocolitis]. / Sténoses intestinales au cours des entérocolites ulcéronécrosantes.

BACKGROUND: Intestinal stenosis following necrotizing enterocolitis (NE) occurred both in surgically-treated neonates after perforation, distal to an enterostomy and in medically-treated patients developing symptoms of obstruction. It has been proposed to detect stenosis by contrast enema before refeeding in those medically-treated patients. The aim of this study was to compare delay, clinical and pathological characteristics of surgical and medical patients, both after occlusion and prospective contrast studies. PATIENTS AND METHODS: Fifteen patients out of 50 with NE observed from 1984 to 1994 developed one or several intestinal stenosis. Diagnosis of NE was based on usual clinical signs, X-ray pneumatosis (43 to 50) and/or perforation in 16 cases. Among these 16 surgical patients, 12 survived the initial perforation. Among the 34 medical patients, 11 were seen before 1989 and did not have contrast studies before refeeding; 23 seen after 1989 had a contrast enema before. RESULTS: One or several stenosis occurred in four out of 12 surgical patients, four out of 11 medical patients without prospective contrast studies (one of them died from sepsis) and seven out of the 23 of the prospective group. On the whole, 26 stenosis occurred in 15 neonates: ten to the right colon, five to the transverse and 11 to the left colon. One ileal stenosis followed enterostomy. Delay of stenosis development was comparable in the three groups (between 3 weeks and 3 months). Pathologic examination showed similar lesions in the three groups (fibrosis 15, edema nine to 15 and chronic inflammation 12 to 15). CONCLUSION: Among 46 neonates who survived the initial period, 15 developed stenosis, a 30% proportion similar in patients operated on for perforation or in medically-treated patients whose diagnosis was made after occlusion or after contrast enema as well. These results suggest that systematic stenosis detection by contrast enema may avoid complications and permit programmed one-stage surgery.

[Selenium deficiency favors the appearance of heart failure after multiple injury]. / Carence en sélénium favorisant la survenue d'une défaillance cardiaque après un polytraumatisme.

A 47-year-old multiple trauma patient, experiencing a C. Difficile colitis with diarrhoea, developed diffuse oedema with peritoneal and pleural effusion due to global heart failure. Selenium deficiency, reported in trauma patients, may explain the occurrence of cardiomyopathy. The role of selenium in cardiac dysfunction and the various situations inducing a selenium deficiency are discussed.

Enterocolonic fistula, a rare complication of necrotizing enterocolitis.

A case of an enterocolonic fistula as a late complication of necrotizing enterocolitis is presented in a 3-month-old premature baby. The fistula was diagnosed by contrast enema. We describe the typical features of this rare complication.

Is it necrotizing enterocolitis, microcolon of prematurity, or delayed meconium plug? A dilemma in the tiny premature infant.

Failure of a small premature newborn to adequately evacuate meconium for days or weeks has been attributed to "probable necrotizing enterocolitis (NEC)" or "microcolon of prematurity." The authors present an unusual type of "meconium plug syndrome" with the same clinical picture, seen in tiny premature babies (500 to 1,500 g), which required a contrast enema or Gastrografin upper gastrointestinal (UGI) series to evacuate the plugs. The obstruction resolved. Twenty babies (480 to 1,500 g) presented with the same clinical picture without any x-ray suggestion of NEC; contrast enemas were performed because of the suspicion of meconium plug syndrome. All 20 had extensive meconium plugs that were evacuated by the enema or by a Gastrografin UGI series. Most of them improved after the plugs were passed. These infants differ from typical full-term babies with meconium plug syndrome in a number of ways: (1) many of the mothers were on magnesium sulfate (MgSO4) or had eclampsia; (2) the plugs were diagnosed late rather than shortly after birth; and (3) the plugs were significant, extending to the right colon. The authors believe that when a tiny premature baby has findings consistent with meconium plug syndrome, the baby should be transported to radiology, for a Gastrografin enema, despite the difficulties involved. Delay postpones the start of feedings, and increases the number of radiographic studies.

Toxic megacolon complicating pseudomembranous enterocolitis.

PURPOSE: Toxic megacolon is a rare complication of pseudomembranous enterocolitis. We reviewed our recent experience with this complication. METHODS: The first five patients of the series were studied retrospectively, and six others were followed prospectively. RESULTS: Between June 1992 and May 1994, 11 patients (8 male, 3 female) developed toxic megacolon secondary to pseudomembranous enterocolitis. Mean age was 60.7 +/- 11.8 (range, 40-79) years. Presenting symptoms and signs included diarrhea, 100 percent; malaise, 91 percent; abdominal pain, 82 percent; abdominal distention, 82 percent; abdominal tenderness, 72 percent; anemia less than 12 gm, 72 percent; albumin less than 3 gm, 64 percent; tachycardia greater than 100, 55 percent; fever greater than 38.5 degrees celsius, 45 percent; shock or hypotension, 45 percent. Predisposing factors included antibiotics, 64 percent; immunosuppressants or chemotherapy, 36 percent; antidiarrheals, 27 percent; and barium enema in one patient. Five patients (45 percent) had more than one predisposing factor. X-rays showed transverse colon dilation and loss of haustrations in eight patients (72 percent), with a mean diameter of 9.9 +/- 3.4 cm. Flexible proctosigmoidoscopy showed pseudomembranes in all scoped patients, and toxin assay for Clostridium difficile was positive in all patients. One patient had emergency surgery. Ten patients were initially treated medically with nasogastric suction and intravenous resuscitation (90 percent) and antibiotics (100 percent), usually in the intensive care unit (80 percent). Four patients did not respond and underwent surgery; two others improved, then deteriorated, and also underwent surgery. Altogether, 7 of 11 patients (64 percent) underwent surgery. Three patients (27 percent) responded well to medical treatment. One patient was deemed too ill to undergo surgery and died. Mean delay to surgery was 3.0 +/- 1.3 days. No sealed or overt perforation was found at laparotomy. All patients who underwent surgery had a subtotal colectomy, with either a Hartmann's stump (71 percent) or a mucous fistula (29 percent). Eventually, five of seven patients who were operated on and two of four medically treated patients died (overall mortality, 64 percent). Only one patient underwent closure of ileostomy and anastomosis. CONCLUSION: Toxic megacolon complicating pseudomembranous enterocolitis is a serious problem that carries a high morbidity and mortality rate, regardless of treatment.

Vancomycin-dependent Enterococcus faecium isolated from stool following oral vancomycin therapy.

The isolation of clinical strains of enterococci requiring vancomycin for growth has only recently been reported. We describe the isolation of Enterococcus faecium requiring vancomycin for growth from the stool of a patient who had completed oral vancomycin therapy. Growth of the vancomycin-dependent E. faecium was supported by ristocetin and D-alanyl-D-alanine but not by daptomycin, teicoplanin, or D,L-alanine. Spontaneous revertants not requiring vancomycin occurred at a rate of 1 in 10(6). Both the vancomycin-dependent E. faecium and the revertant hybridized with a vanB gene probe and had identical contour-clamped homogeneous electrophoresis patterns. The majority of revertant colonies were resistant to teicoplanin, suggesting constitutive production of the vanB ligase. We believe the vancomycin-dependent E. faecium evolved from a vancomycin-resistant, vancomycin-independent E. faecium in the presence of high concentrations of vancomycin in the intestine.