A Phase 2 Extension Study Evaluating the Immunogenicity, Safety, and Tolerability of 3 or 4 Doses of a Clostridioides difficile Vaccine in Healthy US Adults Aged 65 to 85 Years.

BACKGROUND: This phase 2 extension explored the long-term antibody persistence of an investigational Clostridioides difficile vaccine and the safety, tolerability, and immunogenicity of dose 4 approximately 12 months post-dose 3. METHODS: One year post-dose 3, healthy US 65- to 85-year-olds (N = 300) were randomized to dose 4 of vaccine at previously received antigen levels (100 or 200 µg) or placebo. Assessments included safety and percentages of participants achieving neutralizing antibody titers above prespecified thresholds (≥219 and ≥2586 neutralization units/mL for toxins A and B, respectively). RESULTS: In participants previously given three 200-µg doses and placebo in the extension, toxin A and B neutralizing antibodies were above prevaccination levels 48 months post-dose 3 (36 months after placebo); 24.0% and 26.0% had toxin A and B antibodies at or above prespecified thresholds, respectively. Neutralizing antibodies increased post-dose 4 (12 months post-dose 3) and persisted to 36 months post-dose 4. Thirty days post-dose 4, all participants had toxin A and 86.5% to 100% had toxin B titers at or above prespecified thresholds. Local reactions were more frequent in vaccine recipients. Systemic and adverse event frequencies were similar across groups. CONCLUSIONS: C difficile vaccine immune responses persisted 48 months post-dose 3. Dose 4 was immunogenic and well tolerated, supporting continued development. Clinical Trials Registration. ClinicalTrials.gov NCT02561195.

A phase 3 study evaluating the lot consistency, immunogenicity, safety, and tolerability of a Clostridioides difficile vaccine in healthy adults 65 to 85 years of age.

BACKGROUND: A toxoid-based Clostridioides difficile vaccine is currently in development. Here, we report lot-to-lot consistency, immunogenicity, safety, and tolerability of 3 C difficile vaccine doses in healthy older adults. METHODS: This phase 3, placebo-controlled study randomized (1:1:1:1) healthy adults 65 to 85 years of age to 1 of 3 C difficile vaccine lots or placebo. Participants received C difficile vaccine (200 µg total toxoid) or placebo (Months 0, 1, 6). The primary immunogenicity objective was lot-to-lot consistency (2-sided 95 % CIs within 0.5 and 2 for comparisons of geometric mean concentration [GMC] ratios) for toxins A- and B-specific neutralizing antibody levels 1 month after Dose 3. Safety outcomes included local reactions and systemic events ≤7 days after vaccination, adverse events (AEs), and serious AEs (SAEs). RESULTS: Of 1317 enrolled participants, 1218 completed the study. C difficile vaccine immunogenicity was consistent across lots, with neutralizing antibody responses 1 month after Dose 3 for both toxin A (GMC [95 % CI]: lot 1, 878.8 [786.3, 982.2]; lot 2, 873.0 [779.2, 978.1]; lot 3, 872.9 [782.6, 973.5]) and toxin B (lot 1, 5823.9 [5041.0, 6728.4]; lot 2, 5462.8 [4733.4, 6304.7]; lot 3, 5426.0 [4724.4, 6231.8]). Two-sided 95 % CIs for GMC ratios were within 0.5 and 2 for toxins A and B, indicating lot-to-lot consistency was achieved. C difficile vaccine was well tolerated, with similar rates of local reactions and systemic events among vaccine lots. AE and SAE rates were similar across C difficile vaccine (36.5 % and 4.5 %, respectively) and placebo (35.3 % and 6 %). CONCLUSIONS: Three doses (Months 0,1,6) of toxoid-based C difficile vaccine induced robust neutralizing antibody responses and were well tolerated in healthy participants 65 to 85 years of age. Lot-to-lot consistency was excellent, indicating the manufacturing process for this C difficile vaccine formulation was well controlled. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03579459.

The effect of fiber supplementation on the prevention of diarrhea in hospitalized patients receiving enteral nutrition: A meta-analysis of randomized controlled trials with the GRADE assessment.

Introduction: Enteral nutrition (EN) in hospitalized patients has several advantages. However, post-feeding diarrhea occurs frequently and has been linked to negative outcomes. The EN formula itself may have an impact on how diarrhea develops, and fiber supplements may theoretically help patients experience less diarrhea. This study aimed to thoroughly evaluate whether adding fiber to EN decreases the likelihood of developing diarrhea and whether different types of fibers pose different effects on diarrhea (PROSPERO CRD 42021279971). Methods: We conducted a meta-analysis on fiber supplementation in hospitalized adult patients receiving EN. We thoroughly searched PubMed, Medline, Embase, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov databases from inception to 1 September 2022. Only randomized controlled trials (RCTs) were included. Pooled results on the incidence of diarrhea were calculated using a random-effects model. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was applied. Only fiber types from soy polysaccharides (n = 4), psyllium (n = 3), mixed soluble/insoluble fiber (mixed fiber, n = 3), pectin (n = 2), and partially hydrolyzed guar gum (PHGG, n = 2) were examined in the sensitivity analysis. Results: Among the 4,469 titles found, a total of 16 RCTs were included. Overall, compared to fiber-free formulas, fiber supplementation reduced the occurrence of diarrhea in patients receiving EN by 36% (pooled risk ratio [RR] of 0.64 [95% confidence interval (CI): 0.49-0.82, p = 0.005; I 2 = 45%]), with GRADE showing the evidence of moderate certainty. Only mixed fiber and PHGG significantly decreased the incidence of diarrhea according to the sensitivity analyses for fiber types (RR 0.54, 95%CI: 0.39-0.75, I 2 = 0% and RR 0.47, 95%CI: 0.27-0.83, I 2 = 0%, respectively). The results for the remaining fiber types were unclear. Conclusion: According to a meta-analysis, fiber supplements help lessen post-feeding diarrhea in hospitalized patients receiving EN. However, not all fiber types produced successful outcomes. Diarrhea was significantly reduced by PHGG and mixed soluble/insoluble fiber. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=279971, identifier: PROSPERO CRD 42021279971.

Evaluation of an immunochromatographic test for the detection of glutamate dehydrogenase for the diagnosis of Clostridioides (Clostridium) difficile infection in dogs.

This study aimed to evaluate an immunochromatographic test used to detect glutamate dehydrogenase (GDH) for the diagnosis of Clostridium difficile infection (CDI) in dogs. Fecal samples of 119 diarrheic dogs were subjected to toxigenic culture as the "gold standard" method and to GDH detection (Ecodiagnostica, Brazil). Samples positive for toxigenic C. difficile strains and those positive in the GDH test were also subjected to A/B toxin detection using an enzyme immunoassay kit (C. difficile Tox A/B II, Techlab Inc., USA). Sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were measured for GDH detection and compared with the toxigenic culture results. A total of 19 (15.9%) dogs were positive for toxigenic C. difficile. Of these, 10 (52.6%) dogs were positive for A/B toxins using the enzyme immunoassay kit and 18 (15.2%) were positive in the GDH test, leading to a sensitivity and NPV of 89.4% and 97.9%, respectively. Three animals, two of which were colonized with non-toxigenic strains, were positive for GDH, though not confirmed with CDI, resulting in a high specificity (97%) and PPV (85%). The results suggest that the lateral flow test for GDH detection could be a useful method for diagnosing CDI in dogs, similar to that previously described for humans and other animal species.

Safety and immunogenicity of different Clostridioides (Clostridium) difficile vaccine formulations in two early phase randomized studies of healthy adults aged 50-85 years.

BACKGROUND: Two phase 1/phase 2 studies assessed 2 formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) in healthy adults 50-85 years of age. METHODS: The QS-21 adjuvanted toxoid vaccine study randomized subjects 3:1 to 100 µg QS-21-containing C difficile vaccine or placebo administered in a shortened-month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 µg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (Days 1, 8, 30). Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A- and B-specific neutralizing antibodies. RESULTS: In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%-75.0% and 16.7%-50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen) and remained above baseline throughout follow-up. CONCLUSIONS: Both formulations demonstrated robust immunogenicity. Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies.

Methicillin-Resistant Staphylococcus aureus-Associated Diarrhea in a Critically Ill Burn Patient.

Described in surgical patients after antibiotic use in the 1950s and 1960s, Staphylococcus aureus (S. aureus) enterocolitis is a rare form of nosocomial diarrhea. However, S. aureus is not routinely tested like Clostridium difficile (C. difficile). We report a case of methicillin-resistant S. aureus (MRSA) enterocolitis found on stool culture in a 22-week pregnant female with a previously negative nasal MRSA culture, and a total burn surface area greater than 60%. She also developed necrotizing MRSA pneumonia and bacteremia. After starting broad-spectrum antibiotic for the necrotizing pneumonia with subsequent acute respiratory distress syndrome, the patient exhibited large voluminous diarrhea that tested positive for MRSA and negative for C. difficile in the stool culture. Similar to other reports of high-volume diarrhea, the diarrhea resolved quickly with enteral vancomycin. S. aureus should be considered along with C. difficile during the workup of nosocomial diarrhea, especially with exposure to broad-spectrum antibiotics in the critically ill patient.

Diarrhea in tube-fed hospitalized patients: Feeding formula is not the most common cause.

BACKGROUND AND AIM: Clostridium difficile-associated diarrhea (CDAD) and enteral nutrition (EN)-associated diarrhea are the most common recognized etiologies of nosocomial diarrhea. However, in clinical practice, the data regarding how each etiology contributes to the diarrheal episodes are limited. We identify the causes and factors associated with post-feeding diarrhea. METHODS: Using the data of patients enrolled in "Effect of Psyllium Fiber Supplementation on Diarrhea Incidence in Enteral Tube-Fed Patients: A Prospective, Randomized, and Controlled Trial", the randomized controlled trial showed no difference in diarrheal incidences between fiber-added and fiber-free formulas. Hence, we analyzed the data of all enrolled patients. The causes of diarrhea were classified according to pre-specified definitions. The factors associated with diarrhea were analyzed using logistic regression. RESULTS: Diarrhea was found in 37.3% (n = 31/83). The most common cause was medication associated (61.3%). CDAD and EN-associated diarrhea were found in only 9.7% and 6.5%, respectively. Patients with baseline albumin <3 g/dL and underlying cerebrovascular disease were more likely to develop diarrhea (adjusted odds ratio 5.70, 95% confidence interval 1.79-20.51, and adjusted odds ratio 10.83, 95% confidence interval 2.96-48.57, respectively). Compared with those without diarrhea, the length of hospital stay in CDAD patients was significantly longer (+23.1 days, P = 0.02), a trend of longer hospital stay in patients with diarrhea from other causes was observed (+3.2 days, P = 0.096). CONCLUSIONS: Our study found that the most common cause of post-feeding diarrhea is medication associated. Review and cessation of possible drugs should be undertaken before EN modification. CDAD accounts for <10% of diarrhea causes, but it impacts the clinical outcome and should be identified and treated properly.

Evaluation of glutamate dehydrogenase (GDH) and toxin A/B rapid tests for Clostridioides (prev. Clostridium) difficile diagnosis in a university hospital in Minas Gerais, Brazil.

Clostridioides (Clostridium) difficile is responsible for most cases of nosocomial diarrhea and, despite the high prevalence of the disease worldwide, the best laboratory diagnostic approach to diagnose C. difficile infection (CDI) is a subject of ongoing debate. Although the use of multiple tests is recommended, the cost of these algorithms commonly exceeds the affordability in some countries. Thus, to improve CDI diagnosis in a university hospital in Brazil, this study analyzed two immunochromatographic tests and one enzyme immunoassay (ELISA) to evaluate the detection of glutamate dehydrogenase (GDH) and A/B toxins of C. difficile. Stool samples of 89 adult patients presenting nosocomial diarrhea during hospitalization were included. The toxigenic culture was used as the reference method. GDH detection by both commercial tests showed high sensitivity (100%) and specificity (92.1%). On the other hand, toxin-based methods showed a sensitivity between 19.2 and 57.7%. In conclusion, the results suggest that rapid tests for GDH detection are not only suitable for CDI diagnosis as screening tests but also as a single method.

Immunochromatographic test and ELISA for the detection of glutamate dehydrogenase (GDH) and A/B toxins as an alternative for the diagnosis of Clostridioides (Clostridium) difficile-associated diarrhea in foals and neonatal piglets.

Considering the lack of studies evaluating the performance of commercially available methods for diagnosis of Clostridioides (Clostridium) difficile infection (CDI) in animals, the present study aimed to assess an immunochromatographic test for detection of glutamate dehydrogenase (GDH) and A/B toxins of C. difficile, also evaluated by an ELISA kit, in foals and neonatal piglets. Intestinal contents of 47 piglets and feces of 35 foals were tested to GDH antigen and A/B toxins in a lateral flow method (Ecodiagnostica, Brazil). Also, these samples were submitted to A/B toxin detection by an ELISA kit (C. difficile Tox A/B II, Techlab Inc., USA), using the toxigenic culture (TC) as the reference method. The GDH component of the lateral flow test showed sensitivity and negative predictive value (NPV) of 100% and a high specificity in samples of piglets (82.61%) and foals (100%). Detection of A/B toxins using the lateral flow test and the ELISA resulted in a specificity of 100% in samples of both species. On the other hand, the sensibility ranged from 54.2 to 90% for the ELISA and from 12.5 to 60% for the lateral flow test for piglets' and foals' samples, respectively. In conclusion, the present work suggests that the lateral flow test for GDH detection could be a useful method for diagnosing CDI in these species. On the other hand, the low sensitivity of the lateral flow test for A/B toxins might compromise its utility in piglets.

A Phase 2 Study Evaluating the Safety, Tolerability, and Immunogenicity of Two 3-Dose Regimens of a Clostridium difficile Vaccine in Healthy US Adults Aged 65 to 85 Years.

BACKGROUND: Clostridium difficile causes toxin-mediated nosocomial diarrhea and community-acquired infections; no preventive vaccine is licensed. In this phase 2 study, we explored safety, tolerability, and immunogenicity in older US adults of an investigational bivalent C. difficile vaccine that contains equal dosages of genetically and chemically detoxified toxins A and B. METHODS: Conducted from July 2015 through March 2017, 855 healthy adults aged 65-85 years from 15 US centers were randomized 3:3:1 to receive vaccine (100 or 200 µg) or placebo at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). Serum toxin A- and B-specific neutralizing antibodies were measured. Participant-reported local reactions (LRs) and systemic events (SEs), adverse events (AEs), serious AEs, newly diagnosed chronic medical conditions, and immediate AEs were recorded. RESULTS: The 200-µg dose level elicited higher immune responses than the 100-µg dose level across regimens. Compared with the day regimen, the month regimen induced stronger and more persistent immune responses that remained elevated 12 months after dose 3. Responses peaked at month 7 (month regimen) and day 37 (day regimen). LRs (primarily injection site pain) were more frequent in vaccine recipients than controls; SE frequency was similar across groups. More related AEs were reported in the day regimen group than the month regimen group. CONCLUSIONS: The C. difficile vaccine was safe, well tolerated, and immunogenic in healthy US adults aged 65-85 years. Immune responses were particularly robust in the 200-µg month regimen group. These results support continued vaccine development. CLINICAL TRIALS REGISTRATION: NCT02561195.

Clostridium difficile intervention timelines for diagnosis, isolation, and treatment.

BACKGROUND: Developing timelines of nosocomial Clostridium difficile infection (CDI) is critical to improving control and preventive measures. The objective of this study was to provide data-driven estimates of CDI timelines of diagnosis, isolation, and treatment in a hospital setting. METHODS: We obtained data for all CDI inpatients with symptoms onset occurring between January 1, 2013, and December 30, 2017, from St Joseph's Healthcare in Hamilton, Canada. We analyzed full empirical distributions of timelines associated with the diagnosis, isolation, and treatment of CDI. RESULTS: A total of 683 inpatients with CDI symptoms were recorded, of which 243 cases were identified as health care-associated infection (HAI). The mean time intervals between the onset of CDI symptoms after admission and the release of laboratory results were 1.2 days and 1.9 days for the HAI and community-associated infection (CAI) patient groups, respectively. The mean time intervals from symptoms onset to the start of isolation were 1.5 days and 2.6 days for the corresponding patient groups. The initiation of treatment within 2 days of symptoms onset reduced the duration of first isolation (P value < .0001); however, the type of initial antibiotic used for CDI treatment was not associated with the duration of isolation. CONCLUSIONS: Estimated timelines did not differ (P values > .6) between HAI and CAI patient groups with symptoms onset after admission. These estimates are useful for evaluating the effectiveness of CDI interventions.

A phase 1 randomized study assessing safety and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in healthy older Japanese adults.

BACKGROUND: Clostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B. METHODS: Healthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 µg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A- and toxin B-specific neutralizing antibody levels in human sera. RESULTS: Local reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-µg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-µg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-µg group, peaked at month 7, and remained elevated at month 12. CONCLUSIONS: The C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI. ClinicalTrials.gov identifier: NCT02725437.

Molecular epidemiology of Clostridioides (previously Clostridium) difficile isolates from a university hospital in Minas Gerais, Brazil.

The molecular epidemiology of 38 non-duplicate toxigenic Clostridioides (previously Clostridium) difficile isolates from inpatients from a hospital in Brazil during a 6-year period (2012-2017) were investigated by multilocus sequence typing (MLST) and ribotyping. These isolates were classified into 20 sequence types (ST), six (30%) of which were novel, revealing a high diversity in a single hospital. Classic hypervirulent strains ST1/RT027 and ST11/RT078 were not identified, while ST42 (almost all RT106) was the most common type, being detected in 11 (28.9%) strains. Noteworthy, six (15.8%) isolates were classified into five STs from clade 2, four of which were new ST and RT. Our study suggests that possible hypervirulent strains other than ST1/RT027 might be inadvertently circulating in Brazilian hospitals and highlights the importance of permanent surveillance on circulating strains in a national scale.

Clostridium difficile-associated Diarrhea in Developing Countries: A Systematic Review and Meta-Analysis.

INTRODUCTION: The prevalence of Clostridium difficile infection is rapidly increasing worldwide, but prevalence is difficult to estimate in developing countries where awareness, diagnostic resources, and surveillance protocols are limited. As diarrhea is the hallmark symptom, we conducted a systematic review and meta-analysis to determine the prevalence and incidence of C. difficile infection in patients in these regions who presented with diarrhea. METHODS: We conducted a systematic literature search of MEDLINE/PubMed, Scopus, and Latin-American and Caribbean Health Sciences Literature databases to identify and analyze data from recent studies providing prevalence or incidence rates of C. difficile-associated diarrhea in developing countries within four regions: Africa-Middle East, developing Asia, Latin America, and China. Our objectives were to determine the current prevalence and incidence density rates of first episodes of C. difficile-associated diarrhea in developing countries. RESULTS: Within the regions included in our analysis, prevalence of C. difficile infection in patients with diarrhea was 15% (95% CI 13-17%) (including community and hospitalized patients), with no significant difference across regions. The incidence of C. difficile infection in 17 studies including this information was 8.5 per 10,000 patient-days (95% CI 5.83-12.46). Prevalence was significantly higher in hospitalized patients versus community patients (p  = 0.0227). CONCLUSION: Our prevalence estimate of 15% is concerning; however, low awareness and inconsistent diagnostic and surveillance protocols suggest this is markedly underestimated. Enhanced awareness and management of C. difficile infection in patients with diarrhea, along with improvements in infection control and surveillance practices, should be implemented to reduce prevalence of C. difficile-associated diarrhea in developing countries. FUNDING: Pfizer Inc.

Effect of Psyllium Fiber Supplementation on Diarrhea Incidence in Enteral Tube-Fed Patients: A Prospective, Randomized, and Controlled Trial.

BACKGROUND: Diarrhea in enteral tube-fed patients is not uncommon and can lead to unfavorable outcomes. Fiber in enteral nutrition (EN) formula might play a role in postfeeding diarrhea. Theoretically, soluble fiber is beneficial for both prevention and treatment of postfeeding diarrhea, but different types of soluble fiber may not provide the same effect. This study aims to determine whether supplementation with psyllium in standard EN reduces the incidence of diarrhea in tube-fed patients. METHODS: We conducted a prospective, randomized, double-blind, controlled study in general medical wards patients who were expected to receive EN for ≥5 days. Exclusion criteria were hemodynamic instability, known significant gastrointestinal problems, and recent pancreatitis. Eligible patients were randomized to receive either Mucilin SF (15.2 g/L)-added Blendera (psyllium-added formula: Psyllium group [PG]) or Blendera (fiber-free formula: Control group [CG]). All patients were given EN for 10 days or until discharge/oral intake/death. Bowel movements (BMs) were monitored using King's Stool Chart. RESULTS: Eighty-three patients were enrolled, 42 in the PG and 41 in the CG. Baseline characteristics were similar. The proportion of patients with ≥1 day of diarrhea (King's stool score ≥15) was comparable (42.9% vs 31.7%; P = 0.41, in PG and CG, respectively). There were no significant differences in the frequency of daily BMs and the median diarrhea score between PG and CG (3 vs 2, P = 0.06 and 3.8 vs 2.4, P = 0.42, respectively). CONCLUSION: Supplementation with psyllium showed no beneficial effect on reducing incidence of diarrhea in general medical patients receiving EN. This study was registered on Thai Clinical Trials Registry (http://www.clinicaltrials.in.th: TCTR identification number TCTR20170821004).

Meta-analysis comparing the effects of statins on the risk of Clostridium difficile diarrhea.

A literature search was performed through May 2017. Studies that compared the risk of developing Clostridium difficile infection (CDI) and/or the clinical outcomes of CDI in patients who received statin treatment versus those who did not receive statins were included. Ten observational studies with 37,109 patients were included. Compared to no treatment, statins reduced the risk of CDI development (odds ratio [OR] = 0.66, 95% confidence interval [CI], 0.44-0.99). However, among patients who developed CDI, the use of statins did not significantly reduce recurrent CDI risk (OR = 0.69, 95% CI, 0.28-1.71) or 30-day mortality (OR = 0.77, 95% CI, 0.51-1.14). In conclusion, our study demonstrates a significant association between statin use and a reduced risk of CDI development. However, the findings of our study suggest no significant associations between statin use and improvement in clinical outcomes of CDI. These findings might impact the clinical management and primary prevention of CDI.

Prevalence of Nosocomial Diarrhea Due to Adenoviruses 40 and 41 in a Paediatric Ward in Iran.

BACKGROUND: Enteric adenoviruses 40 (Ad40) and adenovirus 41 (Ad41) have been shown to be a significant cause of paediatric gastroenteritis worldwide, but no data are available for nosocomial diarrhea due to adenovirus in Iran. AIM: The present study was performed to determine the incidence of Ad40 and Ad41 in children less than five years with nosocomial diarrhea in Shahrekord, southwest Iran. MATERIALS AND METHODS: Adenovirus was detected by polymerase chain reaction (PCR) in stool samples collected during one year (2010-2011) from children less than five years with nosocomial diarrhea admitted to a paediatric center in Shahrekord, Iran. Nosocomial diarrhea was defined as those occurring more than 72 hours after admission to hospital for non-diarrheal causes. PCR technique was used for investigation of Ad40 and Ad41. RESULTS: In total of 100 samples, Ad40 and Ad41 DNA was found to be positive in 14/100 (14%), and 8/100 (8%) of diarrheic patients less than five years, respectively. CONCLUSION: Ad40 and Ad41 are important causes of nosocomial diarrhea in less than five-year, hospitalized Iranian children.

Esporas de Clostridium difficile y su relevancia en la persistencia y transmisión de la infección / Clostridium difficile spores and its relevance in the persistence and transmission of the infection

C. difficile is an anaerobic spore former pathogen and the most important etiologic agent of nosocomial and community acquired antibiotics associated diarrheas. C. difficile infections (CDI) are responsible for an elevated rate of morbidity in developed and developing countries. Although the major virulence factors responsible for clinical symptoms of CDI are the two toxins TcdA and TcdB, C. difficile spores are the main vehicle of infection, persistence and transmission of CDI. Recent work has unrevealed unique properties of C. difficile spores that make them remarkable morphotypes of persistence and transmission in the host, including their resistance to antibiotics, the host immune response and disinfectants. The present review summarizes relevant aspects of C. difficile spore biology that have major implications from a clinical and medical perspective.

Clostridium difficile es un patógeno anaerobio, formador de esporas y el agente etiológico más importante de las diarreas asociadas a antimicrobianos, tanto nosocomiales como adquiridas en la comunidad. Las infecciones asociadas a C. difficile poseen una elevada tasa de morbilidad en países desarrollados y en vías de desarrollo. Los dos factores de virulencia principales son TcdA y TcdB, toxinas que causan la remodelación del citoesqueleto lo cual desencadena los síntomas clínicos asociados a esta enfermedad infecciosa. A pesar que las esporas de C. difficile son el principal vehículo de infección, persistencia en el hospedero y de transmisión, pocos estudios se han enfocado sobre este clave aspecto. Es altamente probable que la espora juegue roles esenciales en los episodios de recurrencia y de transmisión horizontal de la infección por este microorganismo. Estudios recientes han revelado características únicas de las esporas de C. difficile que las hacen capaces de ser altamente transmisibles y persistir dentro del hospedero. Más aún, algunas de estas propiedades están relacionadas con la resistencia de sus esporas a los desinfectantes más comúnmente usados en los recintos hospitalarios. La presente revisión resume los conocimientos más relevantes en la biología de las esporas de C. difficile, con un énfasis en aquellos aspectos con implicancias clínicas, incluido el control de infecciones en el ambiente hospitalario.

John G. Bartlett: Contributions to the discovery of Clostridium difficile antibiotic-associated diarrhea.

In 1975 John Bartlett began trials investigating the problem of antibiotic-associated diarrhea and pseudomembranous colitis. His work led the discovery of Clostridium difficile and he identified it as the leading cause of hospital-associated infections.

Padronização de um modelo de infecção por Clostridium difficile em hamsters sírios Mesocricetus auratus / Standardization of a model of Clostridium difficile infection in syrian hamsters Mesocricetus auratus

O objetivo do presente trabalho foi padronizar um modelo de infecção por Clostridium difficile (ICD) em hamsters sírios (Mesocricetus auratus). Para seleção dos isolados capazes de causar letalidade, cinco animais por grupo receberam uma dose de clindamicina (30mg kg-1) por gavagem. Após 48 horas, administraram-se 107 unidades formadoras de colônia (UFC), por animal, de quatro diferentes isolados toxigênicos de C. difficile. Selecinou-se um dos isolados capazes de causar diarreia e letalidade e administrou-se 4x102; 4x104; 4x106; 4x108UFC por animal, novamente com cinco hamsters por grupo. Em todas as diluições testadas, foi possível observar a ocorrência de diarreia e morte. A maior concentração testada (4x108UFC por animal) causou óbito de 100% dos hamsters do grupo. Todos os animais que vieram a óbito apresentaram tiflite hemorrágica, foram positivos para as toxinas A/B e foi possível isolar C. difficile do conteúdo intestinal, confirmando a reprodução experimental da doença. A dose letal para 50% da população foi estabelecida em 6,3x104UFC por animal. O modelo de indução de ICD em hamsters descritos no presente estudo passa a ser uma ferramenta valiosa para estudos relativos à patogenia, tratamento e controle dessa doença.

The aim of this study was to standardize a model of Clostridium difficile infection (CDI) in Syrian hamsters (Mesocricetus auratus). In order to evaluate strains capable of causing lethality, five hamsters per group received clindamycin (30mg kg-1) by gavage. After 48 hours, 107 colony forming units (CFU) of spores' solution of four strains were administered per animal. One strain capable of causing diarrhea and death was selected and administered at the following concentrations: 4x102; 4x104; 4x106; 4x108 CFU per animal. All dilutions tested were able to cause diarrhea and death. The highest concentration showed 100% of mortality. Post mortem evaluation revealed hemorrhagic typhlitis in all death animals. In addition, all intestinal contents were positive for A/B toxins, and toxigenic C. difficile strains were isolated, confirming the induction of infection by this microorganism. The dose lethal to 50% of the population was calculated: 6.3x104 CFU per animal. The standardized model of CDI in hamster is now available for studies on pathogenesis, treatment and control of this disease.