[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA(-) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms.
Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to C. difficile during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.
[Show abstract][Hide abstract] ABSTRACT: Despite advances in the diagnosis and treatment of Clostridium difficile infection (CDI) and prevention efforts to reduce the spread of C. difficile, CDI remains a significant challenge to healthcare systems worldwide. Further advances in prevention of CDI may need to focus on those who continue to be exposed to the organism and who are susceptible. Interventions directed toward this susceptible population, particularly hospitalized patients who receive antibiotics, may be effective. There is moderate evidence on the effectiveness of probiotics to prevent primary CDI, but there are few data to support use in secondary prevention of recurrent CDI. This review discusses the literature available on the use of probiotics to prevent primary and secondary CDI.
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
[Show abstract][Hide abstract] ABSTRACT: Vancomycin and metronidazole were historically considered equivalent therapies for the management of Clostridium difficile infections (CDI); however, recent data confirm more favorable outcomes with vancomycin. Fidaxomicin is a narrow spectrum antibiotic that has an advantage in reducing recurrence rates compared with vancomycin, possibly owing to its sparing effect on normal colonic microbiota. Data are limited for guiding management of CDI recurrences, particularly multiple recurrences. Several empiric approaches to manage these cases are reviewed.
Published by Elsevier Inc.
Infectious Disease Clinics of North America 01/2015; 29(1). DOI:10.1016/j.idc.2014.11.005 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reports of fidaxomicin treatment for patients with multiple recurrent Clostridium difficile infections ([mrCDI] ie, more than 2 CDI episodes) indicate symptomatic response to this agent, but 50% have subsequent mrCDI episodes. In an effort to improve outcomes in patients with mrCDI we used novel regimens of fidaxomicin based on strategies used with vancomycin. Of 8 patients who received a 10-day chaser of fidaxomicin given twice daily after a course of vancomycin, 3 (38%) experienced a subsequent recurrence. Two (18%) of 11 patients who completed a 14- to 33-day course of fidaxomicin in a tapering dose experienced a recurrence, both of whom received additional antibiotics before that recurrence. The median symptom-free interval (SFI) after fidaxomicin taper was greater than the median SFI after the most effective prior regimen for those patients (257 days [interquartile range, 280] vs 25 days [interquartile range, 30], respectively; P = .003). A fidaxomicin chaser or taper regimen may be effective in patients with mrCDI, but the number of patients treated is small, and randomized comparative data are not available.
[Show abstract][Hide abstract] ABSTRACT: We report the results of an international Clostridium difficile typing study to cross reference strain designations for seven typing methodologies and facilitate inter-laboratory communication. Four genotypic and three phenotypic methods were used to type 100 isolates and compare the results to 39 PCR ribotypes identified among the collection.
[Show abstract][Hide abstract] ABSTRACT: Background:
Clostridium difficile infection (CDI) is a common complication of antibiotic therapy that is treated with antibiotics, contributing to ongoing disruption of the colonic microbiota and CDI recurrence. Two multinational trials were conducted to compare the efficacy of tolevamer, a nonantibiotic, toxin-binding polymer, with vancomycin and metronidazole.
Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer 9 g (loading dose) followed by 3 g every 8 hours for 14 days, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days. The primary endpoint was clinical success, defined as resolution of diarrhea and absence of severe abdominal discomfort for more than 2 consecutive days including day 10.
In a pooled analysis, 563 patients received tolevamer, 289 received metronidazole, and 266 received vancomycin. Clinical success of tolevamer was inferior to both metronidazole and vancomycin (P < .001), and metronidazole was inferior to vancomycin (P = .02; 44.2% [n = 534], 72.7% [n = 278], and 81.1% [n = 259], respectively). Clinical success in patients with severe CDI who received metronidazole was 66.3% compared with vancomycin, which was 78.5%. (P = .059). A post-hoc multivariate analysis that excluded tolevamer found 3 factors that were strongly associated with clinical success: vancomycin treatment, treatment-naive status, and mild or moderate CDI severity. Adverse events were similar among the treatment groups.
Tolevamer was inferior to antibiotic treatment of CDI, and metronidazole was inferior to vancomycin. Trial Registration. clinicaltrials.gov NCT00106509 and NCT00196794.
[Show abstract][Hide abstract] ABSTRACT: Background
Recurrent Clostridium difficile (CDI) infection is a growing concern; however, there are little data on impact of recurrent CDI on those with spinal cord injury and disorder (SCI/D). Therefore, the objective of this study was to identify risk factors associated with recurrence of CDI among Veterans with SCI/D.
This was a retrospective cohort study with data from outpatient, inpatient, and extended care settings at 83 Department of Veterans Affairs facilities from 2002 to 2009.
Of 1,464 cases of CDI analyzed, 315 cases (21.5%) had a first recurrence of CDI. Multivariable regression demonstrated that risk factors significantly associated with increased recurrence were concomitant fluoroquinolone use (odds ratio [OR], 1.39; 95% confidence interval [CI]: 1.08-1.80), whereas concomitant tetracycline use (OR, 0.35; 95% CI: 0.14-0.90), and cerebrovascular accident (OR, 0.46; 95% CI: 0.25-0.85) were associated with decreased recurrence. A subanalysis in those with health care facility-onset CDI showed that increased length of stay postinitial CDI was a significant risk factor for recurrence as was concomitant use of fluoroquinolones and that tetracycline remained protective for recurrence.
Concomitant fluoroquinolone use was a risk factor for the recurrence of CDI. In contrast, tetracyclines and cerebrovascular accident were protective. Length of stay greater than 90 days from the initial CDI episode was also a risk factor for recurrence among those with health care facility-onset CDI. Future studies should focus on effective strategies to prevent these risk factors among the SCI/D population.
American journal of infection control 05/2014; 42(2):168–173. DOI:10.1016/j.ajic.2013.08.009 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer patients, particularly those with neutropenia, are at risk for enteric and intra-abdominal infections. Specific infections and infectious syndromes in this setting include neutropenic enterocolitis, bacterial infections such as Clostridium difficile infection (CDI), viral infections such as CMV colitis, and parasitic infections such as strongyloidiasis. Diagnosing and gauging the severity of CDI presents challenges, as chemotherapy may produce symptoms that mimic CDI and laboratory findings such as leukocytosis are not reliable in this population. Treatment for enteric infections should be pathogen specific, although broad-spectrum antibiotics are often required as initial empiric therapy in patients with neutropenia.
Cancer treatment and research 04/2014; 161:237-51. DOI:10.1007/978-3-319-04220-6_8
[Show abstract][Hide abstract] ABSTRACT: Binary toxin (CDT) is frequently observed in Clostridium difficile strains associated with increased severity of C. difficile infection (CDI). CDT belongs to the family of binary ADP-ribosylating toxins consisting of two separate toxin components: CDTa, the enzymatic ADP-ribosyltransferase which modifies actin, and CDTb which binds to host cells and translocates CDTa into the cytosol. CDTb is activated by serine proteases and binds to lipolysis stimulated lipoprotein receptor. ADP-ribosylation induces depolymerization of the actin cytoskeleton. Toxin-induced actin depolymerization also produces microtubule-based membrane protrusions which form a network on epithelial cells and increase bacterial adherence. Multiple clinical studies indicate an association between binary toxin genes in C. difficile and increased 30-d CDI mortality independent of PCR ribotype. Further studies including measures of binary toxin in stool, analyses of CDI mortality caused by CDT-producing strains, and examination of the relationship of CDT expression to TcdA and TcdB toxin variants and PCR ribotypes are needed.
Gut Microbes 10/2013; 5(1). DOI:10.4161/gmic.26854
[Show abstract][Hide abstract] ABSTRACT: Clinical guidelines exist to promote antibiotic stewardship, particularly in ambulatory care settings such as the emergency department (ED). However, there is limited evidence on prescribing practice for persons with spinal cord injury and disorder (SCI/D). The goal of this study was to assess trends in antibiotic prescribing in the ED setting for persons with SCI/D.
A retrospective dynamic cohort study design.
ED visits that did not result in same day hospitalization over 6 years (fiscal year (FY) 2002-FY2007) in Department of Veterans Affairs (VA) facilities Participants Veterans with SCI/D.
VA clinical and administrative databases were used to identify the cohort and to obtain demographics, diagnoses, and medications. The rate of antibiotic prescribing for ED visits was defined as the number of antibiotics/total ED visits.
Veterans with SCI/D had 21 934 ED visits and 5887 antibiotics prescribed over the study period (rate of 268.4 prescriptions/1000 visits). The antibiotic prescribing rate increased from 238.8/1000 visits in FY2002 to 310.8/1000 visits in FY2007 (P < 0.0001). This increase in the rate of prescribing was seen across all patient demographics and factors assessed.
Although clinical guidelines for judicious use of antibiotics in persons with SCI/D have been disseminated to providers, antibiotic prescribing in an ED setting is high and continuing to rise in this population.
The journal of spinal cord medicine 09/2013; 36(5):492-8. DOI:10.1179/2045772312Y.0000000076 · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nontoxigenic Clostridium difficile (NTCD) has been shown to prevent fatal C. difficile infection in the hamster model when hamsters are challenged with standard toxigenic C. difficile strains. The purpose of this study was to determine if NTCD can prevent C. difficile infection in the hamster model when hamsters are challenged with restriction endonuclease analysis group BI C. difficile strains. Groups of 10 hamsters were given oral clindamycin, followed on day 2 by 106 CFU of spores of NTCD strain M3 or T7, and were challenged on day 5 with 100 CFU of spores of BI1 or BI6. To conserve animals,
results for control hamsters challenged with BI1 or BI6 from the present study and controls from previous identical experiments
were combined for statistical comparisons. NTCD strains M3 and T7 achieved 100% colonization and were 100% protective against
challenge with BI1 (P ≤ 0.001). M3 colonized 9/10 hamsters and protected against BI6 challenge in the colonized hamsters (P = 0.0003). T7 colonized 10/10 hamsters, but following BI6 challenge, cocolonization occurred in 5 hamsters, 4 of which died,
for protection of 6/10 animals (P = 0.02). NTCD colonization provides protection against challenge with toxigenic BI group strains. M3 is more effective than
T7 in preventing C. difficile infection caused by the BI6 epidemic strain. Prevention of C. difficile infection caused by the epidemic BI6 strain may be more challenging than that of infections caused by historic BI1 and non-BI
C. difficile strains.
[Show abstract][Hide abstract] ABSTRACT: This study determined whether surrogate organisms can predict activity against Clostridium difficile spores and compared the efficacy of hand hygiene preparations against C. difficile. Our data suggest that surrogate organisms were not predictive of C. difficile spore removal. Four preparations were significantly more effective than tap water at removing C. difficile.
Infection Control and Hospital Epidemiology 03/2013; 34(3):302-5. DOI:10.1086/669521 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. To describe characteristics of Clostridium difficile infection (CDI) and markers of severe CDI among patients with hematologic malignancies. Design. Case-control study. Setting. Tertiary care teaching hospital. Patients and Methods. Inpatients with hematologic malignancies and CDI were age and time matched with 2 control inpatients without hematologic malignancies. Chart reviews were performed, and C. difficile isolates were strain typed. Results. Case patients ([Formula: see text]) and control patients ([Formula: see text]) patients were different in respect to receipt of immunosuppressive agents within 2 months (92.7% vs 25.6%; [Formula: see text]); neutropenia within 2 months (75.6% vs 3.7%; [Formula: see text]) and mean (± standard deviation) white blood cell (WBC) count at diagnosis ([Formula: see text] vs [Formula: see text] cells/mL; [Formula: see text]); baseline mean creatinine level ([Formula: see text] vs [Formula: see text] mg/dL; [Formula: see text]), mean creatinine level at diagnosis ([Formula: see text] vs [Formula: see text] mg/dL; [Formula: see text]), and creatinine increases of 1.5 times over baseline (2.4% vs 15.1%; [Formula: see text]). Immunosuppressive agents and creatinine level remained significant in multivariable analysis ([Formula: see text] for both variables). Severity correlated with mortality when measured by alternate severity criteria but not when measured by the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America criteria, which are based solely on WBC count and creatinine elevation. The prevalence of the epidemic BI/NAP1/027 strain was similar in both groups. Conclusions. Patients with hematologic malignancies had lower creatinine levels at the time of CDI diagnosis compared with control patients. WBC counts also tended to be lower in case patients. CDI severity criteria based on WBC count and creatinine level may not be applicable to patients with hematologic malignancies.
Infection Control and Hospital Epidemiology 02/2013; 34(2):127-32. DOI:10.1086/669081 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: V and M are commonly used for treatment of CDAD (aka, CDI). Head-to-head trials are limited but data suggest improved outcomes in patients with severe CDAD treated with V. Tolevamer, a “toxin-binding resin,” was inferior to V and M in two large randomized clinical trials. We compared V vs M for CDAD from these trials.
Methods: Data were pooled, in a post-hoc analysis, from 2 Phase 3, multi-center, randomized, double-blind, double-dummy, active control, parallel-design efficacy and safety trials at 209 sites. Subjects with primary or recurrent CDAD were treated with V (125mg QID) or M (375mg QID) for 10 days with 4-wk follow up. The primary end-point was resolution of diarrhea and abdominal pain (clinical success). Secondary evaluations included time to resolution of diarrhea (TTROD), recurrence of CDAD, and adverse events (AEs). Treatments were compared via logistic and proportional hazards regression models and uni- and multivariate logistic regression analysis (OR 95% CI) was performed to assess potential factors impacting the primary outcome. Kaplan-Meier estimates were used for TTROD.
Results: 537 subjects were evaluated for efficacy (V: 259; M: 278); 53% age > 65 yrs, 29% had severe CDAD, 78% were being treated for primary CDAD, and 23% had infection due to a BI strain (aka, NAP1/027). Overall, V significantly improved clinical success [81.1% vs 72.7%; OR (95% CI): 1.681 (1.114, 2.537), p= 0.0134]. Factors associated with clinical success included treatment naïve status, primary CDAD, and mild/moderate CDAD. In multivariate analysis, treatment with V, treatment naïve status, and mild/moderate disease severity remained significantly associated with clinical success. Median TTROD was similar between groups (5 days). Recurrence rates were 20.6% (V) and 23.0% (M). The proportion of subjects reporting related treatment emergent AEs was similar between groups. AE discontinuations were more frequent with M (11.2% vs 6.5%). More subjects experienced nephrotoxicity-related AEs with V [n=12 (4.6%)] than M [n=3 (1.0%)], predominantly among older subjects.
Conclusion: CDAD clinical success was statistically superior for V compared to M in the largest multicenter, randomized, blinded, head-to-head clinical trials conducted to date.
IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
[Show abstract][Hide abstract] ABSTRACT: Background: Polymerase chain reaction (PCR) assays have superior sensitivity compared to toxin A/B Enzyme Immunoassay (EIA) testing for the detection of C. difficile (CD). Low sensitivity testing methods may lead to diagnostic uncertainty and impact use of ancillary services, specialty consultations and antibiotics (ABX). We assessed how switching from EIA to PCR testing affected ABX prescribing practices and other aspects of patient management at our institution.
Methods: We conducted a retrospective chart review of adult inpatients tested for CD between 7/1/09-12/31/09 (EIA group) and 07/01/11-12/31/11 (PCR group) and treated with oral/IV metronidazole (metro) or oral vancomycin (vanc). We excluded patients receiving metro for non-CD indications or receiving oral vanc tapers for previous CD. Use of ABXs, diagnostic testing and specialty consultations were examined for CD-negative patients in both groups.
Results: Overall, 1,003 CD tests were performed on 664 patients in the EIA group, and 12.6% (n=97) were positive, while 955 tests were performed on 668 patients in the PCR group and 25% (n=167) were positive (p<0.001). The PCR group had fewer repeat CD tests (p<0.001). After exclusions there were 246 patients in the EIA group and 237 patients in PCR group. 1418 vs 636 doses of metro were administered to CD-negative patients in the EIA vs PCR groups (p=0.23). 388 vs 43 doses of oral vanc were administered to CD-negative patients in the EIA vs PCR groups (p=0.007). Compared to the EIA group, the PCR group had significantly decreased ABX treatment days (p=0.004), abdominal radiologic imaging studies (abdominal x-ray p=0.013, abdominal/pelvic CT scan p=0.002), sigmoidoscopy/colonoscopy (p=0.006), and infectious disease consults (p=0.033).
Conclusion: With PCR testing significantly more CD was detected. There was a marked decrease in total ABX treatment days, overall oral vanc use, use of radiologic testing, sigmoidoscopy/colonoscopy, and infectious diseases consultations amongst patients who tested CD-negative by PCR vs EIA. We postulate that lack of confidence in a negative result by the lower sensitivity EIA drove physicians to continue CD treatment and obtain more ancillary tests and services in order to obtain an accurate CD diagnosis.
IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012