[Show abstract][Hide abstract] ABSTRACT: Background. Clostridium difficile infection (CDI) is a common complication of antibiotic therapy that is also 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 non-antibiotic, toxin-binding polymer with vancomycin and metronidazole. Methods. Patients with CDI were randomly assigned 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 in a 2:1:1 ratio. The primary endpoint was clinical success defined as resolution of diarrhea and absence of severe abdominal discomfort for >2 consecutive days including day 10. Results. 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<0.001), and metronidazole was inferior to vancomycin (P=0.02) (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=0.059). A post-hoc multivariate analysis that excluded tolevamer found three factors that were strongly associated with clinical success: vancomycin treatment, treatment-naïve status, and mild or moderate CDI severity. Adverse events were similar among the treatment groups. Conclusion. 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 01/2014; 42(2):168–173. · 3.01 Impact Factor
[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: 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.
[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. · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Non-toxigenic C. difficile (NTCD) has been shown to prevent fatal Clostridium difficile infection in the hamster model when 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 challenged with BI group C. difficile strains.Methods:Groups of 10 hamsters were given oral clindamycin followed on day 2 by 10(6) cfu spores of NTCD strains M3 or T7, and were challenged on day 5 with 100 cfu spores of BI1 or BI6. To conserve animals control hamsters challenged with BI1 or BI6 from the present study and controls from previous identical experiments were combined for statistical comparisons.Results:NTCD strains M3 and T7 achieved 100% colonization and were 100% protective from 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 co-colonization occurred in 5 hamsters, 4 of which died, for a protection of 6/10 animals (p=0.02).Conclusion:NTCD colonization provides protection against challenge with toxigenic BI group strains. M3 is more effective than T7 in preventing CDI caused by the BI6 epidemic strain. Prevention of C. difficile infection caused by epidemic BI6 may be more challenging than for historic BI1 and non-BI C. difficile strains.
Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
[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. · 4.02 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. · 4.02 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
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The efficacy of probiotics for the prevention of Clostridium difficile infection (CDI) is highly controversial, particularly with regard to the prevention of recurrent CDI. We hypothesize that primary prevention of CDI among patients receiving antibiotics might be a more achievable goal for probiotics than prevention in patients with previous CDI where the host flora is markedly altered. METHODS: We conducted a literature search for randomized, placebo-controlled efficacy studies of probiotic use among adults receiving antibiotics, in which CDI was one of the outcomes measured. In addition, we conducted meta-analyses of probiotics that were included in more than one randomized trial. RESULTS: Eleven studies were identified; most were seriously underpowered to determine the efficacy of probiotics in the prevention of CDI. Two showed significantly lower rates of CDI among the probiotic recipients. A meta-analysis of three studies that used the probiotic combination Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R and a combined analysis of those studies with four studies that used Saccharomyces boulardii, showed lower CDI rates in recipients of probiotics compared with recipients of placebo (risk ratio=0.39; 95% confidence interval 0.19-0.79). CONCLUSIONS: While potential flaws in study design were identified, a review of the available literature suggests that the primary prevention of CDI with specific probiotic agents may be achievable. Additional studies of sufficient size and with rigorous design are needed to confirm these findings.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 08/2012; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (± 2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (± 6.4) days for relapses and 14.7 (± 6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates.
[Show abstract][Hide abstract] ABSTRACT: Recent reports of reduced response to standard therapies for Clostridium difficile infection (CDI) and the risk for recurrent CDI that is common with all currently available treatment agents have posed a significant challenge to clinicians. Current recommendations include metronidazole for treatment of mild to moderate CDI and vancomycin for severe CDI. Results from small clinical trials suggest that nitazoxanide and teicoplanin may be alternative options to standard therapies, whereas rifaximin has demonstrated success in uncontrolled trials for the management of multiple recurrences. Anecdotal reports have also suggested that tigecycline might be useful as an adjunctive agent for the treatment of severe complicated CDI. Reports of resistance will likely limit the clinical use of fusidic acid and bacitracin and, possibly, rifaximin if resistance to this agent becomes widespread. Treatment of patients with multiple CDI recurrences and those with severe complicated CDI is based on limited clinical evidence, and new treatments or strategies are needed.
[Show abstract][Hide abstract] ABSTRACT: Recurrence of diarrhea following initially successful treatment is a major shortcoming in the treatment of C. difficile-associated diarrhea (CDAD or CDI for C. difficile infection).…
Antimicrobial Agents and Chemotherapy 05/2012; 56(8):4043-5. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An epidemic strain of Clostridium difficile designated by restriction endonuclease analysis (REA) as group BI has caused multiple outbreaks of severe C. difficile infection (CDI). The treatment response of patients infected with this strain is uncertain.
Clostridium difficile isolates were collected from 2 phase 3 clinical trials comparing fidaxomicin to vancomycin and typed using REA. Clinical cure and recurrence outcomes were analyzed by strain type of the infecting organism, BI and non-BI, using both univariate and multivariate analyses.
From 999 patients, 719 isolates were available for typing (356 fidaxomicin treated and 363 vancomycin treated). BI was the most common REA group (34% of isolates). Patients infected with BI had lower cure rates (86.6%; 214 of 247) than those infected with non-BI strains (94.3%; 445 of 472) (P < .001). The cure rate difference between the BI and non-BI patients was significant for both vancomycin (P = .02) and fidaxomicin (P = .007). BI patients had a recurrence rate of 27.4% (51 of 186), compared with a recurrence rate of 16.6% (66 of 397) in non-BI patients (P = .002). By multivariate analysis, BI infection was statistically significant as a risk factor for reduced cure (odds ratio [OR], 0.48; 95% confidence interval [CI], .27-.85; P = .030) and for increased recurrence (OR, 1.57; 95% CI, 1.01-2.45; P = .046).
The clinical cure rate of patients infected with the epidemic BI C. difficile strain is lower than the cure rate of those infected with non-BI strains whether treated with fidaxomicin or vancomycin. Similarly, the CDI recurrence rate is increased in patients with the BI strain compared with patients with other C. difficile strains.
[Show abstract][Hide abstract] ABSTRACT: Recurrent Clostridium difficile infection (CDI) is a growing problem that poses significant management challenges. There is no strong evidence to support a particular treatment strategy for recurrent CDI, especially those with multiple recurrences. However, a key strategy for reducing recurrent CDI is prompt diagnosis and treatment, facilitated by early recognition of patients at risk for recurrence.
Journal of Hospital Medicine 03/2012; 7 Suppl 3:S11-3. · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fidaxomicin, a nonabsorbed macrocyclic compound, is the first antimicrobial agent approved by the FDA for the treatment of Clostridium difficile infection (CDI) in adults over the last 25 years. It is bactericidal, and its mechanism of action relates to inhibition of a RNA polymerase at a site distinct from where rifamycins interact. Fidaxomicin, 200 milligrams by mouth twice daily, is not inferior to vancomycin, 125 milligrams by mouth 4 times daily, for treatment of CDI as determined by clinical response after 10 days of treatment and is superior to vancomycin for sustained response without recurrence 25 days after treatment completion. These results are a significant advance in the treatment of CDI and herald the development of narrow-spectrum anti-C. difficile agents that relatively spare the indigenous fecal microbiota. Continued vigilance for the development of resistance and unanticipated side affects will be important as the drug is introduced into clinical practice.