Jacques Pépin

Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)

Since publication of the Society for Healthcare Epidemiology of America position paper on Clostridium difficile infection in 1995, significant changes have occurred in the epidemiology and treatment of this infection. C. difficile remains the most important cause of healthcare-associated diarrhea and is increasingly important as a community pathogen. A more virulent strain of C. difficile has been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management.

Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe

BACKGROUND Toxins A and B are the primary virulence factors of Clostridium difficile. Since 2002, an epidemic of C difficile-associated disease with increased morbidity and mortality has been present in Quebec province, Canada. We characterised the dominant strain of this epidemic to determine whether it produces higher amounts of toxins A and B than those produced by non-epidemic strains. METHODS We obtained isolates from 124 patients from Centre Hospitalier Universitaire de Sherbrooke in Quebec. Additional isolates from the USA, Canada, and the UK were included to increase the genetic diversity of the toxinotypes tested. Isolate characterisation included toxinotyping, pulsed-field gel electrophoresis (PFGE), PCR ribotyping, detection of a binary toxin gene, and detection of deletions in a putative negative regulator for toxins A and B (tcdC). By use of an enzyme-linked immunoassay, we measured the in-vitro production of toxins A and B by epidemic strain and non-dominant strain isolates. FINDINGS The epidemic strain was characterised as toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027). This strain carried the binary toxin gene cdtB and an 18-bp deletion in tcdC. We isolated this strain from 72 patients with C difficile-associated disease (58 [67%] of 86 with health-care-associated disease; 14 [37%] of 38 with community-acquired disease). Peak median (IQR) toxin A and toxin B concentrations produced in vitro by NAP1/027 were 16 and 23 times higher, respectively, than those measured in isolates representing 12 different PFGE types, known as toxinotype 0 (toxin A, median 848 microg/L [IQR 504-1022] vs 54 microg/L [23-203]; toxin B, 180 microg/L [137-210] vs 8 microg/L [5-25]; p<0.0001 for both toxins). INTERPRETATION The severity of C difficile-associated disease caused by NAP1/027 could result from hyperproduction of toxins A and B. Dissemination of this strain in North America and Europe could lead to important changes in the epidemiology of C difficile-associated disease.

Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity

Background: Recent reports suggest that Clostridium difficile colitis may be evolving into a more severe disease. During the second half of 2002 we noted an increase in the number of patients with severe C. difficile-associated diarrhea (CDAD) in our institution. We describe cases of CDAD at our institution over a 13-year period and investigate changes in illness severity. Methods: We undertook a retrospective chart review of all cases of CDAD diagnosed at the Centre hospitalier universitaire de Sherbrooke from Jan. 1, 1991, to Dec. 31, 2003. Because the hospital serves a well-defined population of Quebec, we were also able to calculate population-based incidence during this period. We abstracted data on individual patients from patient charts and from hospital and pharmacy computer databases. We defined cases of CDAD as having a positive C. difficile cytotoxicity assay result, or endoscopic or histopathological evidence of pseudomembranous colitis. A case was considered complicated if one or more of the following was observed: megacolon, perforation, colectomy, shock requiring vasopressor therapy, or death within 30 days after diagnosis. Results: A total of 1721 cases of CDAD were diagnosed during the study period. The incidence increased from 35.6 per 100 000 population in 1991 to 156.3 per 100 000 in 2003; among patients aged 65 years or more, it increased from 102.0 to 866.5 per 100 000. The proportion of cases that were complicated increased from 7.1% (12/169) in 1991–1992 to 18.2% (71/390) in 2003 (p < 0.001), and the proportion of patients who died within 30 days after diagnosis increased from 4.7% (8/169) in 1991– 1992 to 13.8% (54/390) in 2003 (p < 0.001). A high leukocyte count (20.0 х 109/L or greater) and an elevated creatinine level (200 μmol/L or greater) were strongly associated with adverse outcomes: in 2003, 45 (40.9%) of 110 patients with a high leukocyte count or creatinine level, or both, had complicated CDAD and 28 (25.5%) died within 30 days after diagnosis. After adjustment for age and other confounding factors, patients initially given oral vancomycin therapy had a risk of progression to complicated CDAD that was 79% lower than the risk among patients initially treated with metronidazole (adjusted odds ratio 0.2, 95% confidence interval 0.06–0.8, p = 0.02). Interpretation: An epidemic of CDAD with an increased case-fatality rate has had important consequences on the elderly population of our region. Our observational data suggest that the equivalence of vancomycin and metronidazole in the treatment of CDAD needs to be questioned.

Emergence of Fluoroquinolones as the Predominant Risk Factor for Clostridium difficile–Associated Diarrhea: A Cohort Study during an Epidemic in Quebec

BACKGROUND Since 2002, an epidemic of Clostridium difficile-associated-diarrhea (CDAD) associated with a high case-fatality rate has involved >30 hospitals in the province of Quebec, Canada. In 2003, a total of 55% of patients with CDAD at our hospital had received fluoroquinolones in the preceding 2 months. It has been suggested that massive use of proton pump inhibitors might have facilitated this epidemic. METHODS To delineate the risk of CDAD associated with specific classes of antibiotics and whether this is modulated by concomitant use of proton pump inhibitors and other drugs altering gastric acidity or gastrointestinal motility, we conducted a retrospective cohort study of patients hospitalized in a teaching hospital in Sherbrooke, Canada, during the period of January 2003 through June 2004. We obtained data on 7421 episodes of care corresponding to 5619 individuals. Patients were observed until they either developed CDAD or died or for 60 days after discharge from the hospital. Adjusted hazard ratios (AHRs) were calculated using Cox regression. RESULTS CDAD occurred in 293 patients. Fluoroquinolones were the antibiotics most strongly associated with CDAD (AHR, 3.44; 95% confidence interval [CI], 2.65-4.47). Almost one-fourth of all inpatients received quinolones, for which the population-attributable fraction of CDAD was 35.9%. All 3 generations of cephalosporins, macrolides, clindamycin, and intravenous beta-lactam/beta-lactamase inhibitors were intermediate-risk antibiotics, with similar AHRs (1.56-1.89). Proton pump inhibitors (AHR, 1.00, 95% CI, 0.79-1.28) were not associated with CDAD. CONCLUSIONS Administration of fluoroquinolones emerged as the most important risk factor for CDAD in Quebec during an epidemic caused by a hypervirulent strain of C. difficile.

Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec

Background: Since 2002 an epidemic of Clostridium difficile–associated disease (CDAD) caused by a hypervirulent toxinotype III ribotype 027 strain has spread to many hospitals in Quebec. The strain has also been found in the United States, the United Kingdom and the Netherlands. The effects of this epidemic on mortality and duration of hospital stay remain unknown. We measured these effects among patients admitted to a hospital in Quebec during 2003 and 2004. Methods: We compared mortality and total length of hospital stay among inpatients in whom nosocomial CDAD developed and among control subjects without CDAD matched for sex, age, Charlson Comorbidity Index score and length of hospital stay up to the diagnosis of CDAD in the corresponding case. Results: Thirty days after diagnosis 23.0% (37/161) of the patients with CDAD had died, compared with 7.0% (46/656) of the matched control subjects (p < 0.001). Twelve months after diagnosis, mortality was 37.3% (60/161) among patients with CDAD and 20.6% (135/656) among the control subjects (p < 0.001), for a cumulative attributable mortality of 16.7% (95% confidence interval 8.6%–25.2%). Each case of nosocomial CDAD led, on average, to 10.7 additional days in hospital. Interpretation: This study documented a high attributable mortality among elderly patients with CDAD mostly caused by a hypervirulent strain, which represents a dramatic change in the severity of this infection.

Increasing Risk of Relapse after Treatment of Clostridium difficile Colitis in Quebec, Canada

BACKGROUND Clinicians who treat patients with Clostridium difficile-associated diarrhea (CDAD) in Quebec, Canada, have noted an apparent increase in the proportion of patients who experience relapse. METHODS To determine whether there was an increase in the frequency of treatment failure and of recurrence of CDAD after treatment, we reviewed data on cases that had been diagnosed in a hospital in the province of Quebec during the period 1991-2004. The frequency of recurrences within 60 days after the initial diagnosis was measured using Kaplan-Meier analysis, and Cox regression was used for multivariate analysis. RESULTS Among patients who had initially been treated with metronidazole, the proportion whose regimens were switched to vancomycin or for whom vancomycin was added because of a disappointing response did not vary between 1991 and 2002 (66 [9.6%] of 688 patients overall) but more than doubled in 2003-2004 (112 [25.7%] of 435; P < .001). Among 845 patients treated with metronidazole only, the 60-day probability of recurrence increased dramatically in 2003-2004 (47.2%), compared with 1991-2002 (20.8%; P < .001). During 1991-2002, the probabilities of recurrence were 20.0%, 13.8%, and 28.9% among individuals aged 0-17, 18-64, and > or = 65 years, respectively; during 2003-2004, the probabilities were 25.0%, 27.1%, and 58.4%, respectively. CONCLUSION In 2003-2004, there was an increase in the proportion of patients with CDAD believed, by their attending physicians, to have experienced metronidazole treatment failure, as well as an increase in the frequency of post-metronidazole therapy recurrences, especially among elderly persons.

Comparison of Seven Techniques for Typing International Epidemic Strains of Clostridium difficile: Restriction Endonuclease Analysis, Pulsed-Field Gel Electrophoresis, PCR-Ribotyping, Multilocus Sequence Typing, Multilocus Variable-Number Tandem-Repeat Analysis, Amplified Fragment Length Polymorphism, and Surface Layer Protein A Gene Sequence Typing

ABSTRACT Using 42 isolates contributed by laboratories in Canada, The Netherlands, the United Kingdom, and the United States, we compared the results of analyses done with seven Clostridium difficile typing techniques: multilocus variable-number tandem-repeat analysis (MLVA), amplified fragment length polymorphism (AFLP), surface layer protein A gene sequence typing (slpAST), PCR-ribotyping, restriction endonuclease analysis (REA), multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). We assessed the discriminating ability and typeability of each technique as well as the agreement among techniques in grouping isolates by allele profile A (AP-A) through AP-F, which are defined by toxinotype, the presence of the binary toxin gene, and deletion in the tcdC gene. We found that all isolates were typeable by all techniques and that discrimination index scores for the techniques tested ranged from 0.964 to 0.631 in the following order: MLVA, REA, PFGE, slpAST, PCR-ribotyping, MLST, and AFLP. All the techniques were able to distinguish the current epidemic strain of C. difficile (BI/027/NAP1) from other strains. All of the techniques showed multiple types for AP-A (toxinotype 0, binary toxin negative, and no tcdC gene deletion). REA, slpAST, MLST, and PCR-ribotyping all included AP-B (toxinotype III, binary toxin positive, and an 18-bp deletion in tcdC) in a single group that excluded other APs. PFGE, AFLP, and MLVA grouped two, one, and two different non-AP-B isolates, respectively, with their AP-B isolates. All techniques appear to be capable of detecting outbreak strains, but only REA and MLVA showed sufficient discrimination to distinguish strains from different outbreaks.

Impact of Emergency Colectomy on Survival of Patients With Fulminant Clostridium difficile Colitis During an Epidemic Caused by a Hypervirulent Strain

Objectives:To determine whether emergency colectomy reduces mortality in patients with fulminant Clostridium difficile-associated disease (CDAD), and to identify subgroups of patients more likely to benefit from the procedure. Summary Background Data:Many hospitals in Quebec, Canada, have noted since 2003 a dramatic increase in CDAD incidence and in the proportion of cases severe enough to require intensive care unit (ICU) admission. The decision to perform an emergency colectomy remains largely empirical. Methods:Retrospective observational cohort study of 165 cases of CDAD that required ICU admission or prolongation of ICU stay between January 2003 and June 2005 in 2 tertiary care hospitals of Quebec. Multivariate analysis was performed through logistic regression; adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated. The primary outcome was mortality within 30 days of ICU admission. Results:Eighty-seven (53%) cases resulted in death within 30 days of ICU admission, almost half (38 of 87, 44%) within 48 hours of ICU admission. The independent predictors of 30-day mortality were: leukocytosis ≥50 × 109/L (AOR, 18.6; 95% CI, 3.7–94.7), lactate ≥5 mmol/L (AOR, 12.4; 95% CI, 2.4–63.7), age ≥75 years (AOR, 6.5; 95% CI, 1.7–24.3), immunosuppression (AOR, 7.9; 95% CI, 2.3–27.2) and shock requiring vasopressors (AOR, 3.4; 95% CI, 1.3–8.7). After adjustment for these confounders, patients who had an emergency colectomy were less likely to die (AOR, 0.22; 95% CI, 0.07–0.67, P = 0.008) than those treated medically. Colectomy seemed more beneficial in patients aged 65 years or more, in those immunocompetent, those with a leukocytosis ≥20 × 109/L or lactate between 2.2 and 4.9 mmol/L. Conclusion:Emergency colectomy reduces mortality in some patients with fulminant CDAD.

Impact of a Reduction in the Use of High-Risk Antibiotics on the Course of an Epidemic of Clostridium difficile-Associated Disease Caused by the Hypervirulent NAP1/027 Strain

A series of measures were implemented, in a secondary/tertiary-care hospital in Quebec, to control an epidemic of nosocomial Clostridium difficile-associated disease (n-CDAD) caused by a virulent strain; these measures included the development of a nonrestrictive antimicrobial stewardship program. Interrupted time-series analysis was used to evaluate the impact of these measures on n-CDAD incidence. From 2003-2004 to 2005-2006, total and targeted antibiotic consumption, respectively, decreased by 23% and 54%, and the incidence of n-CDAD decreased by 60%. No change in n-CDAD incidence was noted after strengthening of infection control procedures (P=.63), but implementation of the antimicrobial stewardship program was followed by a marked reduction in incidence (P=.007). This suggests that nonrestrictive measures to optimize antibiotic usage can yield exceptional results when physicians are motivated and that such measures should be a mandatory component of n-CDAD control. The inefficacy of infection control measures targeting transmission through hospital personnel might be a result of their implementation late in the epidemic, when the environment was heavily contaminated with spores.

Management and Outcomes of a First Recurrence of Clostridium difficile-Associated Disease in Quebec, Canada

BACKGROUND During an epidemic of Clostridium difficile-associated disease (CDAD) caused by a strain that is a hyper-producer of toxins A and B, the frequency of a first recurrence after metronidazole treatment of the initial episode doubled in 2003-2004, compared with 1991-2002. METHODS To examine whether administration of metronidazole as treatment for a first recurrence of CDAD remained appropriate, we reviewed data for patients with CDAD diagnosed in a hospital in Quebec, Canada, during 1991-2005, who experienced a first recurrence. The frequency of a second recurrence within 60 days after the first one was measured using Kaplan-Meier analysis. Cox regression was used for multivariate analysis. RESULTS A total of 463 patients had a first recurrence of CDAD, of whom 154 (33.3%) experienced a second recurrence. Independent predictors of a second recurrence were age and duration of hospitalization after the first recurrence; this latter finding suggested that many such episodes were reinfections rather than relapses. Neither choice of treatment drug (metronidazole or vancomycin) nor use of the same drug for treatment of first recurrence, as had been used during the initial episode, was associated with increased risk of a second recurrence. However, 51 patients (11.0%) developed at least 1 complication (i.e., shock, need for colectomy, megacolon, perforation, or death within 30 days) during the first recurrence. Older age, a high leukocyte count, and renal failure at first recurrence were strongly associated with a complicated CDAD. CONCLUSIONS Metronidazole is not inferior to vancomycin for treatment of patients with a first recurrence of CDAD, but the risk of complications with any treatment of CDAD may be higher than has previously been documented.