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Background: Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through external validation, and none is widely recommended in clinical practice., Methods: CPRs were identified through a systematic review. We included studies that predicted severe or complicated CDI (cCDI) and mortality, reported at least an internal validation step, and for which data were available with minimal modifications. Data from a multicenter prospective cohort of 1380 adults with confirmed CDI were used for external validation. In this cohort, cCDI occurred in 8% of the patients and 30-day all-cause mortality occurred in 12%. The performance of each tool was assessed using individual outcomes, with the same cut-offs and standard parameters., Results: Seven CPRs were assessed. Three predictive scores for cCDI showed low sensitivity (25-61%) and positive predictive value (PPV; 9-31%), but moderate specificity (54-90%) and negative predictive value (NPV; 82-95%). One model [using age, white blood cell count (WBC), narcotic use, antacids use, and creatinine ratio > 1.5× the normal level as covariates] showed a probability of 25% of cCDI at the optimal cut-off point with 36% sensitivity and 84% specificity. Two scores for mortality had low sensitivity (4-55%) and PPV (25-31%), and moderate specificity (71-78%) and NPV (87-92%). One predictive model for 30-day all-cause mortality [Charlson comorbidity index, WBC, blood urea nitrogen (BUN), diagnosis in ICU, and delirium] showed an AUC-ROC of 0.74. All other CPRs showed lower AUC values (0.63-0.69). Errors in calibration ranged from 12%- 27%., Conclusions: Included CPRs showed moderate performance for clinical use in a large validation cohort with a majority of patients infected with ribotype 027 strains and a low rate of cCDI and mortality. These data show that better CPRs need to be developed and validated., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: L.V. has served on advisory boards for Merus, Merck, Abbott, and Wyeth, and has received compensation to conduct clinical trials involving antibacterials from Wyeth, Pfizer, Optimer, Cubist, Merck and Actelion. A.E.S. served on Merck Advisory Boards and received honoraria for speaking on behalf of Merck Canada Inc. All other authors have no competing interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no restrictions on sharing of data and/or materials.

The epidemiology of Clostridioides difficile infection (CDI) has drastically changed since the emergence of the epidemic strain BI/NAP1/027, also known as ribotype 027 (R027). However, the relationship between the infecting C. difficile strain and clinical outcomes is still debated. We hypothesized that certain subpopulations of R027 isolates could be associated with unfavorable outcomes. We applied high-resolution multilocus variable-number tandem-repeat analysis (MLVA) to characterize C. difficile R027 isolates collected from confirmed CDI patients recruited across 10 Canadian hospitals from 2005 to 2008. PCR ribotyping was performed first to select R027 isolates that were then analyzed by MLVA ( n  = 450). Complicated CDI (cCDI) was defined by the occurrence of any of admission to an intensive care unit, colonic perforation, toxic megacolon, colectomy, and if CDI was the cause or contributed to death within 30 days after enrollment. Three major MLVA clusters were identified, MC-1, MC-3, and MC-10. MC-1 and MC-3 were exclusive to Quebec centers, while MC-10 was found only in Ontario. Fewer cases infected with MC-1 developed cCDI (4%) than those infected with MC-3 and MC-10 (15% and 16%, respectively), but a statistically significant difference was not reached. Our data did not identify a clear association between subpopulations of R027 and different clinical outcomes; however, the data confirmed the utility of MLVA's higher discrimination potential to better characterize CDI populations in an epidemiological analysis. For a patient with CDI, the progression toward an unfavorable outcome is a complex process that probably includes several interrelated strain and host characteristics., (Copyright © 2019 American Society for Microbiology.)

Background: Clostridium difficile infection (CDI) is associated with a high risk of recurrence (rCDI). Few studies have focused on multiple recurrences. To evaluate the potential of novel treatments targeting recurrence, we assessed the burden and severity of rCDI., Methods: This was a retrospective cohort of adults diagnosed with CDI in a hospital in Sherbrooke, Canada (1998-2013). An rCDI episode was defined by the reappearance of diarrhea leading to a treatment, with or without a positive toxin assay, within 14-60 days after the previous episode., Results: We included 1527 patients. The probability of developing a first rCDI was 25% (354/1418); a second, 38% (128/334); a third, 29% (35/121); and a fourth or more, 27% (9/33). Two or more rCDIs were observed in 9% (128/1389) of patients. The risk of a first recurrence fluctuated over time, but there was no such variation for second or further recurrences. The proportion of severe cases decreased (47% for initial episodes, 31% for first recurrences, 25% for second, 17% for third), as did the risk of complicated CDI (5.8% to 2.8%). The severity and risk of complications of first recurrences decreased over time, while oral vancomycin was used more systemically. A hospital admission was needed for 34% (148/434) of recurrences., Conclusions: This study documented the clinical and healthcare burden of rCDI: 34% of patients with rCDI needed admission, 28% developed severe CDI, and 4% developed a complication. Secular changes in the severity of recurrences could reflect variations in the predominant strain, or better management., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Clostridium difficile infection (CDI) is the most common cause of nosocomial infectious diarrhea and may result in severe complications including death. We conducted a prospective study to identify risk factors for complications of CDI (cCDI)., Methods: Adult inpatients with confirmed CDI in 10 Canadian hospitals were enrolled and followed for 90 days. Potential risk factors were measured within 24 hours of diagnosis. Isolates were typed by polymerase chain reaction ribotyping. cCDI was defined as 1 or more of the following: colonic perforation, toxic megacolon, colectomy, admission to an intensive care unit for cCDI, or if CDI contributed to death within 30 days of enrollment. Risk factors for cCDI were investigated by logistic regression., Results: A total of 1380 patients were enrolled. cCDI was observed in 8% of patients. The ribotype was identified in 922 patients, of whom 52% were infected with R027. Age ≥ 80 years, heart rate >90/minute, respiratory rate >20/minute, white cell count <4 × 10(9)/L or ≥ 20 × 10(9)/L, albumin <25 g/L, blood urea nitrogen >7 mmol/L, and C-reactive protein ≥ 150 mg/L were independently associated with cCDI. A higher frequency of cCDI was observed among R027-infected patients (10.9% vs 7.2%), but the association was not significant in adjusted analysis., Conclusions: CDI complications were associated with older age, abnormal blood tests, and abnormal vital signs. These factors, which are readily available to clinicians at the time of diagnosis, could be used for outcome prediction and risk stratification to select patients who may need closer monitoring or more aggressive therapy., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We aimed to estimate the risk of secondary cases of Clostridium difficile infection (CDI) among household contacts of index cases., Methods: We reviewed all 2222 patients with confirmed CDI in a region of Quebec, Canada, during 1998-2009. Our laboratory serves a well-defined population for which it is the sole centre providing CDI testing, enabling us to calculate accurate population annual incidence rates of CDI. Cases with the same phone number were verified individually to determine whether they were indeed related. We considered as related two cases occurring in the same household within one year of each other., Results: We estimated that 1061 spouses and 501 children (<25 years-old) lived in the same household as the index cases, of which respectively 5 and 3 developed CDI. Among spouses and children, the attack rate was 4.71/1000 and 5.99/1000 respectively, and the relative risk was 7.61 (95%CI: 5.77-9.78) and 90.6 (95%CI: 33.89-487.64) for the three months after the diagnosis in the index case., Conclusions: Although the relative risk of CDI among household contacts is somewhat increased for a few months, the absolute risk is too low to justify interventions, apart from avoiding unnecessary courses of antimicrobials., (Copyright © 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Clostridium difficile infection (CDI) is an increasing nosocomial problem in North America and Western Europe, where outbreaks caused by a more virulent, toxin-hyperproducing strain have been recently reported. Clostridium difficile infection is now characterized by a higher incidence, more frequent relapses, and a higher case-fatality ratio. As a consequence, fulminant cases requiring admission to the intensive care unit (ICU) are much more common than previously. In recent years, metronidazole has appeared to lose some of its effectiveness in CDI management and vancomycin is now recognized as the first-line treatment of severe cases. Rapid diagnosis and institution of infection control measures are critical components of CDI management. The current review focuses on recent changes in the epidemiology, diagnostic methods, and treatment of CDI, with special emphasis on complicated cases managed in the ICU.

Clostridium difficile generally causes diarrhoea and colitis. Small-bowel infections are considered to be rare. Twelve cases of ileal C. difficile infections are presented, including the first reported case proven to be caused by the hypervirulent BI/NAP1/027 strain. This case series suggests that small bowel involvement in C. difficile infections may be more frequent than previously thought.

Background: Abdominal computed tomography (CT) is often used to evaluate complications in patients with Clostridium difficile infection (CDI), but no study has correlated CT findings with the risk of developing a complicated CDI. Furthermore, the value of CT has not been evaluated since the emergence of the BI/NAP1/027 hypervirulent strain of C. difficile. We sought to describe and correlate abdominal CT findings with complicated CDI and to compare them before and after the emergence of the epidemic strain., Methods: We conducted a retrospective cohort study of all hospitalized patients 18 years or older who, from 1 January 1998 through 31 December 2006, underwent abdominal CT within 72 h of their first positive stool sample., Results: Of 1189 patients with newly diagnosed CDI, 165 satisfied the inclusion criteria. Patients who underwent CT were younger, had higher peak white blood cell counts and serum creatinine levels, and were more likely to experience fever than those who did not undergo CT. No difference in CT findings was noted before and after the emergence of BI/NAP1/027 CDI. Pleural effusion (adjusted odds ratio [AOR], 2.6; 95% confidence interval [CI], 1.1-6.6), colonic wall thickness >15 mm (AOR, 6.0; 95% CI, 1.1-33.9), peak white blood cell count > or =30 x 10(9) cells/L (AOR, 4.8; 95% CI, 1.4-16.4), albumin level <20 g/L (AOR, 6.9; 95% CI, 2.4-20.1), and immunosuppression (AOR, 4.7; 95% CI, 1.5-15.3) were independently associated with complicated CDI., Conclusions: In a selected sample of patients with CDI, CT provided prognostic information additional to what could be obtained from clinical and laboratory parameters. No change in CT characteristics was noted after the introduction of the BI/NAP1/027 strain in our center.

Since 2002, an epidemic of Clostridium difficile infections has occurred in southern Quebec, Canada. At Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada, the incidence of C. difficile infections increased from 11/1,000 admissions (1999 to 2002) to 27/1,000 admissions (2003 to 2005). We compared the exposures and outcomes for patients infected with strains with different ribopatterns isolated before (n = 55) and during (n = 175) the epidemic, as well as the in vitro activities of antibiotics against those isolates. During the preepidemic period, 46 isolates (84%) were of ribotype 001, 1 was of ribotype 027, and 8 were of other ribopattern types. During the epidemic period, ribotype 027 strains accounted for 140 (80%) isolates; 26 (15%) were of ribotype 001, and 7 were of other ribopattern types. Ribotype 027 strains were highly resistant to fluoroquinolones (FQs) but were susceptible to clindamycin. A pattern of prior specific antibiotic exposure that selected for antibiotic-resistant ribotype C. difficile infections was observed for FQs (ribotype 027) and clindamycin (ribotype 001). The rate of mortality was higher among older patients, those with a high Charlson comorbidity index, and those with longer previous hospitalizations. By multivariate analysis, patients infected with ribotype 027 were twice as likely to die within 30 days of diagnosis than patients infected with other ribotypes (adjusted odds ratio, 2.06; 95% confidence interval, 1.00 to 4.22). The observations from this study support the notion that continued selective antibiotic pressure resulted in the superimposition of the hypertoxigenic ribotype 027 clone on top of the prior dominant ribotype 001 clone in a setting of preexisting high endemicity, thus leading to the high rates of morbidity and mortality seen in the Quebec outbreak. Stringent antibiotic stewardship measures, combined with aggressive infection control, are required to curtail the epidemic of C. difficile infections.

Background: Perioperative antibacterial prophylaxis (PAP) is an important component of surgical site infection prevention but may be associated with adverse effects, such as Clostridium difficile infection (CDI). Since the emergence of a hypervirulent strain of C. difficile, the risk of development of CDI after PAP has not been evaluated. The purpose of this study was to determine the risk of PAP-induced CDI after selected surgical procedures and to compare such risk before with such risk after the emergence of the hypervirulent strain of C. difficile., Methods: We performed a retrospective cohort study including all patients aged > or = 18 years who underwent either abdominal hysterectomy, hip arthroplasty, craniotomy, or colon, cardiac, or vascular surgery from August 1999 through May 2005 in a tertiary care hospital in Quebec, Canada., Results: A total of 8373 surgical procedures were performed, and PAP was used in 7600 of these interventions. Of 98 CDI episodes identified, 40 occurred after patients received PAP only. The risk of CDI was 14.9 cases per 1000 surgical procedures among patients who received PAP only during the period 2003-2005, compared with 0.7 cases per 1000 surgical procedures during the period 1999-2002 (P < .001). The independent risk factors associated with CDI in patients given PAP only were older age, administration of cefoxitin (rather than cefazolin) alone or in combination with another drug, and year of surgery., Conclusions: In the context of a large epidemic of CDI associated with the emergence of a novel strain, 1.5% of patients who received PAP as their sole antibiotic treatment developed CDI. In situations in which the only purpose of PAP is to prevent infrequent and relatively benign infections, the risks may outweigh the benefits in some elderly patients.

Objective: To reassess the comparative efficacy of vancomycin versus metronidazole in the treatment of Clostridium difficile-associated disease (CDAD) after the emergence in 2003 of the hypervirulent NAP1/027 strain., Methods: A retrospective cohort study was conducted in a tertiary-care Canadian hospital among 1,616 patients treated initially with metronidazole (N=1,360), vancomycin (N=219), or both (N=37), between 1991 and 2006, and followed for 60 days after diagnosis. Primary outcome was severe/complicated CDAD (SC-CDAD) defined as any of: (a) death within 30 days, (b) septic shock, (c) megacolon, (d) perforation, or (e) emergency colectomy. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated, stratifying into pre-epidemic (1991-2002) and epidemic (2003-2006) periods. Secondary outcome was recurrence within 60 days., Results: Risk factors for SC-CDAD were the same in both periods: age>or=65 yr, male sex, immunosuppression, hospital acquisition, tube feeding, short duration of diarrhea, fever, elevated leukocytosis, or creatinine. Adjusting for confounders and using metronidazole therapy as baseline, vancomycin therapy was associated with a lower probability of developing SC-CDAD in 1991-2002 (AOR 0.21, 95% CI 0.05-0.99, P=0.048) but not during 2003-2006 (AOR 0.90, 95% CI 0.53-1.55, P=0.71). For both metronidazole and vancomycin, risk of recurrence increased in 2003-2004 but decreased in 2005-2006., Conclusions: Loss of superiority of vancomycin over metronidazole coincided with the emergence of NAP1/027. Toxin hyperproduction by NAP1/027 might be such that the disease follows its natural course. Novel therapeutic approaches are needed. The higher risk of recurrence in 2003-2004 probably reflected reinfections rather than relapses.

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.

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 >or=50 x 10(9)/L (AOR, 18.6; 95% CI, 3.7-94.7), lactate >or=5 mmol/L (AOR, 12.4; 95% CI, 2.4-63.7), age >or=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 >or=20 x 10(9)/L or lactate between 2.2 and 4.9 mmol/L., Conclusion: Emergency colectomy reduces mortality in some patients with fulminant CDAD.

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.

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.

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 small ha, Cyrillic 10(9)/L or greater) and an elevated creatinine level (200 micromol/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.