Clostridium difficile infection (CDI) is a common cause of diarrhoea in hospitalised patients. Around the world, the incidence and severity of CDI appears to be increasing, particularly in the northern hemisphere. The purpose of this integrative review was to investigate and describe mortality in hospitalised patients with CDI.
A search of the literature between 1 January 2005 and 30 April 2011 focusing on mortality and CDI in hospitalised patients was conducted using electronic databases. Papers were reviewed and analysed individually and themes were combined using integrative methods.
All cause mortality at 30 days varied from 9% to 38%. Three studies report attributable mortality at 30 days, varying from 5.7% to 6.9%. In hospital mortality ranged from 8% to 37.2%
All cause 30 day mortality appeared to be high, with 15 studies indicating a mortality of 15% or greater. Findings support the notion that CDI is a serious infection and measures to prevent and control CDI are needed. Future studies investigating the mortality of CDI in settings outside of Europe and North America are needed. Similarly, future studies should include data on patient co-morbidities.
Clostridium difficile infection; Clostridium difficile associated diarrhoea; Mortality; Death
The incidence of Clostridium difficile infection (CDI) has been increasing. Previous studies report that the number of colectomies for CDI is also rising. Outside of a few notable outbreaks, there are few published data documenting increasing severity of CDI. The specific aims of this multiyear, multicenter study were to assess CDI-related colectomy rates and compare CDI-related colectomy rates by CDI surveillance definition.
Cases of CDI and patients who underwent colectomy were identified electronically from 5 US tertiary-care centers from July 2000 through June 2006. Chart review was performed to determine if a colectomy was for CDI. Monthly CDI-related colectomy rates were calculated as the number of CDI-related colectomies per 1,000 CDI cases. Data between observational groups were compared using χ2 and Mann-Whitney U tests. Logistic regression was performed to evaluate risk factors for CDI-related colectomy.
8569 cases of CDI were identified and 75 patients had CDI-related colectomy. The overall colectomy rate was 8.7/1,000 CDI cases. The CDI-related colectomy rate ranged from 0 to 23 per 1,000 CDI episodes across hospitals. The colectomy rates for healthcare facility (HCF)-onset CDI was 4.3/1000 CDI cases and 16.5 /1000 CDI cases for community-onset CDI (p <.05). There were significantly more CDI-related colectomies at hospitals B and C (p<.05).
The overall CDI-related colectomy rate was low, and there was no significant change in the CDI-related colectomy rate over time. Onset of disease outside of the study hospital was an independent risk factor for colectomy.
Compare Clostridium difficile infection (CDI) rates using a traditional definition [i.e. diagnosed > 48 hours after admission, healthcare-onset CDI (HO/CDI)] versus expanded definitions, including both HO/CDI cases and community-onset CDI cases diagnosed ≤ 48 hours from admission who were hospitalized in the previous 30 or 60 days [healthcare facility-associated (HCFA)-30 and HCFA-60]. Determine if differences exist between patients with CDI onset in the community versus healthcare setting.
Tertiary acute-care facility.
Medicine patients diagnosed with CDI from 1/1/04 through 12/31/05.
CDI cases were classified as HO/CDI, HCFA-30, and/or HCFA-60. Patient demographics and medication exposures were obtained. The CDI incidence per the definitions, CDI rate variability, patient demographics, and medication exposures were compared.
The HO/CDI rate (1.6 cases/1000 patient days) was significantly lower than the HCFA-30 (2.4) and the HCFA-60 (2.6) rates (p<0.01, both). There was good correlation between the HO/CDI rate and both the HCFA-30 and HCFA-60 rates (correlation=0.69 and 0.70, p<0.01 both). There were no months where the CDI rate was > 3 SD from the mean. Patients with community-onset CDI were less likely to have received a fourth-generation cephalosporin (p=0.02) or IV vancomycin (p=0.01) while hospitalized.
Expanded definitions identify more patients with CDI. There is good correlation between traditional and expanded CDI definitions; therefore it is unclear if expanded surveillance is necessary to identify an abnormal change in CDI rates. Cases that met the expanded definitions were less like to have fourth-generation cephalosporin and vancomycin exposure.
Clostridium difficile; surveillance; hospitals
Incidence of Clostridium difficile infection (CDI) is increasing among hospitalized patients. Liver transplant patients are at higher risk for acquiring CDI. Small, single-center studies, but no nation-wide analyses, have assessed this association.
We used the Healthcare Cost and Utilization Project- Nationwide Inpatient Sample (HCUP-NIS) from years 2004–2008 for this retrospective cross sectional study. Patients with any discharge diagnosis of liver transplant comprised the study population and were identified using ICD-9-CM codes. Those with a discharge diagnosis of CDI were considered cases. Our primary outcomes were prevalence of CDI and effect of CDI on inpatient mortality. Our secondary outcomes included length of stay and hospitalization charges. Regression analysis was used to derive odds ratios adjusted for potential confounders.
There were 193,714 discharges with a diagnosis of liver transplant from 2004–2008. Prevalence of CDI was 2.7% in liver transplant population compared to 0.9% in non liver transplant population (p <0.001). Most of the liver transplant patients were in the 50–64 age group. Liver transplant patients were at higher odds of developing CDI (OR 2.88, 95% CI 2.68–3.10). Increasing age, increasing comorbidity, IBD and NG tube placement were also independent risk factors for CDI. CDI in liver transplant was associated with a higher mortality, 5.5% as compared to 2.3% in liver transplant only population (adjusted OR 1.7, 95% CI 1.3–2.2).
Liver transplant patients have a higher prevalence of CDI as compared to non liver transplant patients (2.7% vs. 0.9%).CDI was an independent risk factor for mortality in liver transplant population.
Solid organ transplant; complications; outcomes research; cross sectional
Clostridium difficile is the most common cause of nosocomial infectious diarrhea in the United States. However, recent reports have documented that C. difficile infections (CDIs) are occurring among patients without traditional risk factors. The purpose of this study was to examine the epidemiology of CA-CDI, by estimating the incidence of CA-CDI and HA-CDI, identifying patient-related risk factors for CA-CDI, and describing adverse health outcomes of CA-CDI.
We conducted a population-based, retrospective, nested, case-control study within the University of Iowa Wellmark Data Repository from January 2004 to December 2007. We identified persons with CDI, determined whether infection was community-associated (CA) or hospital-acquired (HA), and calculated incidence rates. We collected demographic, clinical, and pharmacologic information for CA-CDI cases and controls (i.e., persons without CDI). We used conditional logistic regression to estimate the odds ratios (ORs) for potential risk factors for CA-CDI.
The incidence rates for CA-CDI and HA-CDI were 11.16 and 12.1 cases per 100,000 person-years, respectively. CA-CDI cases were more likely than controls to receive antimicrobials (adjusted OR, 6.09 [95% CI 4.59-8.08]) and gastric acid suppressants (adjusted OR, 2.30 [95% CI 1.56-3.39]) in the 180 days before diagnosis. Controlling for other covariates, increased risk for CA-CDI was associated with use of beta-lactam/beta-lactamase inhibitors, cephalosporins, clindamycin, fluoroquinolones, macrolides, and penicillins. However, 27% of CA-CDI cases did not receive antimicrobials in the 180 days before their diagnoses, and 17% did not have any traditional risk factors for CDI.
Our study documented that the epidemiology of CDI is changing, with CA-CDI occurring in populations not traditionally considered "high-risk" for the disease. Clinicians should consider this diagnosis and obtain appropriate diagnostic testing for outpatients with persistent or severe diarrhea who have even remote antimicrobial exposure.
To characterize the temporal progression of the monthly incidence of Clostridium difficile infections (CDIs) and to determine whether the incidence of CDI is related to the incidence of seasonal influenza.
A retrospective study of patients in the Nationwide Inpatient Sample during the period from 1998 through 2005.
We identified all hospitalizations with a primary or secondary diagnosis of CDI with use of International Classification of Diseases, 9th Revision, Clinical Modification codes, and we did the same for influenza. The incidence of CDI was modeled as an autoregression about a linear trend. To investigate the association of CDI with influenza, we compared national and regional CDI and influenza series data and calculated cross-correlation functions with data that had been prewhitened (filtered to remove temporal patterns common to both series). To estimate the burden of seasonal CDI, we developed a proportional measure of seasonal CDI.
Time-series analysis of the monthly number of CDI cases reveals a distinct positive linear trend and a clear pattern of seasonal variation (R2 = 0.98). The cross-correlation functions indicate that influenza activity precedes CDI activity on both a national and regional basis. The average burden of seasonal (ie, winter) CDI is 23%.
The epidemiologic characteristics of CDI follow a pattern that is seasonal and associated with influenza, which is likely due to antimicrobial use during influenza seasons. Approximately 23% of average monthly CDI during the peak 3 winter months could be eliminated if CDI remained at summer levels.
Recent reports suggest that community-associated Clostridium difficile infection (CDI) (i.e., no healthcare facility admission within 90 days) may be increasing in frequency. We hypothesized that outpatient clinics could be an important source for acquisition of community-associated CDI.
We performed a 6-month prospective study of CDI patients to determine frequency of and risk factors for skin and environmental shedding during outpatient visits and to derive a prediction rule for positive cultures. We performed a point–prevalence culture survey to assess the frequency of C. difficile contamination in outpatient settings and evaluated the frequency of prior outpatient visits in patients with community-associated CDI.
Of 67 CDI patients studied, 54 (81%) had 1 or more outpatient visits within 12 weeks after diagnosis. Of 44 patients cultured during outpatient visits, 14 (32%) had skin contamination and 12 (27%) contaminated environmental surfaces. Decreased mobility, fecal incontinence, and treatment with non-CDI antibiotics were associated with positive cultures, whereas vancomycin taper therapy was protective. In patients not on CDI therapy, a prediction rule including incontinence or decreased mobility was 90% sensitive and 79% specific for detection of spore shedding. Of 84 clinic and emergency department rooms cultured, 12 (14%) had 1 or more contaminated environmental sites. For 33 community-associated CDI cases, 31 (94%) had an outpatient visit during the 12 weeks prior to onset of diarrhea.
Patients with recent CDI present a significant risk for transmission of spores during outpatient visits. The outpatient setting may be an underappreciated source of community-associated CDI cases.
To describe a Clostridium difficile infection (CDI) pseudo-outbreak caused by a faulty toxin assay lot, and to determine the effect of sensitivity, specificity, and repeat testing for C. difficile on CDI burden, positive predictive value (PPV), and false positive results.
Outbreak investigation and criterion standard
Patients hospitalized at a tertiary-care hospital who had at least one toxin assay test for C. difficile from July 1, 2004 through June 30, 2006.
Run-control chart methodology and chi-square tests were used to compare CDI rates and proportion of positive tests before, during, and after the pseudo-outbreak. The impact of repeat testing was evaluated using three hypothetical models with a sample of 10,000 patients and various assay sensitivity and specificity estimates.
In November of 2005, the hospital CDI rate increased from 1.5/1000 patient-days to 2.6/1000 patient-days (p<0.01) and the proportion of positive tests increased from 13.6% to 22.1% (p<0.01). Investigation revealed a pseudo-outbreak caused by a faulty toxin assay lot. A decrease of only 1.2% in the specificity of the toxin assay would result in a 32% increased in perceived CDI incidence at this institution. Using the manufacturer's specificity and sensitivity and this institution's testing practices, the PPV of the test decreased from 80.6% in a first test to 4.1% in patients who received three tests.
Specificity is as important as sensitivity when testing for CDI. False positive CDI cases can drain hospital resources and adversely affect patients. Repeat testing for C. difficile should be performed with caution.
Although Clostridium difficile (C. difficile) is the leading cause of infectious diarrhoea in hospitalized patients, the economic burden of this major nosocomial pathogen for hospitals, third-party payers and society remains unclear. We developed an economic computer simulation model to determine the costs attributable to healthcare-acquired C. difficile infection (CDI) from the hospital, third-party payer and societal perspectives. Sensitivity analyses explored the effects of varying the cost of hospitalization, C. difficile-attributable length of stay, and the probability of initial and secondary recurrences. The median cost of a case ranged from $9179 to $11 456 from the hospital perspective, $8932 to $11 679 from the third-party payor perspective, and $13 310 to $16 464 from the societal perspective. Most of the costs incurred were accrued during a patient’s primary CDI episode. Hospitals with an incidence of 4.1 CDI cases per 100 000 discharges would incur costs ≥$3.2 million (hospital perspective); an incidence of 10.5 would lead to costs ≥$30.6 million. Our model suggests that the annual US economic burden of CDI would be ≥$496 million (hospital perspective), ≥$547 million (third-party payer perspective) and ≥$796 million (societal perspective). Our results show that C. difficile infection is indeed costly, not only to third-party payers and the hospital, but to society as well. These results are consistent with current literature citing C. difficile as a costly disease.
Burden; Clostridium difficile; cost; economics; stochastic model
To determine whether doxycycline protects against development of Clostridium difficile infection (CDI), we studied a cohort of adult inpatients who received at least one dose of ceftriaxone. Addition of doxycycline was associated with low risk of CDI.
Background. Receipt of antibiotics is a major risk factor for Clostridium difficile infection (CDI). Doxycycline has been associated with a lower risk for CDI than other antibiotics. We investigated whether doxycycline protected against development of CDI in hospitalized patients receiving ceftriaxone, a high-risk antibiotic for CDI.
Methods. We studied adults admitted to an academic county hospital between 1 June 2005 and 31 December 2010 who received ceftriaxone to determine whether the additional receipt of doxycycline decreased the risk of CDI. Patients were followed from first administration of ceftriaxone to occurrence of CDI or administrative closure 30 days later.
Results. Two thousand three hundred five unique patients comprising 2734 hospitalizations were studied. Overall, 43 patients developed CDI within 30 days of ceftriaxone receipt, an incidence of 5.60 cases per 10 000 patient-days. The incidence of CDI was 1.67 cases per 10 000 patient-days in those receiving doxycycline, compared to 8.11 per 10 000 patient-days in those who did not receive doxycycline. In a multivariable model adjusted for age, gender, race, comorbidities, hospital duration, pneumonia diagnosis, surgical admission, and duration of ceftriaxone and other antibiotics, for each day of doxycycline receipt the rate of CDI was 27% lower than a patient who did not receive doxycycline (hazard ratio, 0.73; 95% confidence interval, .56–.96).
Conclusions. In this cohort of patients receiving ceftriaxone, doxycycline was associated with lower risk of CDI. Guidelines recommend this combination as a second-line regimen for some patients with community-acquired pneumonia (CAP). Further clinical studies would help define whether doxycycline-containing regimens should be a preferred therapy for CAP.
Objective. An outbreak of 20 peripartum Clostridium difficile infections (CDI) occurred on the obstetrical service at the University of Washington Medical Center (UWMC) between April 2006 and June 2007. In this report, we characterize the clinical manifestations, describe interventions that appeared to reduce CDI, and determine potential risk factors for peripartum CDI. Methods. An investigation was initiated after the first three peripartum CDI cases. Based on the findings, enhanced infection control measures and a modified antibiotic regimen were implemented. We conducted a case-control study of peripartum cases and unmatched controls. Results. During the outbreak, there was an overall incidence of 7.5 CDI cases per 1000 deliveries. Peripartum CDI infection compared to controls was significantly associated with cesarean delivery (70% versus 34%; P = 0.03
), antibiotic use (95% versus 56%; P = 0.001), chorioamnionitis (35% versus 5%; P = 0.001), and the use of the combination of ampicillin, gentamicin, and clindamycin (50% versus 3%; P < 0.001
). Use of combination antibiotics remained a significant independent risk factor for CDI in the multivariate analysis. Conclusions. The outbreak was reduced after the implementation of multiple infection control measures and modification of antibiotic use. However, sporadic CDI continued for 8 months after these measures slowed the outbreak. Peripartum women appear to be another population susceptible to CDI.
Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea in elderly patients, accounting for 15% to 25% of all cases of antibiotic-induced diarrhea in those patients. Virulent forms of this organism have developed, increasing the associated morbidity, mortality, and complication rates. The average patient undergoing total joint arthroplasty is at particular risk of CDI because of advanced age, the use of prophylactic antibiotic coverage in the perioperative period, multiple comorbid conditions, and length of hospital stay. In addition, patients who have had one CDI are at risk of another; the rate of recurrent CDI (RCDI) is 15% to 30%. To review the available information on RCDI, we conducted an extensive literature search, focusing on its epidemiology and the management strategies for its treatment and prevention. We found the management of RCDI is a controversial topic, with as yet no consensus regarding specific treatment guidelines. Several experienced clinicians have published suggested treatment algorithms, but they are based on anecdotal experience. With regard to the prevention of RCDI, the literature is scarce, and currently, the only effective strategies remain judicious use of perioperative antibiotics and appropriate implementation of infection control procedures. There are several vaccination medications that are currently being studied but are not yet ready for clinical use. We agree with the approach to management of RCDI that has been proposed in several articles, that is, on confirmation of a first recurrence of CDI by a stool toxin assay and clinical symptoms, a 14-day course of metronidazole or vancomycin; for a second recurrence, a tapered-pulsed course of vancomycin; and, for 3 or more recurrences, a repeat course of the tapered-pulsed vancomycin and adjunctive Saccharomyces boulardii or cholestyramine.
recurrent; Clostridium difficile; infection; arthroplasty
The purpose of this investigation was to study risk factors for Clostridium difficile infection (CDI) in an endemic setting. In a 34-month prospective case–control study, we compared the risk factors and clinical characteristics of all consecutively diagnosed hospitalised CDI patients (n = 93) with those of patients without diarrhoea (n = 76) and patients with non-CDI diarrhoea (n = 64). The incidence of CDI was 17.5 per 10,000 hospital admissions. C. difficile polymerase chain reaction (PCR) ribotype 014 was the most frequently found type (15.9%), followed by types 078 (12.7%) and 015 (7.9%). Independent risk factors for endemic CDI were the use of second-generation cephalosporins, previous hospital admission and previous stay at the intensive care unit (ICU). The use of third-generation cephalosporins was a risk factor for diarrhoea in general. We found no association of CDI with the use of fluoroquinolones or proton pump inhibitors (PPIs). The overall 30-day mortality among CDI patients, patients without diarrhoea and patients with non-CDI diarrhoea was 7.5%, 0% and 1.6%, respectively. In this endemic setting, risk factors for CDI differed from those in outbreak situations. Some risk factors that have been ascribed to CDI earlier were, in this study, not specific for CDI, but for diarrhoea in general. The 30-day mortality among CDI patients was relatively high.
Community-acquired Clostridium difficile infection (CA-CDI) is an increasingly appreciated condition. It is being described in populations lacking traditional predisposing factors that have been previously considered at low-risk for this infection. As most studies of CDI are hospital-based, outcomes in these patients are not well known.
To examine outcomes and their predictors in patients with CA-CDI.
A sub-group analysis of a population-based epidemiological study of CDI in Olmsted County, Minnesota from 1991-2005 was performed. Data regarding outcomes, including severity, treatment response, need for hospitalization and recurrence were analyzed.
Of 157 CA-CDI cases, the median age was 50 years and 75.3% were female. Among all CA-CDI cases, 40% required hospitalization, 20% had severe and 4.4% had severe-complicated infection, 20% had treatment failure and 28% had recurrent CDI. Patients who required hospitalization were significantly older (64 vs 44 years, p<0.001), more likely to have severe disease (33.3% vs 11.7%, p=0.001), and had higher mean Charlson comorbidity index scores (2.06 vs 0.84, p=0.001). They had similar treatment failure and recurrence rates as patients who did not require hospitalization.
CA-CDI can be associated with complications and poor outcomes, including hospitalization and severe CDI. As the incidence of CA-CDI increases, clinicians should be aware of risk factors (increasing age, comorbid conditions and disease severity) that predict the need for hospitalization and complications in patients with CA-CDI.
Clostridium difficile infection; community-acquired; outcomes; predictors of hospitalization
The purpose of this study was to develop and validate a risk prediction model that could identify patients at high risk for Clostridium difficile infection (CDI) before they develop disease.
Tertiary care medical center.
Patients admitted to the hospital for ≥48 hours from 1-1-2003 through 12-31-2003.
Data were collected electronically from the hospital’s Medical Informatics database and analyzed with logistic regression to determine variables that best predicted patients’ risk for development of CDI. Model discrimination and calibration were calculated. The model was bootstrapped 500 times to validate the predictive accuracy. A receiver operating characteristic (ROC) curve was calculated to evaluate potential risk cut-offs.
35,350 admissions with 329 CDI cases were included. Variables in the risk prediction model were age, CDI pressure, admissions in previous 60 days, modified Acute Physiology Score, days on high risk antibiotics, low albumin, admission to an ICU, and receipt of laxatives, gastric acid suppressors, or antimotility drugs. The calibration and discrimination of the model were very good to excellent (C index=0.88; Brier score 0.009).
The CDI risk prediction model performed well. Further study is needed to determine if it could be used in a clinical setting to prevent CDI-associated outcomes and reduce costs.
Clostridium difficile; risk prediction
Clostridium difficile infection (CDI) is associated with medical care and may cause readmission following hospitalization for any reason. The incidence of readmissions due to CDI is not well known.
Retrospective cohort study of adult inpatients in one county from 2000–2007, using mandatory hospital discharge data.
All hospitals in Orange County, California
All adult inpatients readmitted with new-onset Clostridium difficile infection within 12 weeks of discharge.
We assessed trends in hospital-associated CDI (HA-CDI) incidence, with and without inclusion of post-discharge CDI (PD-CDI) events resulting in re-hospitalization within 12 weeks of discharge. We measured the effect of including PD-CDI events on hospital-specific CDI incidence, a mandatory reporting measure in California, and on relative hospital ranks by CDI incidence.
From 2000 to 2007, countywide hospital-onset CDI (HO-CDI) incidence increased from 15/10,000 to 22/10,000 admissions. When including PD-CDI events, HA-CDI incidence doubled (29/10,000 in 2000 and 52/10,000 in 2007). Overall, including PD-CDI events resulted in significantly higher hospital-specific CDI incidence, although hospitals had disproportionate amounts of HA-CDI occurring post-discharge. This resulted in substantial shifts in some hospitals’ rankings by CDI incidence. In multivariate models, both HO and PD-CDI were associated with increasing age, higher length of stay, and select comorbidities. Race and Hispanic ethnicity were predictive of PD-CDI but not HO-CDI.
PD-CDI incidence may be underestimated since outpatient events were not evaluated. Inaccuracies in claims data may cause under or over-estimation of CDI cases. Whether C. difficile was acquired in the hospital or community post-discharge for PD-CDI is not known.
PD-CDI events associated with re-hospitalization are increasingly common. The majority of HA-CDI cases now may be occurring post-discharge, raising important questions about both accurate reporting and effective prevention strategies. Some risk factors for PD-CDI may be different than those for HO-CDI, allowing additional identification of high-risk groups before discharge.
Clostridium difficile infection (CDI) is an increasingly recognized nosocomial infection in Singapore. Surveillance methods include laboratory reporting of Clostridium difficile toxin assays (CDTA) or use of International Classification of Diseases, 9th Revision (ICD-9) discharge code 008.45. Previous US studies showed good correlation between CDTA and ICD-9 codes. However, the use of ICD-9 codes for CDI surveillance has not been validated in other healthcare settings.
We compared CDI rates based on CDTA to ICD-9 codes for all discharges in 2007 from our hospital to determine sensitivity and specificity of ICD-9 codes. Demographic and hospitalization data were analyzed to determine predictors for missing ICD-9 codes.
During 2007, there were 56,352 discharges. Of these, 268 tested CDTA-positive but only 133 were assigned the CDI ICD-9 code. A total of 141 discharges had the ICD-9 code; 8 were CDTA-negative, the rest were CDTA-positive. Community-acquired CDI accounted for only 3.2% of cases. The sensitivity and specificity of ICD-9 codes compared to CDTA were 49.6% and 100% respectively. Concordance between CDTA and ICD-9 codes was 0.649 (p<.001). Comparing concordant patients (CDTA+/ICD9+) to discordant patients (CDTA+/ICD9−), concordant patients were more likely to be over 50 years of age (OR 3.49, 95% CI 1.66–7.34, p = .001) and have shorter time from admission to testing (OR 0.98, 95% CI 0.97–0.99, p = .009).
Unlike previous studies in the US, ICD-9 codes substantially underestimate CDI in Singapore compared to microbiological data. Older patients with shorter time to testing were less likely to have missing ICD-9 codes.
Efforts are currently underway to develop a vaccine against Clostridium difficile infection (CDI). We developed two decision analytic Monte Carlo computer simulation models: (1) an Initial Prevention Model depicting the decision whether to administer C. difficile vaccine to patients at-risk for CDI and (2) a Recurrence Prevention Model depicting the decision whether to administer C. difficile vaccine to prevent CDI recurrence. Our results suggest that a C. difficile vaccine could be cost-effective over a wide range of C. difficile risk, vaccine costs, and vaccine efficacies especially when being used post-CDI treatment to prevent recurrent disease.
Clostridium difficile; vaccine; economics; computer simulation
AIM: To examine if fulminant Clostridium difficile infections (CDI) resulting in colectomy was associated with a prior appendectomy and whether any association affected the severity of the disease.
METHODS: A retrospective chart review was performed on patients who underwent colectomy for CDI between 2001 and 2011. The appendectomy rate was calculated based on the absence of an appendix on the surgical pathology report. This was compared to an established lifetime risk of appendectomy in the general population. A chart review was performed for mortality and traditional markers of CDI disease severity. Fisher’s exact test was used to calculate the likelihood of association between prior appendectomy, mortality, and clinical markers of severity of infection.
RESULTS: Fifty-five specimens were identified with pseudomembranous colitis consistent with CDI. All patients had a clinical history consistent with CDI and 45 of 55 (81.8%) specimens also had microbiological confirmation of CDI. Appendectomy was observed in 24 of 55 specimens (0.436, 99%CI: 0.280-0.606). This was compared to the lifetime incidence of appendectomy of 17.6%. The rate of appendectomy in our sample was significantly higher than would be expected in the general population (43.6% vs 17.6%, P < 0.01). Disease severity did not differ based on presence or absence of an appendix and no association was detected between prior appendectomy and mortality (OR = 0.588, 95%CI: 0.174-1.970).
CONCLUSION: The rate of appendectomy in the patients whose CDI led to colectomy, was significantly higher than the calculated lifetime risk, suggesting an association of appendectomy and severe CDI resulting in colectomy. Larger prospective studies are needed to assess any potential causal relationships affecting fulminant CDI.
Appendectomy; Fulminant colitis; Clostridium difficile
Clostridium difficile (C. difficile) infection (CDI) is the leading identifiable cause of antibiotic-associated diarrhea. While there is an alarming trend of increasing incidence and severity of CDI in the United States and Europe, superimposed CDI in patients with inflammatory bowel disease (IBD) has drawn considerable attention in the gastrointestinal community. The majority of IBD patients appear to contract CDI as outpatients. C. difficile affects disease course of IBD in several ways, including triggering disease flares, sustaining activity, and in some cases, acting as an “innocent” bystander. Despite its wide spectrum of presentations, CDI has been reported to be associated with a longer duration of hospitalization and a higher mortality in IBD patients. IBD patients with restorative proctocolectomy or with diverting ileostomy are not immune to CDI of the small bowel or ileal pouch. Whether immunomodulator or corticosteroid therapy for IBD should be continued in patients with superimposed CDI is controversial. It appears that more adverse outcomes was observed among patients treated by a combination of immunomodulators and antibiotics than those treated by antibiotics alone. The use of biologic agents does not appear to increase the risk of acquisition of CDI. For CDI in the setting of underlying IBD, vancomycin appears to be more efficacious than metronidazole. Randomized controlled trials are required to clearly define the appropriate management for CDI in patients with IBD.
Clostridium difficile; Inflammatory bowel disease; Antibiotics; Colectomy
Oral immunization with vaccines may be an effective strategy for prevention of Clostridium difficile infection (CDI). However, application of previously developed vaccines for preventing CDI has been limited due to various reasons. Here, we developed a recombinant Lactococcus lactis oral vaccine and evaluated its effect on a C. difficile-infected animal model established in golden hamsters in attempt to provide an alternative strategy for CDI prevention.
Recombinant L. lactis vaccine was developed using the pTRKH2 plasmid, a high-copy-number Escherichia coli-L. shuttle vector: 1) L. lactis expressing secreted proteins was constructed with recombinant pTRKH2 (secreted-protein plasmid) carrying the Usp45 signal peptide (SPUsp45), nontoxic adjuvanted tetanus toxin fragment C (TETC), and 14 of the 38 C-terminal repeats (14CDTA) of nontoxic C. difficile toxin A (TcdA); and 2) L. lactis expressing secreted and membrane proteins was constructed with recombinant pTRKH2 (membrane-anchored plasmid) carrying SPUsp45, TETC, 14CDTA, and the cell wall-anchored sequence of protein M6 (cwaM6). Then, 32 male Syrian golden hamsters were randomly divided into 4 groups (n = 8 each) for gavage of normal saline (blank control) and L. lactis carrying the empty shuttle vector, secreted-protein plasmid, and membrane-anchored plasmid, respectively. After 1-week gavage of clindamycin, the animals were administered with C. difficile spore suspension. General symptoms and intestinal pathological changes of the animals were examined by naked eye and microscopy, respectively. Protein levels of anti-TcdA IgG/IgA antibodies in intestinal tissue and fluid were analyzed by enzyme-linked immunosorbent assay (ELISA). A cell culture cytotoxicity neutralization assay was done by TcdA treatment with or without anti-TcdA serum pre-incubation or treatment. Apoptosis of intestinal epithelial cells was examined by flow cytometry (FL) assay. Expression of mucosal inflammatory cytokines in the animals was detected by polymer chain reaction (PCR) assay.
After the C. difficile challenge, the animals of control group had severe diarrhea symptoms on day 1 and all died on day 4, indicating that the CDI animal model was established in hamster. Of the 3 immunization groups, secreted-protein and membrane-anchored plasmid groups had significantly lower mortalities, body weight decreases, and pathological scores, with higher survival rate/time than the empty plasmid group (P < 0.05). The tilter of IgG antibody directed against TcdA was significantly higher in serum and intestinal fluid of secreted-protein and membrane-anchored plasmid groups than in the empty plasmid group (P < 0.05) while the corresponding titer of IgA antibody directed against TcdA had no substantial differences (P > 0.05). The anti-TcdA serum of membrane-anchored plasmid group neutralized the cytotoxicity of 200 ng/ml TcdA with the best protective effect achieved by anti-TcdA serum pre-incubation. The incidences of TcdA-induced death and apoptosis of intestinal epithelial cells were significantly reduced by cell pre-incubation or treatment with anti-TcdA serum of membrane-anchored plasmid group (P < 0.05). MCP-1, ICAM-1, IL-6, and Gro-1 mRNA expression levels were the lowest in cecum tissue of the membrane-anchored groups compared to the other groups.
Recombinant L. lactis live vaccine is effective for preventing CDI in the hamster model, thus providing an alternative for immunization of C. difficile-associated diseases.
Clostridium difficile; Recombinant Lactococcus lactis; Secreted-protein plasmid; Membrane-anchored plasmid; Golden hamsters
Background. Diagnosis and management of Clostridium difficile infection (CDI) rely upon clinical assessments and diagnostic studies. Among diagnostic tests, lower gastrointestinal (GI) endoscopy in the setting of CDI remains controversial. Objective. To describe the role of lower endoscopy in CDI management. Methods. Retrospective study of lower endoscopies in CDI at four metropolitan hospitals, July 2005 through December 2007. Results. Of 1760 CDI inpatients, 45 lower endoscopies were performed on 43 patients. Most common indications were ruling out other etiologies (42%), inconclusive stool studies (36%), and worsening course (11%). Most endoscopies (73%) had positive findings, including pseudomembranous colitis (49%) and nonspecific colitis (24%). Biopsies were performed in 31 cases, more with nonspecific colitis (10/11, 92%) compared to pseudomembranous colitis (14/22, 64%). Conclusion. While not recommended as a primary screening tool, lower GI endoscopy can add valuable information in CDI when other colonic pathologies may exist, studies are inconclusive, or clinical status worsens.
Clostridium difficile is a major cause of antibioticassociated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established.
To review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii.
A literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention.
Four studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.53; P<0.05). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.33; P=0.05). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation.
S boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.
C difficile infection; Saccharomyces boulardii; Probiotic
The dramatic changes in the epidemiology of Clostridium difficile infection (CDI) during recent years, with increases in incidence and severity of disease in several countries, have made CDI a global public health challenge. Increases in CDI incidence have been largely attributed to the emergence of a previously rare and more virulent strain, BI/NAP1/027. Increased toxin production and high-level resistance to fluoroquinolones have made this strain a very successful pathogen in healthcare settings. In addition, populations previously thought to be at low risk are now being identified as having severe CDI. Recent genetic analysis suggests that C. difficile has a highly fluid genome with multiple mechanisms to modify its content and functionality, which can make C. difficile adaptable to environmental changes and potentially lead to the emergence of more virulent strains. In the face of these changes in the epidemiology and microbiology of CDI, surveillance systems are necessary to monitor trends and inform public health actions.
Identifying patients at risk for adverse outcomes of Clostridium difficile infection (CDI), including recurrence and death, will become increasingly important as novel therapies emerge, which are more effective than traditional approaches but very expensive. Clinical prediction rules (CPRs) can improve the accuracy of medical decision-making. Several CPRs have been developed for CDI, but none has gained a widespread acceptance.
We systematically reviewed studies describing the derivation or validation of CPRs for unfavourable outcomes of CDI, in medical databases (Medline, Embase, PubMed, Web of Science and Cochrane) and abstracts of conferences.
Of 2945 titles and abstracts screened, 13 studies on the derivation of a CPR were identified: two on recurrences, five on complications (including mortality), five on mortality alone and one on response to treatment. Two studies on the validation of different severity indices were also retrieved. Most CPRs were developed as secondary analyses using cohorts assembled for other purposes. CPRs presented several methodological limitations that could explain their limited use in clinical practice. Except for leukocytosis, albumin and age, there was much heterogeneity in the variables used, and most studies were limited by small sample sizes. Eight models used a retrospective design. Only four studies reported the incidence of the outcome of interest, even if this is essential to evaluate the potential usefulness of a model in other populations. Only five studies performed multivariate analyses to adjust for confounders.
The lack of weighing variables, of validation, calibration and measures of reproducibility, the weak validities and performances when assessed, and the absence of sensitivity analyses, all led to suboptimal quality and debatable utility of those CPRs. Evidence-based tools developed through appropriate prospective cohorts would be more valuable for clinicians than empirically-developed CPRs.