Mortality of patients with antibiotic-associated diarrhoea: the impact of Clostridium difficile

doi:10.1016/j.jhin.2008.01.033

Journal of Hospital Infection

Volume 68, Issue 4, April 2008, Pages 308-314

https://doi.org/10.1016/j.jhin.2008.01.033 Get rights and content

Summary

Previous studies have shown conflicting results concerning mortality related to Clostridium difficile infection. The objective of this study was to determine the impact of C. difficile infection on short- and long-term mortality in hospitalised patients with antibiotic-associated diarrhoea. We therefore undertook a prospective case–control study of 217 hospitalised patients who received antibiotics, developed diarrhoea and underwent stool enzyme immunoassay for C. difficile TOX A/B. The Kaplan–Meier and the log-rank test were used to determine univariate survival analysis and a Cox regression model for multivariate analysis of 28 day and long-term mortality. Fifty-two (24%) of the 217 patients who met the study criteria were positive for C. difficile TOX A/B. The crude 28 day and long-term mortality rates of the entire cohort were 12.4% and 56%, respectively. On Cox regression analysis, hypoalbuminaemia, impaired functional capacity and elevated serum urea levels were found to be the only independent and statistically significant variables associated with long-term mortality. C. difficile toxin positivity per se was not associated with increased short- or long-term mortality rates. In conclusion, hypoalbuminaemia, renal failure, and impaired function capacity predict mortality due to antibiotic-associated diarrhoea, but C. difficile involvement by itself does not further increase the risk of death in these patients.

Introduction

Clostridium difficile-associated diarrhoea (CDAD) is the most common type of infectious nosocomial diarrhoea in adults in the developed world.¹ C. difficile infection is implicated in 20–30% of all cases of antibiotic-associated diarrhoea, 50–75% of cases of antibiotic-associated colitis and more than 90% of cases of antibiotic-associated pseudomembranous colitis in hospitalised patients.² The reported mortality rates associated with C. difficile diarrhoea in observational and case–control studies vary from 0.6% to 83%.3, 4, 5, 6, 7

The objective of this prospective non-interventional study was to determine the impact of C. difficile infection on short- and long-term mortality in two hospital patient cohorts; one consisting of patients who received antibiotics and developed CDAD, and the other consisting of patients who received antibiotics and developed diarrhoea unrelated to C. difficile.

Section snippets

Patients

All patients with diarrhoea, hospitalised in our centre from October 15, 1999 to January 15, 2000 and whose stool samples were collected for C. difficile toxin assay in the Microbiology Laboratory, were identified and followed prospectively. Only patients who had received antibiotics within 40 days prior to the diarrhoeal episode were included. Diarrhoea was defined as the passage of three or more unformed stools for at least two days.⁸ CDAD was defined as diarrhoea unattributable to any other

Results

A total of 217 patients met the inclusion criteria, of whom 52 (24%) were found to have CDAD. The demographic, clinical and laboratory characteristics of the entire cohort and by subgroups with positive or negative stool assays are shown in Table I. The patients with CDAD were significantly older than those without CDAD and had a worse functional capacity on admission to hospital in addition to more comorbidities, such as diabetes mellitus, congestive heart failure and decubitus ulcers. There

Discussion

We evaluated the short- and long-term mortality rates in a cohort of hospitalised patients with antibiotic-associated diarrhoea with and without proven C. difficile aetiology.

The most interesting finding of this prospective case–control study was that C. difficile infection was not associated with higher overall 28 day or long-term mortality rates in hospitalised patients with antibiotic-associated diarrhoea. Although both the crude 28 day and long-term mortality rates in our entire study

References (19)

Z. Samra et al.
High prevalence of toxin A-negative toxin B-positive Clostridium difficile in hospitalised patients with gastrointestinal diseases
Diagn Microbiol Infect Dis
(2002)
U. Changela et al.
Risk factors and mortality associated with Clostridium difficile-associated diarrhea at a VA hospital
Int J Antimicrob Agents
(2004)
S. Nair et al.
Clostridium difficile colitis: factors influencing treatment failure and relapse, a prospective evaluation
Am J Gastroenterol
(1998)
T.S. Dharmarajan et al.
Co-morbidity, not age, predicts adverse outcome in Clostridium difficile colitis
World J Gastoenterol
(2000)
C.P. Kelly et al.
Clostridium difficile colitis
N Engl J Med
(1994)
L. Kyne et al.
Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile
Clin Infect Dis
(2002)
M.M. Olson et al.
Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982–1991
Infect Control Hosp Epidemiol
(1994)
M. Lesna et al.
Risk of diarrhoea due to Clostridium difficile during cefotaxime treatment; mortality due to C. difficile colitis in elderly people has been underestimated
Br Med J
(1996)
R. Ramaswamy et al.
Prognostic criteria in Clostridium difficile colitis
Am J Gastroenterol
(1996)

There are more references available in the full text version of this article.

Cited by (52)

Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection
2022, Journal of Infection and Chemotherapy
Clostridioides difficile epidemiology in the Middle and the Far East
2022, Anaerobe
Citation Excerpt :
Of them, 130 were excluded due to incomplete data (specific reasons are provided in the Supplementary Material). From 153 studies from 21 countries, 111 studies (18 countries) were included in the CDI prevalence meta-analysis (Supplementary Material) [10–29], [30-49], [50-69], [70-89], [90-109], [110-120]. Forty-two studies were excluded because of the selection of the patient population tested (e.g. children, cancer patients, inflammatory bowel disease, diabetes etc.).
Clostridioides difficile is an important pathogen of healthcare-associated gastrointestinal infections. Recently, an increased number of C. difficile infection (CDI) surveillance data has been reported from Asia. The aim of this review is to summarize the data on the prevalence, distribution and molecular epidemiology of CDI in the Middle and the Far East.
Literature was drawn from a search of PubMed up to September 30, 2021.
The meta-analysis of data from 111 studies revealed the pooled CDI prevalence rate in the Middle and the Far East of 12.4% (95% CI 11.4–13.3); 48 studies used PCR for CDI laboratory diagnoses. The predominant types (RT)/sequence type (ST) differ between individual countries (24 studies, 14 countries). Frequently found RTs were 001, 002, 012, 017, 018 and 126; RT017 was predominant in the Far East. The epidemic RT027 was detected in 8 countries (22 studies), but its predominance was reported only in three studies (Israel and Iran). The contamination of vegetable and meat or meat products and/or intestinal carriage of C. difficile in food and companion animals have been reported; the C. difficile RTs/STs identified overlapped with those identified in humans.
A large number of studies on CDI prevalence in humans from the Middle and the Far East have been published; countries with no available data were identified. The number of studies on C. difficile from non-human sources is limited. Comparative genomic studies of isolates from different sources are needed.
A multi-institutional cohort study confirming the risks of Clostridium difficile infection associated with prolonged antibiotic prophylaxis
2018, Journal of Thoracic and Cardiovascular Surgery
The incidence and severity of Clostridium difficile infection (CDI) have increased rapidly over the past 2 decades, particularly in elderly patients with multiple comorbidities. This study sought to characterize the incidence and risks of these infections in cardiac surgery patients.
A total of 5158 patients at 10 Cardiothoracic Surgical Trials Network sites in the US and Canada participated in a prospective study of major infections after cardiac surgery. Patients were followed for infection, readmission, reoperation, or death up to 65 days after surgery. We compared clinical and demographic characteristics, surgical data, management practices, and outcomes for patients with CDI and without CDI.
C difficile was the third most common infection observed (0.97%) and was more common in patients with preoperative comorbidities and complex operations. Antibiotic prophylaxis for >2 days, intensive care unit stay >2 days, and postoperative hyperglycemia were associated with increased risk of CDI. The median time to onset was 17 days; 48% of infections occurred after discharge. The additional length of stay due to infection was 12 days. The readmission and mortality rates were 3-fold and 5-fold higher, respectively, in patients with CDI compared with uninfected patients.
In this large multicenter prospective study of major infections following cardiac surgery, CDI was encountered in nearly 1% of patients, was frequently diagnosed postdischarge, and was associated with extended length of stay and substantially increased mortality. Patients with comorbidities, longer surgery time, extended antibiotic exposure, and/or hyperglycemic episodes were at increased risk for CDI.
Excess mortality between 2007 and 2014 among patients with Clostridium difficile infection: a French health insurance database analysis
2018, Journal of Hospital Infection
The impact of Clostridium difficile infection (CDI) on mortality is controversial.
To assess excess mortality due to CDI in France.
Two cohorts of patients with CDI and a cohort of matched controls were extracted from a 1% representative sample of subjects covered by the general health insurance system in France (Echantillon Généraliste de Bénéficiaires database, 660,000 patients). The CDI patients were hospitalized with CDI as a principal diagnosis or an associated diagnosis between 2007 and 2014, but not in 2006. Controls were patients hospitalized between 2007 and 2014 but not hospitalized with CDI between 2006 and 2014. The one-year incidence of deaths between 2007 and 2014 was estimated and compared with that of a propensity score (PS)-matched control group with no CDI (two controls per case). The PS was calculated with the following variables: age; sex; Charlson Comorbidity Index score; duration of stay; year of index stay; and main comorbidities. Cox and Poisson models were used to estimate the increased risk of death while adjusting for PS. Sensitivity analyses (timeframe, diarrhoea, recurrent hospitalization for CDI) were used to explore the robustness of the results.
In total, 482 patients who had been infected with C. difficile were matched with 964 controls. A significantly higher risk of death was observed among the subjects with CDI, with a non-adjusted hazard ratio of 1.65 [95% confidence interval (CI) 1.33–2.04] and an adjusted ratio of 1.58 (95% CI 1.27–1.97). The adjusted relative risk of death was 1.78 (95% CI 1.18–2.70]) at 28 days, 1.52 (95% CI 1.17–1.98) at three months, 1.52 (95% CI 1.20–1.93) at six months and 1.64 (95% CI 1.32–2.03) at 12 months. Sensitivity analyses produced similar results; the hazard ratio ranged from 1.53 to 1.86, and was always statistically significant.
CDI is responsible for excess mortality after taking age, sex, comorbidities and length of hospital stay into account.
Analysis of risk factors and clinical manifestations associated with Clostridium difficile disease in Serbian hospitalized patients
2016, Brazilian Journal of Microbiology
Clostridium difficile is the leading cause of infectious diarrhoea in hospitalized patients. The aim of this study was to determine the risk factors important for the development of hospital-acquired Clostridium difficile-associated disease and clinical manifestations of Clostridium difficile-associated disease. The clinical trial group included 37 hospitalized patients who were selected according to the inclusion criteria. A control group of 74 hospitalized patients was individually matched with cases based on hospital, age (within 4 years), sex and month of admission.
Clostridium difficile-associated disease most commonly manifested as diarrhoea (56.76%) and colitis (32%), while in 8.11% of patients, it was diagnosed as pseudomembranous colitis, and in one patient, it was diagnosed as fulminant colitis. Statistically significant associations (p < 0.05) were found with the presence of chronic renal failure, chronic obstructive pulmonary disease, cerebrovascular accident (stroke) and haemodialysis. In this study, it was confirmed that all the groups of antibiotics, except for tetracycline and trimethoprim–sulfamethoxazole, were statistically significant risk factors for Clostridium difficile-associated disease (p < 0.05). However, it was difficult to determine the individual role of antibiotics in the development of Clostridium difficile-associated disease. Univariate logistic regression also found that applying antibiotic therapy, the duration of antibiotic therapy, administration of two or more antibiotics to treat infections, administering laxatives and the total number of days spent in the hospital significantly affected the onset of Clostridium difficile-associated disease (p < 0.05), and associations were confirmed using the multivariate model for the application of antibiotic therapy (p = 0.001), duration of antibiotic treatment (p = 0.01), use of laxatives (p = 0.01) and total number of days spent in the hospital (p = 0.001). In this study of patients with hospital-acquired diarrhoea, several risk factors for the development of Clostridium difficile-associated disease were identified.
Evaluation of advanced age as a risk factor for severe Clostridium difficile infection
2016, Journal of Clinical Gerontology and Geriatrics
Citation Excerpt :
Kyne et al11 found that the use of any GI instrumentation (colonoscopy, sigmoidoscopy, endoscopy) was associated with a fourfold increase in risk of severe disease compared with those who did not undergo any of these procedures. Although nasogastric tube feedings have also been shown to increase mortality in CDI, Dharmarajan et al7 and Bishara et al8 found no relationship between disease severity and nasogastric feeding. It is important to note that the definition of CDI severity differed among the mentioned studies, thus results should be interpreted carefully and applied to the appropriate patient populations.
Although advanced age has been associated with the incidence of Clostridium difficile infection (CDI), its relationship with disease severity remains inconclusive. The objective of this study was to evaluate risk factors, specifically advanced age, which may be associated with the acquisition of severe CDI.
A retrospective chart review at a Veterans Affairs Hospital was conducted on hospitalized veterans aged ≥ 18 years with a positive stool toxin assay for Clostridium difficile between May 2008 and September 2012 (n = 224). One hundred and sixty-one (72%) patients were in the mild–moderate infection group and 63 (28%) patients in the severe infection group. The primary outcome was to determine the effect of advanced age (≥70 years old) on the acquisition of severe CDI. The secondary outcome was to identify other potential risk factors for severe CDI. Disease severity was classified according to the criteria established in the 2010 Society for Healthcare Epidemiology of America/Infectious Disease Society of America practice guidelines for CDI. Demographic and disease-specific data were collected. A logistic regression model was used to identify characteristics predictive of disease severity.
Our regression model found advanced age to be significantly associated with severe CDI (odds ratio 2.43, p ≤ 0.005, 95% confidence interval 1.31–4.50). A larger proportion of veterans were diagnosed with severe CDI in the intensive care unit (p = 0.004). In addition, multiple antibiotic use (≥3) and association with severe CDI was statistically significant (34% mild–moderate vs. 48% severe, p = 0.041). The univariate analyses did not reveal any other characteristics predictive of disease severity.
Advanced age was associated with severe CDI. A prospective evaluation is warranted to validate this finding. Efforts to identify patients at risk for severe CDI will be important as it may direct treatment and positively affect outcomes.

View all citing articles on Scopus

View full text

Article preview

Journal of Hospital Infection

Summary

Introduction

Section snippets

Patients

Results

Discussion

References (19)

High prevalence of toxin A-negative toxin B-positive Clostridium difficile in hospitalised patients with gastrointestinal diseases

Diagn Microbiol Infect Dis

Risk factors and mortality associated with Clostridium difficile-associated diarrhea at a VA hospital

Int J Antimicrob Agents

Clostridium difficile colitis: factors influencing treatment failure and relapse, a prospective evaluation

Am J Gastroenterol

Co-morbidity, not age, predicts adverse outcome in Clostridium difficile colitis

World J Gastoenterol

Clostridium difficile colitis

N Engl J Med

Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile

Clin Infect Dis

Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982–1991

Infect Control Hosp Epidemiol

Risk of diarrhoea due to Clostridium difficile during cefotaxime treatment; mortality due to C. difficile colitis in elderly people has been underestimated

Br Med J

Prognostic criteria in Clostridium difficile colitis

Am J Gastroenterol

Cited by (52)

Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection

Clostridioides difficile epidemiology in the Middle and the Far East

A multi-institutional cohort study confirming the risks of Clostridium difficile infection associated with prolonged antibiotic prophylaxis

Excess mortality between 2007 and 2014 among patients with Clostridium difficile infection: a French health insurance database analysis

Analysis of risk factors and clinical manifestations associated with Clostridium difficile disease in Serbian hospitalized patients

Evaluation of advanced age as a risk factor for severe Clostridium difficile infection